Bio


Mads Melbye is Visiting Professor at Stanford University School of Medicine, and President and CEO at Statens Serum Institut in Copenhagen, Denmark. Previous positions at e.g. the National Cancer Institute, NIH, USA, before he became State Epidemiologist in Denmark, and later Head of Department of Epidemiology Research, Director of Division of Epidemiology, Director of Division of Epidemiology and Disease Surveillance and The Danish National Biobank and most recently CEO of Statens Serum Institut in Copenhagen, Denmark. Previous academic positions as Danish Research Council Professor, NORFA professor, Foreign Adjunct Professor at Karolinska Institute in Sweden, and Professor in Medical Epidemiology at Copenhagen University. He has written more than 590 publications (H-index: 88 (Web of Science), 110 (Google Scholar)) and is the Dane with most papers in high impact journals in general medicine (NEJM, Lancet, JAMA).

Academic Appointments


Administrative Appointments


  • Head, Department of Epidemiology Research, SSI, Denmark (1992 - Present)
  • Director, Danish National Biobank (2012 - Present)
  • President, CEO, Statens Serum Institut (SSI), Copenhagen, Denmark (2016 - Present)

Honors & Awards


  • Knighted, Queen Margrethe II (2018)
  • The Erhoff Prize, Erhoff Prize Committee, Denmark (2014)
  • The Novo Nordisk Prize, Novo Nordisk Foundation (2005)
  • The Thorvald Madsen Prize, Statens Serum Institut, Denmark (1998)
  • Ipsen Lecture, University of Aarhus, Denmark (1993)
  • The Anders Jahre Prize, Anders Jahre Prize Committee, Oslo, Norway (1992)
  • Danish AIDS Society Prize, Danish AIDS Society (1989)
  • Research Prize, Hjortenberg Foundation (1985)
  • Gold medal in microbiology and oncology, University of Aarhus, Denmark (1983)

Boards, Advisory Committees, Professional Organizations


  • Member, Scientific Advisory Board, Oslo University Hospital, Norway (2019 - Present)
  • Chair, Governing Council, International Agency for Research on Cancer (IARC)/World Health Organisation, Lyon, France (2017 - Present)
  • Member, International Scientific Advisory Board, UK Biobank, UK (2014 - Present)
  • Chairman, Board of Scientific Councillors, International Agency for Research on Cancer (IARC), Lyon, France (2012 - 2014)
  • Member, Medical Research Committee, AP Møller and Chastine Mc-Kinney Møllers Fund (2011 - Present)
  • Member, Novo Nordisk Prize Committee (2007 - Present)
  • Chairman, Board of Nordic Medical Research Councils (NOS-M) (2007 - 2010)
  • Vice-Chair, Danish Medical Research Council (2006 - 2010)
  • Chairman, Scientific Committee, Danish Health Insurance Fund (2005 - Present)
  • Member, Danish Medical Research Council (2004 - 2006)
  • Associate Editor, Journal National Cancer Institute (2001 - 2016)
  • Chairman, Ministry of Research's working group on registry research, Denmark (2000 - 2012)

Professional Education


  • DMSc, University of Aarhus, Denmark, Epidemiology and Science (1988)
  • MD, University of Aarhus, Denmark, Medicine (1984)

All Publications


  • Oral corticosteroids during pregnancy and offspring risk of congenital heart defects: a nationwide cohort study. International journal of epidemiology Schmidt, A. B., Lund, M., Corn, G., Oyen, N., Wohlfahrt, J., Melbye, M. 2019

    Abstract

    BACKGROUND: Pre-pregnancy diabetes is a strong risk factor for congenital heart defects (CHDs), suggesting a role for glucose in the causal pathway. Oral corticosteroids may cause hyperglycemia and maternal use could affect embryonic heart development. The objective of this study was to determine the association between maternal intake of oral corticosteroids 0-8weeks after conception and CHDs in offspring.METHODS: A register-based nationwide prevalence study including all live singleton births in Denmark, 1996-2016, was conducted. In total, 1194687 individuals and their mothers were identified and linked with information on offspring CHDs and the mothers' use of oral corticosteroids in early pregnancy. Corticosteroid use was defined as a filled prescription for maternal use of oral corticosteroid 0-8weeks after conception. CHDs were identified through International Classification of Diseases codes. The association was estimated by prevalence (odds) ratios using logistic regression and propensity score-matched analyses.RESULTS: Among 1194687 live births, 2032 had a mother who had used oral corticosteroids 0-8weeks from conception. Of these offspring, 32 had a heart defect. Among the offspring of never-users of oral corticosteroids, 10534 had a heart defect. The adjusted prevalence ratio was 1.29 (95% confidence interval, 0.90-1.84) comparing offspring prevalence of heart defects in oral corticosteroid users with that in oral corticosteroid never-users. Propensity score-matched analysis yielded similar results (prevalence ratio 1.38; 95% confidence interval, 0.95-2.02).CONCLUSIONS: This study supports that there is no association between maternal use of oral corticosteroids in the first 8weeks after conception and CHDs.

    View details for DOI 10.1093/ije/dyz213

    View details for PubMedID 31628805

  • Evaluation of the antibody response to the EBV proteome in EBV-associated classic Hodgkin lymphoma. International journal of cancer Liu, Z., Jarrett, R. F., Hjalgrim, H., Proietti, C., Chang, E. T., Smedby, K. E., Yu, K. J., Lake, A., Troy, S., McAulay, K. A., Pfeiffer, R. M., Adami, H., Glimelius, B., Melbye, M., Hildesheim, A., Doolan, D., Coghill, A. E. 2019

    Abstract

    The humoral immune response to Epstein-Barr virus (EBV) in classic Hodgkin lymphoma (cHL) stratified by EBV tumor status is unclear. We examined IgG and IgA antibody responses against 202 protein sequences representing 86 EBV proteins using a microarray and sera from 139 EBV-positive cHL cases, 70 EBV-negative cHL cases, and 141 population-based controls frequency matched to EBV-positive cHL cases on sex and age by area (UK, Denmark, and Sweden). We leveraged existing data on the proportion of circulating B-cells infected by EBV and levels of serum CCL17, a chemokine secreted by cHL tumor cells, from a subset of the cHL cases in the UK. Total IgG but not IgA response level was significantly different between EBV-positive cHL cases and controls. The distinct serological response included significant elevations in 16 IgG antibodies and 2 IgA antibodies, with odds ratios highest vs. lowest tertile >3 observed for the following EBV proteins: LMP1 (oncogene), BcLF1 (VCAp160, two variants), and BBLF1 (two variants). Our cHL IgG signature correlated with the proportion of circulating EBV-infected B-cells, but not serum CCL17 levels. We observed no differences in the anti-EBV antibody profile between EBV-negative cHL cases and controls. BdRF1(VCAp40)-IgG and BZLF1(Zta)-IgG were identified as the serological markers best able to distinguish EBV-positive from EBV-negative cHL tumors. Our results support the hypothesis that differences in the EBV antibody profile are specific to patients with EBV-positive cHL and are not universally observed as part of a systematically dysregulated immune response present in all cHL cases. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ijc.32741

    View details for PubMedID 31618442

  • Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways. Human molecular genetics Kleinstern, G., Yan, H., Hildebrandt, M. A., Vijai, J., Berndt, S. I., Ghesquieres, H., McKay, J., Wang, S. S., Nieters, A., Ye, Y., Monnereau, A., Brooks-Wilson, A. R., Lan, Q., Melbye, M., Jackson, R. D., Teras, L. R., Purdue, M. P., Vajdic, C. M., Vermeulen, R. C., Giles, G. G., Cocco, P. L., Birmann, B. M., Kraft, P., Albanes, D., Zeleniuch-Jacquotte, A., Crouch, S., Zhang, Y., Sarangi, V., Asmann, Y., Offit, K., Salles, G., Wu, X., Smedby, K. E., Skibola, C. F., Slager, S. L., Rothman, N., Chanock, S. J., Cerhan, J. R. 2019

    Abstract

    We previously identified five SNPs at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate 2 loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5,662 cases and 9,237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF]=0.40) was associated with DLBCL risk (OR=0.83, P=3.62x10-13). rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5,510 cases and 12,817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF=0.45) was also associated with DLBCL risk (OR=1.20, P=2.31x10-12). This SNP is 29,426 bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

    View details for DOI 10.1093/hmg/ddz228

    View details for PubMedID 31600786

  • The genetic background of hydrocephalus - candidate gene analysis from+6,000 exomes Munch, T. M., Hedley, P. L., Hagen, C. M., Baekvad-Hansen, M., Bybjerg-Grauholm, J., Melbye, M., Hougaard, D., Christiansen, M. NATURE PUBLISHING GROUP. 2019: 1439
  • Measles, Mumps, Rubella Vaccination and Autism. Annals of internal medicine Hviid, A., Hansen, J. V., Frisch, M., Melbye, M. 2019; 171 (5): 388

    View details for DOI 10.7326/L19-0383

    View details for PubMedID 31476225

  • Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration. Nature communications Liu, X., Helenius, D., Skotte, L., Beaumont, R. N., Wielscher, M., Geller, F., Juodakis, J., Mahajan, A., Bradfield, J. P., Lin, F. T., Vogelezang, S., Bustamante, M., Ahluwalia, T. S., Pitkanen, N., Wang, C. A., Bacelis, J., Borges, M. C., Zhang, G., Bedell, B. A., Rossi, R. M., Skogstrand, K., Peng, S., Thompson, W. K., Appadurai, V., Lawlor, D. A., Kalliala, I., Power, C., McCarthy, M. I., Boyd, H. A., Marazita, M. L., Hakonarson, H., Hayes, M. G., Scholtens, D. M., Rivadeneira, F., Jaddoe, V. W., Vinding, R. K., Bisgaard, H., Knight, B. A., Pahkala, K., Raitakari, O., Helgeland, O., Johansson, S., Njolstad, P. R., Fadista, J., Schork, A. J., Nudel, R., Miller, D. E., Chen, X., Weirauch, M. T., Mortensen, P. B., Borglum, A. D., Nordentoft, M., Mors, O., Hao, K., Ryckman, K. K., Hougaard, D. M., Kottyan, L. C., Pennell, C. E., Lyytikainen, L., Bonnelykke, K., Vrijheid, M., Felix, J. F., Lowe, W. L., Grant, S. F., Hypponen, E., Jacobsson, B., Jarvelin, M., Muglia, L. J., Murray, J. C., Freathy, R. M., Werge, T. M., Melbye, M., Buil, A., Feenstra, B. 2019; 10 (1): 3927

    Abstract

    The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P=3.96*10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.

    View details for DOI 10.1038/s41467-019-11881-8

    View details for PubMedID 31477735

  • GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI SCIENCE ADVANCES Alves, A., De Silva, N. G., Karhunen, V., Sovio, U., Das, S., Taal, H., Warrington, N. M., Lewin, A. M., Kaakinen, M., Cousminer, D. L., Thiering, E., Timpson, N. J., Bond, T. A., Lowry, E., Brown, C. D., Estivill, X., Lindi, V., Bradfield, J. P., Geller, F., Speed, D., Coin, L. M., Loh, M., Barton, S. J., Beilin, L. J., Bisgaard, H., Bonnelykke, K., Alili, R., Hatoum, I. J., Schramm, K., Cartwright, R., Charles, M., Salerno, V., Clement, K., Claringbould, A. J., van Duijn, C. M., Moltchanova, E., Eriksson, J. G., Elks, C., Feenstra, B., Flexeder, C., Franks, S., Frayling, T. M., Freathy, R. M., Elliott, P., Widen, E., Hakonarson, H., Hattersley, A. T., Rodriguez, A., Banterle, M., Heinrich, J., Heude, B., Holloway, J. W., Hofman, A., Hypponen, E., Inskip, H., Kaplan, L. M., Hedman, A. K., Laara, E., Prokisch, H., Grallert, H., Lakka, T. A., Lawlor, D. A., Melbye, M., Ahluwalia, T. S., Marinelli, M., Millwood, I. Y., Palmer, L. J., Pennell, C. E., Perry, J. R., Ring, S. M., Savolainen, M. J., Rivadeneira, F., Standl, M., Sunyer, J., Tiesler, C. T., Uitterlinden, A. G., Schierding, W., O'Sullivan, J. M., Prokopenko, I., Herzig, K., Smith, G., O'Reilly, P., Felix, J. F., Buxton, J. L., Blakemore, A. F., Ong, K. K., Jaddoe, V. V., Grant, S. A., Sebert, S., McCarthy, M. I., Jarvelin, M., BIOS Consortium, Early Growth Genetics EGG Conso 2019; 5 (9)
  • Retrospective markers of paediatric atopic dermatitis persistence after hospital diagnosis: a nationwide cohort study. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology Thyssen, J. P., Corn, G., Wohlfahrt, J., Melbye, M., Bager, P. 2019

    Abstract

    BACKGROUND: Atopic dermatitis (AD) normally onsets in childhood and mostly resolves before adolescences. Disease persistence is known to be difficult to study properly, and current predictors are insufficient to identify more than a small fraction of patients at risk.OBJECTIVE: To study personal AD medicine history as a retrospective marker of persistent AD.METHODS: The study population included all Danish first hospital contacts with a diagnosis of AD (ICD-10, L20) between 1995 and 2012. National register data following the diagnosis was used to define persistent AD activity until 2017 according to personal AD medicine history before diagnosis. Activity was defined as filled prescriptions for topical corticosteroids (TCS) or calcineurin inhibitors (TCI), dermatologist contacts, or hospital re-contacts for AD. Risk ratios (RR) for persistent activity (defined as activity >4 of the most recent 5 years) were estimated according to AD medicine history (prescriptions filled prior to diagnosis) adjusted for age at onset, parental AD, and basic covariates.RESULTS: 13628 patients were diagnosed at ages 0-16 years and had up to 21 years of follow-up. 10 years after diagnosis, 67% showed activity (9.5% persistent). Among prior TCS users (69%), the RR10y of persistent activity increased 1-6 fold with increasing strength of strongest TCS/TCI ever, and with number of TCS courses. Prior use of antibiotics (RR10y 1.32, 95%CI 1.09-1.59) and antihistamines (RR10y 1.65, 95%CI 1.42-1.91) increased the RR10y in a dose-dependent manner. In >90% of patients, prior medication use occurred <4 years before diagnosis.CONCLUSIONS AND CLINICAL RELEVANCE: The strength and type of AD medication used in the previous 4 years may predict 10-year persistence of AD. Since children may be misjudged as having milder disease when seen between flares of skin lesions, this information may improve physicians' ability to determine the correct prognosis independently of current AD severity. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/cea.13487

    View details for PubMedID 31464039

  • Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes. Genetic epidemiology Din, L., Sheikh, M., Kosaraju, N., Smedby, K. E., Bernatsky, S., Berndt, S. I., Skibola, C. F., Nieters, A., Wang, S., McKay, J. D., Cocco, P., Maynadie, M., Foretova, L., Staines, A., Mack, T. M., de Sanjose, S., Vyse, T. J., Padyukov, L., Monnereau, A., Arslan, A. A., Moore, A., Brooks-Wilson, A. R., Novak, A. J., Glimelius, B., Birmann, B. M., Link, B. K., Stewart, C., Vajdic, C. M., Haioun, C., Magnani, C., Conti, D. V., Cox, D. G., Casabonne, D., Albanes, D., Kane, E., Roman, E., Muzi, G., Salles, G., Giles, G. G., Adami, H., Ghesquieres, H., De Vivo, I., Clavel, J., Cerhan, J. R., Spinelli, J. J., Hofmann, J., Vijai, J., Curtin, K., Costenbader, K. H., Onel, K., Offit, K., Teras, L. R., Morton, L., Conde, L., Miligi, L., Melbye, M., Ennas, M. G., Liebow, M., Purdue, M. P., Glenn, M., Southey, M. C., Din, M., Rothman, N., Camp, N. J., Wong Doo, N., Becker, N., Pradhan, N., Bracci, P. M., Boffetta, P., Vineis, P., Brennan, P., Kraft, P., Lan, Q., Severson, R. K., Vermeulen, R. C., Milne, R. L., Kaaks, R., Travis, R. C., Weinstein, S. J., Chanock, S. J., Ansell, S. M., Slager, S. L., Zheng, T., Zhang, Y., Benavente, Y., Taub, Z., Madireddy, L., Gourraud, P., Oksenberg, J. R., Cozen, W., Hjalgrim, H., Khankhanian, P. 2019

    Abstract

    Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p=.0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

    View details for DOI 10.1002/gepi.22242

    View details for PubMedID 31407831

  • Oral corticosteroids during pregnancy and offspring risk of congenital heart defects - a Nationwide cohort study Schmidt, A. B., Lund, M., Corn, G., Oyen, N., Wohlfahrt, J., Melbye, M. WILEY. 2019: 367
  • Use of Pregabalin and worsening heart failure: A Nationwide cohort study Lund, M., Poulsen, G., Pasternak, B., Andersson, N., Melbye, M., Svanstrom, H. WILEY. 2019: 561
  • Nationwide study associates atrial fibrillation with titin-truncating variants Ahlberg, G., Refsgaard, L., Lundegaard, P. R., Andreasen, L. S., Ranthe, M. F., Linscheid, N. S., Nielsen, J. S., Melbye, M. S., Haunso, S., Sajadieh, A., Olesen, S., Rasmussen, S., Lundby, A., Ellinor, P. T., Holst, A. G., Svendsen, J. H., Olesen, M. S. NATURE PUBLISHING GROUP. 2019: 846
  • Co-occurrence of infantile hypertrophic pyloric stenosis and congenital heart defects: a nationwide cohort study PEDIATRIC RESEARCH Feenstra, B., Gortz, S., Lund, M., Ranthe, M. F., Geller, F., Melbye, M. 2019; 85 (7): 955–60
  • Glucagon-Like Peptide 1 Receptor Agonists and Risk of Diabetic Retinopathy Complications: Cohort Study in Nationwide Registers From Two Countries DIABETES CARE Ueda, P., Pasternak, B., Eliasson, B., Svensson, A., Franzen, S., Gudbjornsdottir, S., Hveem, K., Jonasson, C., Melbye, M., Svanstrom, H. 2019; 42 (6): E92–E94

    View details for DOI 10.2337/dc18-2532

    View details for Web of Science ID 000478835000003

  • Multiple sclerosis among first- and second-generation immigrants in Denmark: a population-based cohort study BRAIN Nielsen, N., Corn, G., Frisch, M., Stenager, E., Koch-Henriksen, N., Wohlfahrt, J., Magyari, M., Melbye, M. 2019; 142: 1587–97
  • Roadmap for a precision-medicine initiative in the Nordic region NATURE GENETICS Njolstad, P., Andreassen, O., Brunak, S., Borglum, A. D., Dillner, J., Esko, T., Franks, P. W., Freimer, N., Groop, L., Heimer, H., Hougaard, D. M., Hovig, E., Hveem, K., Jalanko, A., Kaprio, J., Knudsen, G., Melbye, M., Metspalu, A., Mortensen, P., Palmgren, J., Palotie, A., Reed, W., Stefansson, H., Stitziel, N. O., Sullivan, P. F., Thorsteinsdottir, U., Vaudel, M., Vuorio, E., Werge, T., Stoltenberg, C., Stefansson, K. 2019; 51 (6): 924–30
  • Vasectomy and prostate cancer risk: a 38-year nationwide cohort study. Journal of the National Cancer Institute Husby, A., Wohlfahrt, J., Melbye, M. 2019

    Abstract

    BACKGROUND: A man's risk of prostate cancer has been linked to his prior reproductive history, with low sperm quality, low ejaculation frequency, and a low number of offspring being associated with increased prostate cancer risk. It is however highly controversial whether vasectomy, a common sterilization procedure for men, influences prostate cancer risk.METHODS: We established a cohort of all Danish men (born from 1937) and linked information on vasectomy, doctor visits, socioeconomic factors and cancer from nationwide registries using unique personal identification numbers. Incidence risk ratios for prostate cancer by time since vasectomy and age at vasectomy during the follow-up were estimated using log-linear Poisson regression.RESULTS: Overall, 26,238 cases of prostate cancer occurred among 2,150,162 Danish men during 53.4 million person-years of follow-up. Overall, vasectomized men had an increased risk of prostate cancer compared with non-vasectomized men (relative risk 1.15; 95% CI, 1.10 to 1.20). The increased risk of prostate cancer following vasectomy persisted for at least 30 years after the procedure and was observed regardless of age at vasectomy and cancer stage at diagnosis. Adjustment for the number of visits to doctor and socioeconomic factors did not explain the association.CONCLUSIONS: Vasectomy is associated with a statistically significant increased long-term risk of prostate cancer. The absolute increased risk following vasectomy is nevertheless small, but our finding supports a relationship between reproductive factors and prostate cancer risk.

    View details for DOI 10.1093/jnci/djz099

    View details for PubMedID 31119294

  • Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors NATURE GENETICS Warrington, N. M., Beaumont, R. N., Horikoshi, M., Day, F. R., Helgeland, O., Laurin, C., Bacelis, J., Peng, S., Hao, K., Feenstra, B., Wood, A. R., Mahajan, A., Tyrrell, J., Robertson, N. R., Rayner, N., Qiao, Z., Moen, G., Vaudel, M., Marsit, C. J., Chen, J., Nodzenski, M., Schnurr, T. M., Zafarmand, M. H., Bradfield, J. P., Grarup, N., Kooijman, M. N., Li-Gao, R., Geller, F., Ahluwalia, T. S., Paternoster, L., Rueedi, R., Huikari, V., Hottenga, J., Lyytikainen, L., Cavadino, A., Metrustry, S., Cousminer, D. L., Wu, Y., Thiering, E., Wang, C. A., Have, C. T., Vilor-Tejedor, N., Joshi, P. K., Painter, J. N., Ntalla, I., Myhre, R., Pitkanen, N., van Leeuwen, E. M., Joro, R., Lagou, V., Richmond, R. C., Espinosa, A., Barton, S. J., Inskip, H. M., Holloway, J. W., Santa-Marina, L., Estivill, X., Ang, W., Marsh, J. A., Reichetzeder, C., Marullo, L., Hocher, B., Lunetta, K. L., Murabito, J. M., Relton, C. L., Kogevinas, M., Chatzi, L., Allard, C., Bouchard, L., Hivert, M., Zhang, G., Muglia, L. J., Heikkinen, J., Morgen, C. S., van Kampen, A. C., van Schaik, B. C., Mentch, F. D., Langenberg, C., Luan, J., Scott, R. A., Zhao, J., Hemani, G., Ring, S. M., Bennett, A. J., Gaulton, K. J., Fernandez-Tajes, J., van Zuydam, N. R., Medina-Gomez, C., de Haan, H. G., Rosendaal, F. R., Kutalik, Z., Marques-Vidal, P., Das, S., Willemsen, G., Mbarek, H., Mueller-Nurasyid, M., Standl, M., Appel, E. R., Fonvig, C. E., Trier, C., van Beijsterveldt, C. M., Murcia, M., Bustamante, M., Bonas-Guarch, S., Hougaard, D. M., Mercader, J. M., Linneberg, A., Schraut, K. E., Lind, P. A., Medland, S. E., Shields, B. M., Knight, B. A., Chai, J., Panoutsopoulou, K., Bartels, M., Sanchez, F., Stokholm, J., Torrents, D., Vinding, R. K., Willems, S. M., Atalay, M., Chawes, B. L., Kovacs, P., Prokopenko, I., Tuke, M. A., Yaghootkar, H., Ruth, K. S., Jones, S. E., Loh, P., Murray, A., Weedon, M. N., Toenjes, A., Stumvoll, M., Michaelsen, K. F., Eloranta, A., Lakka, T. A., van Duijn, C. M., Kiess, W., Koerner, A., Niinikoski, H., Pahkala, K., Raitakari, O. T., Jacobsson, B., Zeggini, E., Dedoussis, G. V., Teo, Y., Saw, S., Montgomery, G. W., Campbell, H., Wilson, J. F., Vrijkotte, T. M., Vrijheid, M., de Geus, E. N., Hayes, M., Kadarmideen, H. N., Holm, J., Beilin, L. J., Pennell, C. E., Heinrich, J., Adair, L. S., Borja, J. B., Mohlke, K. L., Eriksson, J. G., Widen, E. E., Hattersley, A. T., Spector, T. D., Kaehoenen, M., Viikari, J. S., Lehtimaeki, T., Boomsma, D. I., Sebert, S., Vollenweider, P., Sorensen, T. A., Bisgaard, H., Bonnelykke, K., Murray, J. C., Melbye, M., Nohr, E. A., Mook-Kanamori, D. O., Rivadeneira, F., Hofman, A., Felix, J. F., Jaddoe, V. V., Hansen, T., Pisinger, C., Vaag, A. A., Pedersen, O., Uitterlinden, A. G., Jarvelin, M., Power, C., Hypponen, E., Scholtens, D. M., Lowe, W. L., Smith, G., Timpson, N. J., Morris, A. P., Wareham, N. J., Hakonarson, H., Grant, S. A., Frayling, T. M., Lawlor, D. A., Njolstad, P. R., Johansson, S., Ong, K. K., McCarthy, M. I., Perry, J. B., Evans, D. M., Freathy, R. M., EGG Consortium 2019; 51 (5): 804-+
  • Glucagon-Like Peptide 1 Receptor Agonists and Risk of Diabetic Retinopathy Complications: Cohort Study in Nationwide Registers From Two Countries. Diabetes care Ueda, P., Pasternak, B., Eliasson, B., Svensson, A., Franzen, S., Gudbjornsdottir, S., Hveem, K., Jonasson, C., Melbye, M., Svanstrom, H. 2019

    View details for PubMedID 31010872

  • Measles, Mumps, Rubella Vaccination and Autism A Nationwide Cohort Study ANNALS OF INTERNAL MEDICINE Hviid, A., Hansen, J., Frisch, M., Melbye, M. 2019; 170 (8): 513-+

    View details for DOI 10.7326/M18-2101

    View details for Web of Science ID 000465499900014

  • Roadmap for a precision-medicine initiative in the Nordic region. Nature genetics Njolstad, P. R., Andreassen, O. A., Brunak, S., Borglum, A. D., Dillner, J., Esko, T., Franks, P. W., Freimer, N., Groop, L., Heimer, H., Hougaard, D. M., Hovig, E., Hveem, K., Jalanko, A., Kaprio, J., Knudsen, G. P., Melbye, M., Metspalu, A., Mortensen, P. B., Palmgren, J., Palotie, A., Reed, W., Stefansson, H., Stitziel, N. O., Sullivan, P. F., Thorsteinsdottir, U., Vaudel, M., Vuorio, E., Werge, T., Stoltenberg, C., Stefansson, K. 2019

    View details for PubMedID 30988515

  • Association Between Maternal Folic Acid Supplementation and Congenital Heart Defects in Offspring in Birth Cohorts From Denmark and Norway. Journal of the American Heart Association Oyen, N., Olsen, S. F., Basit, S., Leirgul, E., Strom, M., Carstensen, L., Granstrom, C., Tell, G. S., Magnus, P., Vollset, S. E., Wohlfahrt, J., Melbye, M. 2019; 8 (6): e011615

    Abstract

    Background Evidence linking individual-level maternal folic acid supplementation to offspring risk of congenital heart defects is lacking. We investigated whether folic acid supplementation in early pregnancy reduces offspring risk of heart defects in 2 large birth cohort studies. Methods and Results Women recruited in early pregnancy within the DNBC (Danish National Birth Cohort), 1996-2003, and MoBa (Norwegian Mother and Child Cohort Study), 2000-2009, were followed until delivery. Information on periconceptional intake of folic acid and other supplements was linked with information on heart defects from national registers. Among 197123 births, we identified 2247 individuals with heart defects (114/10000). Periconceptional (4weeks before through 8weeks after conception) use of folic acid plus other supplements (54.8%), folic acid only (12.2%), and non-folic acid supplements (5.0%) were compared with no supplement use (28.0%); the adjusted relative risks of heart defects were 0.99 (95% CI, 0.80-1.22), 1.08 (95% CI , 0.93-1.25), and 1.07 (95% CI , 0.97-1.19), respectively. For initiation of folic acid in the preconception period weeks -4 to -1 (33.7%) and the postconception periods 0 to 4weeks (15.5%), 5 to 8weeks (17.8%), and 9 to 12weeks (4.6%), compared with no or late folic acid intake (29.1%), relative risks of heart defect were 1.11 (95% CI , 1.00-1.25), 1.09 (95% CI , 0.95-1.25), 0.98 (95% CI , 0.86-1.12), and 0.97 (95% CI , 0.78-1.20), respectively. Relative risks of severe defects, conotruncal defects, and septal defects showed similar results. Conclusions Folic acid was not associated with offspring risk of heart defects, including severe defects, conotruncal defects, or septal defects.

    View details for PubMedID 30857459

  • Association Between Maternal Folic Acid Supplementation and Congenital Heart Defects in Offspring in Birth Cohorts From Denmark and Norway JOURNAL OF THE AMERICAN HEART ASSOCIATION Oyen, N., Olsen, S. F., Basit, S., Leirgul, E., Strom, M., Carstensen, L., Granstrom, C., Tell, G. S., Magnus, P., Vollset, S. E., Wohlfahrt, J., Melbye, M. 2019; 8 (6)
  • Co-occurrence of infantile hypertrophic pyloric stenosis and congenital heart defects: a nationwide cohort study. Pediatric research Feenstra, B., Gortz, S., Lund, M., Ranthe, M. F., Geller, F., Melbye, M. 2019

    Abstract

    BACKGROUND: Recent studies suggest that infantile hypertrophic pyloric stenosis (IHPS) and congenital heart defects (CHDs) may share some genetic risk factors, but little is known about the co-occurrence of the two conditions in patients.METHODS: Our study cohort included 2,212,756 persons born in Denmark 1977-2013. We identified patients with IHPS and CHD in the National Patient Register. Using log-linear Poisson regression, we estimated the (incidence) rate ratios (RRs) comparing the rate of IHPS among children with a CHD diagnosis (exposed) and the rate among those without such a diagnosis.RESULTS: Twenty-seven thousand three hundred and fifty-seven children in the cohort were diagnosed with CHD out of whom 85 developed IHPS (RR=2.62, 95% confidence interval (CI) 2.09-3.22]). The results were similar for those with and without other congenital malformations, for preterm and term deliveries, and for both sexes. There was, however, a significant effect of calendar period (P=.003). In the period 1977-1996, the RR of IHPS given a CHD diagnosis was 1.96 (95% CI 1.41-2.64); in the period 1997-2014, the RR was 3.75 (95% CI 2.74-4.99).CONCLUSION: CHD was associated with an increased risk of IHPS. Further research is needed to delineate molecular-level mechanisms that may affect both conditions.

    View details for PubMedID 30862960

  • The Metabolomic Clock of Human Pregnancy. Liang, L., Rasmussen, M. H., Piening, B., Rost, H., Chen, S., Skotte, L., Contrepois, K., Feenstra, B., Snyder, M., Melbye, M. SAGE PUBLICATIONS INC. 2019: 118A–119A
  • The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia: design, results and future prospects EUROPEAN JOURNAL OF EPIDEMIOLOGY Middeldorp, C. M., Mahajan, A., Horikoshi, M., Robertson, N. R., Beaumont, R. N., Bradfield, J. P., Bustamante, M., Cousminer, D. L., Day, F. R., De Silva, N., Guxens, M., Mook-Kanamori, D. O., St Pourcain, B., Warrington, N. M., Adair, L. S., Ahlqvist, E., Ahluwalia, T. S., Almgren, P., Ang, W., Atalay, M., Auvinen, J., Bartels, M., Beckmann, J. S., Bilbao, J., Bond, T., Borja, J. B., Cavadino, A., Charoen, P., Chen, Z., Coin, L., Cooper, C., Curtin, J. A., Custovic, A., Das, S., Davies, G. E., Dedoussis, G. V., Duijts, L., Eastwood, P. R., Eliasen, A. U., Elliott, P., Eriksson, J. G., Estivill, X., Fadista, J., Fedko, I. O., Frayling, T. M., Gaillard, R., Gauderman, W., Geller, F., Gilliland, F., Gilsanz, V., Granell, R., Grarup, N., Groop, L., Hadley, D., Hakonarson, H., Hansen, T., Hartman, C. A., Hattersley, A. T., Hayes, M., Hebebrand, J., Heinrich, J., Helgeland, O., Henders, A. K., Henderson, J., Henriksen, T. B., Hirschhorn, J. N., Hivert, M., Hocher, B., Holloway, J. W., Holt, P., Hottenga, J., Hypponen, E., Iniguez, C., Johansson, S., Jugessur, A., Kahonen, M., Kalkwarf, H. J., Kaprio, J., Karhunen, V., Kemp, J. P., Kerkhof, M., Koppelman, G. H., Korner, A., Kotecha, S., Kreiner-Moller, E., Kulohoma, B., Kumar, A., Kutalik, Z., Lahti, J., Lappe, J. M., Larsson, H., Lehtimaki, T., Lewin, A. M., Li, J., Lichtenstein, P., Lindgren, C. M., Lindi, V., Linneberg, A., Liu, X., Liu, J., Lowe, W. L., Lundstrom, S., Lyytikainen, L., Ma, R. W., Mace, A., Magi, R., Magnus, P., Mamun, A. A., Mannikko, M., Martin, N. G., Mbarek, H., McCarthy, N. S., Medland, S. E., Melbye, M., Melen, E., Mohlke, K. L., Monnereau, C., Morgen, C. S., Morris, A. P., Murray, J. C., Myhre, R., Najman, J. M., Nivard, M. G., Nohr, E. A., Nolte, I. M., Ntalla, I., O'Reilly, P., Oberfield, S. E., Oken, E., Oldehinkel, A. J., Pahkala, K., Palviainen, T., Panoutsopoulou, K., Pedersen, O., Pennell, C. E., Pershagen, G., Pitkanen, N., Plomin, R., Power, C., Prasad, R. B., Prokopenko, I., Pulkkinen, L., Raikkonen, K., Raitakari, O. T., Reynolds, R. M., Richmond, R. C., Rivadeneira, F., Rodriguez, A., Rose, R. J., Salem, R., Santa-Marina, L., Saw, S., Schnurr, T. M., Scott, J. G., Selzam, S., Shepherd, J. A., Simpson, A., Skotte, L., Sleiman, P. A., Snieder, H., Sorensen, T. A., Standl, M., Steegers, E. P., Strachan, D. P., Straker, L., Strandberg, T., Taylor, M., Teo, Y., Thiering, E., Torrent, M., Tyrrell, J., Uitterlinden, A. G., van Beijsterveldt, T., van der Most, P. J., van Duijn, C. M., Viikari, J., Vilor-Tejedor, N., Vogelezang, S., Vonk, J. M., Vrijkotte, T. M., Vuoksimaa, E., Wang, C. A., Watkins, W. J., Wichmann, H., Willemsen, G., Williams, G. M., Wilson, J. F., Wray, N. R., Xu, S., Xu, C., Yaghootkar, H., Yi, L., Zafarmand, M., Zeggini, E., Zemel, B. S., Hinney, A., Lakka, T. A., Whitehouse, A. O., Sunyer, J., Widen, E. E., Feenstra, B., Sebert, S., Jacobsson, B., Njolstad, P. R., Stoltenberg, C., Smith, G., Lawlor, D. A., Paternoster, L., Timpson, N. J., Ong, K. K., Bisgaard, H., Bonnelykke, K., Jaddoe, V. V., Tiemeier, H., Jarvelin, M., Evans, D. M., Perry, J. B., Grant, S. A., Boomsma, D. I., Freathy, R. M., McCarthy, M. I., Adair, L. S., Ahlqvist, E., Ahluwalia, T. S., Almgren, P., Ang, W., Atalay, M., Beaumont, R. N., Beckmann, J. S., Bisgaard, H., Bond, T., Bonnelykke, K., Boomsma, D. I., Borja, J. B., Bradfield, J. P., Bustamante, M., Cavadino, A., Charoen, P., Coin, L., Cooper, C., Cousminer, D. L., Curtin, J. A., Custovic, A., Das, S., Day, F. R., De Silva, N., Dedoussis, G. V., Elliott, P., Eriksson, J. G., Evans, D. M., Fadista, J., Feenstra, B., Felix, J. F., Frayling, T. M., Freathy, R. M., Gaillard, R., Geller, F., Gilsanz, V., Grant, S. A., Grarup, N., Groop, L., Guxens, M., Hadley, D., Hakonarson, H., Hansen, T., Hattersley, A. T., Hayes, M., Hebebrand, J., Heinrich, J., Helgeland, O., Henriksen, T. B., Hinney, A., Hirschhorn, J. N., Hivert, M., Hocher, B., Holloway, J. W., Horikoshi, M., Hottenga, J., Hypponen, E., Jacobsson, B., Jaddoe, V. V., Jarvelin, M., Johansson, S., Kalkwarf, H. J., Kerkhof, M., Korner, A., Kotecha, S., Kreiner-Moller, E., Kulohoma, B., Kutalik, Z., Lakka, T. A., Lappe, J. M., Lawlor, D. A., Lehtimaki, T., Lewin, A. M., Lindgren, C. M., Lindi, V., Linneberg, A., Liu, X., Liu, J., Lowe, W. L., Ma, R. W., Mace, A., Magi, R., Magnus, P., Mahajan, A., McCarthy, N. S., McCarthy, M. I., Melbye, M., Mohlke, K. L., Monnereau, C., Mook-Kanamori, D. O., Morgen, C. S., Morris, A. P., Murray, J. C., Myhre, R., Njolstad, P. R., Nohr, E. A., Ntalla, I., O'Reilly, P., Oberfield, S. E., Oken, E., Ong, K. K., Panoutsopoulou, K., Pedersen, O., Pennell, C. E., Perry, J. B., Pitkanen, N., St Pourcain, B., Power, C., Prasad, R. B., Prokopenko, I., Raitakari, O. T., Reynolds, R. M., Richmond, R. C., Rodriguez, A., Salem, R., Saw, S., Schnurr, T. M., Sebert, S., Shepherd, J. A., Simpson, A., Skotte, L., Sorensen, T. A., Standl, M., Steegers, E. P., Strachan, D. P., Sunyer, J., Taylor, M., Teo, Y., Thiering, E., Timpson, N. J., Tyrrell, J., Uitterlinden, A. G., van Duijn, C. M., Vogelezang, S., Vrijkotte, T. M., Wang, C. A., Warrington, N. M., Watkins, W. J., Wichmann, H., Widen, E. E., Willemsen, G., Wilson, J. F., Yaghootkar, H., Zafarmand, M., Zeggini, E., Zemel, B. S., Ahluwalia, T. S., Auvinen, J., Bartels, M., Bilbao, J., Bisgaard, H., Bonnelykke, K., Boomsma, D. I., Bradfield, J. P., Bustamante, M., Chen, Z., Curtin, J. A., Custovic, A., Smith, G., Davies, G. E., Duijts, L., Eastwood, P. R., Eliasen, A. U., Estivill, X., Evans, D. M., Fedko, I. O., Felix, J. F., Gauderman, W., Gilliland, F., Granell, R., Grant, S. A., Guxens, M., Hakonarson, H., Hartman, C. A., Heinrich, J., Henders, A. K., Henderson, J., Holt, P., Hottenga, J., Hypponen, E., Iniguez, C., Jacobsson, B., Jaddoe, V. V., Jarvelin, M., Jugessur, A., Kahonen, M., Kaprio, J., Karhunen, V., Kemp, J. P., Koppelman, G. H., Kumar, A., Lahti, J., Larsson, H., Lawlor, D. A., Lehtimaki, T., Li, J., Lichtenstein, P., Lundstrom, S., Lyytikainen, L., Magnus, P., Mamun, A. A., Mannikko, M., Martin, N. G., Mbarek, H., Medland, S. E., Melen, E., Middeldorp, C. M., Najman, J. M., Nivard, M. G., Nolte, I. M., Oldehinkel, A. J., Pahkala, K., Palviainen, T., Paternoster, L., Pennell, C. E., Pershagen, G., Pitkanen, N., Plomin, R., St Pourcain, B., Power, C., Pulkkinen, L., Raikkonen, K., Raitakari, O. T., Richmond, R. C., Rivadeneira, F., Rose, R. J., Santa-Marina, L., Scott, J. G., Sebert, S., Selzam, S., Simpson, A., Sleiman, P. A., Snieder, H., Standl, M., Stoltenberg, C., Strachan, D. P., Straker, L., Strandberg, T., Sunyer, J., Thiering, E., Tiemeier, H., Timpson, N. J., Torrent, M., Uitterlinden, A. G., van Beijsterveldt, T., van der Most, P. J., van Duijn, C. M., Viikari, J., Vilor-Tejedor, N., Vonk, J. M., Vrijkotte, T. M., Vuoksimaa, E., Wang, C. A., Whitehouse, A. O., Willemsen, G., Williams, G. M., Wray, N. R., Xu, S., Xu, C., Yi, L., Zafarmand, M., EArly Genetics Lifecourse, EGG Consortium, EGG Membership, EAGLE Membership 2019; 34 (3): 279–300

    Abstract

    The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.

    View details for DOI 10.1007/s10654-019-00502-9

    View details for Web of Science ID 000463834200009

    View details for PubMedID 30887376

    View details for PubMedCentralID PMC6447695

  • Breast cancer mortality in synchronous bilateral breast cancer patients. British journal of cancer Mejdahl, M. K., Wohlfahrt, J., Holm, M., Balslev, E., Knoop, A. S., Tjonneland, A., Melbye, M., Kroman, N. 2019

    Abstract

    BACKGROUND: Evidence suggests that patients with synchronous bilateral breast cancer (SBBC), diagnosed within 4 months, have an inferior prognosis compared to unilateral breast cancer (UBC) patients. Using data from nationwide Danish clinical databases, this cohort study investigated whether the inferior prognosis could be explained by SBBC patients having a more aggressive disease, or whether the prognosis could be explained by the fact that they have two simultaneous cancers.METHODS: Patients were diagnosed from 1999-2015. The main outcome was excess mortality, subtracting background population mortality from observed mortality. Differences between SBBC and UBC patients were evaluated by rate ratios (RR) and estimated by Poisson regression.RESULTS: In total, 1214 SBBC and 59 177 UBC patients were included. SBBC patients had a significantly higher excess mortality than UBC patients after adjustment for age and period (RR=1.73; 95% CI:1.44-2.08; p<0.01) and after adjusting for characteristics of the worst tumour as traditionally done (RR=1.31; 95% CI:1.08-1.57; p=0.01). However, adjusting for characteristics of both tumours, using a more advanced competing risks model, no difference was observed (RR=1.01; 95% CI:0.83-1.22; p=0.93).CONCLUSIONS: Our study does not support that the inferior prognosis in SBBC patients is due to having more aggressive tumours per se, but rather the combined effect of having two simultaneous cancers.

    View details for PubMedID 30804429

  • Hypertensive disorders of pregnancy and peripartum cardiomyopathy: A nationwide cohort study PLOS ONE Behrens, I., Basit, S., Lykke, J. A., Ranthe, M. F., Wohlfahrt, J., Bundgaard, H., Melbye, M., Boyd, H. A. 2019; 14 (2)
  • Long-term Risk of Hemorrhagic Stroke in Patients With Infective Endocarditis: A Danish Nationwide Cohort Study CLINICAL INFECTIOUS DISEASES Klein, C. F., Gortz, S., Wohlfahrt, J., Munch, T. N., Melbye, M., Bundgaard, H., Iversen, K. K. 2019; 68 (4): 668–75

    Abstract

    The present study aimed to investigate the long-term risk of hemorrhagic stroke (HS) in patients with infective endocarditis (IE).Using a register-based nationwide cohort of 9 million Danes, we performed propensity score matching between patients with left-sided IE from 1977 to mid-2015 and IE-free individuals (1:10). Follow-up started 1 year after the IE diagnosis. Hazard ratios (HRs) for HS in patients with IE compared with the matched cohort were estimated using Cox regression.During follow-up of 5735 patients with left-sided IE from 1 year after IE diagnosis and up to 37.5 years (median, 6.3 years), 103 cases of HS were observed. Compared with the matched cohort, patients with IE had a higher long-term risk of HS (HR, 1.47; 95% confidence interval, 1.20-1.80; P < .001). The risk of HS was particularly increased in patients within the lowest propensity score quartile (HR, 2.60; 95% confidence interval, 1.89-3.58). Mediation analyses suggested that the increased HS risk could be explained by an indirect effect of mechanical heart valve insertion, atrial fibrillation, or treatment with anticoagulants. The cumulative risk of HS 30 years after start of follow-up was 3.0% in patients with IE.IE does not directly increase the long-term risk of HS. The apparent excess risk of HS in patients with previous IE was explained by mediating factors, including mechanical heart valve insertion, atrial fibrillation, and anticoagulation medication.

    View details for PubMedID 29920590

  • Association between use of azathioprine and risk of acute pancreatitis in children with inflammatory bowel disease: a Swedish-Danish nationwide cohort study. The Lancet. Child & adolescent health Wintzell, V., Svanstrom, H., Olen, O., Melbye, M., Ludvigsson, J. F., Pasternak, B. 2019

    Abstract

    BACKGROUND: Studies have shown an association between use of azathioprine and increased risk of acute pancreatitis in adult inflammatory bowel disease. However, whether an association exists among paediatric patients is not known. We aimed to investigate whether use of azathioprine is associated with the risk of acute pancreatitis in children with inflammatory bowel disease.METHODS: We did a nationwide register-based cohort study in Sweden (2006-16) and Denmark (2000-16). All paediatric patients (<18 years of age) with inflammatory bowel disease during the study period were identified through hospital records. Episodes of incident azathioprine use and no use of any thiopurine were matched (1:1) using propensity scores, controlling for sociodemographic characteristics, comorbidities, previous treatment, indicators of disease severity, and health care use. Incident acute pancreatitis (physician-assigned diagnosis with ICD-10 code K85) occurring in the 90 days following treatment initiation were identified through outpatient and inpatient hospital records.FINDINGS: We identified 3574 azathioprine episodes and 18 700 no-use episodes, which resulted in 3374 pairs after propensity score matching; baseline characteristics in the matched cohort were well balanced. Among the matched azathioprine episodes, mean age was 14·3 years (SD 3·1), 1854 (54·9%) were male, 1923 (57·0%) had Crohn's disease, and 1451 (43·0%) had ulcerative colitis or unclassified inflammatory bowel disease. Within the first 90 days following initiation of azathioprine, 40 acute pancreatitis events occurred (incidence rate 49·1 events per 1000 person-years) compared with six events in the no-use group (8·4 events per 1000 person-years). Azathioprine use was associated with an increased risk of acute pancreatitis (incidence rate ratio 5·82 [95% CI 2·47-13·72]; absolute difference 1·0 [95% CI 0·3-2·6] events per 100 patients) during the 90-day risk period.INTERPRETATION: Use of azathioprine was associated with an increased risk of acute pancreatitis in children with inflammatory bowel disease during the first 90 days following treatment initiation, suggesting the need for regular and rigorous monitoring. The risk of acute pancreatitis needs to be considered when deciding on optimal treatment strategies.FUNDING: Swedish Research Council, Frimurare Barnhuset Foundation, and the Ake Wiberg Foundation.

    View details for PubMedID 30685366

  • Genome-wide meta-analysis identifies BARX1 and EML4-MTA3 as new loci associated with infantile hypertrophic pyloric stenosis HUMAN MOLECULAR GENETICS Fadista, J., Skotte, L., Geller, F., Bybjerg-Grauholm, J., Gortz, S., Romitti, P. A., Caggana, M., Kay, D. M., Matsson, H., Boyd, H. A., Hougaard, D. M., Nordenskjold, A., Mills, J. L., Melbye, M., Feenstra, B. 2019; 28 (2): 332–40

    View details for DOI 10.1093/hmg/ddy347

    View details for Web of Science ID 000461947100013

  • Hypertensive disorders of pregnancy and peripartum cardiomyopathy: A nationwide cohort study. PloS one Behrens, I., Basit, S., Lykke, J. A., Ranthe, M. F., Wohlfahrt, J., Bundgaard, H., Melbye, M., Boyd, H. A. 2019; 14 (2): e0211857

    Abstract

    BACKGROUND: Peripartum cardiomyopathy (PPCM) is a serious cardiac disorder occurring late in pregnancy or early in the postpartum period. We examined associations between hypertensive disorders of pregnancy (HDP: preeclampsia and gestational hypertension) and PPCM, accounting for other pregnancy-related risk factors for PPCM.METHODS: Using nationwide Danish register data, we constructed a cohort of all women with ≥1 live birth or stillbirth in Denmark between 1978 and 2012. Using log-linear binomial regression and generalized estimating equations, we estimated risk ratios (RRs) for PPCM associated with HDP of varying severity.RESULTS: In a cohort of 1,088,063 women with 2,078,822 eligible pregnancies, 126 women developed PPCM (39 in connection with an HDP-complicated pregnancy). The risks of PPCM were significantly higher in women with HDP-complicated pregnancies than in women with normotensive pregnancies (severe preeclampsia, RR 21.2, 95% confidence interval [CI] 12.0-37.4; moderate preeclampsia, RR 10.2, 95% CI 6.18-16.9; gestational hypertension, RR 5.16, 95% CI 2.11-12.6). The RRs for moderate preeclampsia and gestational hypertension were not significantly different from one another (p = 0.18); the RR for severe preeclampsia was significantly different from the RR for moderate preeclampsia and gestational hypertension combined (p = 0.02).CONCLUSIONS: Although 70% of PPCM occurred in women with normotensive pregnancies, HDPs were associated with substantial increases in PPCM risk that depended on HDP severity. The heart's capacity to adapt to a normal pregnancy may be exceeded in some women already susceptible to cardiac insult, contributing to PPCM. HDPs, severe preeclampsia in particular, probably represent an additional cardiac stressor during pregnancy.

    View details for PubMedID 30785920

  • Use of sodium glucose cotransporter 2 inhibitors and risk of major cardiovascular events and heart failure: Scandinavian register based cohort study. BMJ (Clinical research ed.) Pasternak, B., Ueda, P., Eliasson, B., Svensson, A. M., Franzén, S., Gudbjörnsdottir, S., Hveem, K., Jonasson, C., Wintzell, V., Melbye, M., Svanström, H. 2019; 366: l4772

    Abstract

    To investigate the cardiovascular effectiveness of sodium glucose cotransporter 2 (SGLT2) inhibitors in routine clinical practice.Cohort study using data from nationwide registers and an active-comparator new-user design.Denmark, Norway, and Sweden, from April 2013 to December 2016.20 983 new users of SGLT2 inhibitors and 20 983 new users of dipeptidyl peptidase 4 (DPP4) inhibitors, aged 35-84, matched by age, sex, history of major cardiovascular disease, and propensity score.Primary outcomes were major cardiovascular events (composite of myocardial infarction, stroke, and cardiovascular death) and heart failure (hospital admission for heart failure or death due to heart failure). Secondary outcomes were the individual components of the cardiovascular composite and any cause death. In the primary analyses, patients were defined as exposed from treatment start throughout follow-up (analogous to intention to treat); additional analyses were conducted with an as-treated exposure definition. Cox regression was used to estimate hazard ratios.Mean age of the study cohort was 61 years, 60% were men, and 19% had a history of major cardiovascular disease. Of the total 27 416 person years of follow-up in the SGLT2 inhibitor group, 22 627 (83%) was among patients who initiated dapagliflozin, 4521 (16%) among those who initiated empagliflozin, and 268 (1%) among those who initiated canagliflozin. During follow-up, 467 SGLT2 inhibitor users (incidence rate 17.0 events per 1000 person years) and 662 DPP4 inhibitor users (18.0) had a major cardiovascular event, whereas 130 (4.7) and 265 (7.1) had a heart failure event, respectively. Hazard ratios were 0.94 (95% confidence interval 0.84 to 1.06) for major cardiovascular events and 0.66 (0.53 to 0.81) for heart failure. Hazard ratios were consistent among subgroups of patients with and without history of major cardiovascular disease and with and without history of heart failure. Hazard ratios for secondary outcomes, comparing SGLT2 inhibitors with DPP4 inhibitors, were 0.99 (0.85 to 1.17) for myocardial infarction, 0.94 (0.77 to 1.15) for stroke, 0.84 (0.65 to 1.08) for cardiovascular death, and 0.80 (0.69 to 0.92) for any cause death. In the as-treated analyses, hazard ratios were 0.84 (0.72 to 0.98) for major cardiovascular events, 0.55 (0.42 to 0.73) for heart failure, 0.93 (0.76 to 1.14) for myocardial infarction, 0.83 (0.64 to 1.07) for stroke, 0.67 (0.49 to 0.93) for cardiovascular death, and 0.75 (0.61 to 0.91) for any cause death.In this large Scandinavian cohort, SGLT2 inhibitor use compared with DPP4 inhibitor use was associated with reduced risk of heart failure and any cause death, but not with major cardiovascular events in the primary intention-to-treat analysis. In the additional as-treated analyses, the magnitude of the association with heart failure and any cause death became larger, and a reduced risk of major cardiovascular events that was largely driven by the cardiovascular death component was observed. These data help inform patients, practitioners, and authorities regarding the cardiovascular effectiveness of SGLT2 inhibitors in routine clinical practice.

    View details for DOI 10.1136/bmj.l4772

    View details for PubMedID 31467044

  • Pregnancy duration and endometrial cancer risk: nationwide cohort study. BMJ (Clinical research ed.) Husby, A., Wohlfahrt, J., Melbye, M. 2019; 366: l4693

    Abstract

    OBJECTIVE: To explore the association between pregnancy duration and risk of endometrial cancer.DESIGN: Nationwide register based cohort study.SETTING: Denmark.PARTICIPANTS: All Danish women born from 1935 to 2002.MAIN OUTCOME MEASURES: Relative risk (incidence rate ratio) of endometrial cancer by pregnancy number, type, and duration, estimated using log-linear Poisson regression.RESULTS: Among 2311332 Danish women with 3947650 pregnancies, 6743 women developed endometrial cancer during 57347622 person years of follow-up. After adjustment for age, period, and socioeconomic factors, a first pregnancy was associated with a noticeably reduced risk of endometrial cancer, whether it ended in induced abortion (adjusted relative risk 0.53 (95% confidence interval 0.45 to 0.64) or childbirth (0.66, 0.61 to 0.72). Each subsequent pregnancy was associated with an additional reduction in risk, whether it ended in induced abortion (0.81, 0.77 to 0.86) or childbirth (0.86, 0.84 to 0.89). Duration of pregnancy, age at pregnancy, spontaneous abortions, obesity, maternal birth cohort, fecundity, and socioeconomic factors did not modify the results.CONCLUSIONS: The risk of endometrial cancer is reduced regardless of whether a pregnancy ends shortly after conception or at 40 weeks of gestation. This reduction in risk could be explained by a biological process occurring within the first weeks of pregnancy, as pregnancies ending in induced abortions were associated with similar reductions in risk as pregnancies ending in childbirth.

    View details for DOI 10.1136/bmj.l4693

    View details for PubMedID 31412996

  • Measles, Mumps, Rubella Vaccination and Autism: A Nationwide Cohort Study. Annals of internal medicine Hviid, A., Hansen, J. V., Frisch, M., Melbye, M. 2019

    Abstract

    Background: The hypothesized link between the measles, mumps, rubella (MMR) vaccine and autism continues to cause concern and challenge vaccine uptake.Objective: To evaluate whether the MMR vaccine increases the risk for autism in children, subgroups of children, or time periods after vaccination.Design: Nationwide cohort study.Setting: Denmark.Participants: 657461 children born in Denmark from 1999 through 31 December 2010, with follow-up from 1 year of age and through 31 August 2013.Measurements: Danish population registries were used to link information on MMR vaccination, autism diagnoses, other childhood vaccines, sibling history of autism, and autism risk factors to children in the cohort. Survival analysis of the time to autism diagnosis with Cox proportional hazards regression was used to estimate hazard ratios of autism according to MMR vaccination status, with adjustment for age, birth year, sex, other childhood vaccines, sibling history of autism, and autism risk factors (based on a disease risk score).Results: During 5025754 person-years of follow-up, 6517 children were diagnosed with autism (incidence rate, 129.7 per 100 000 person-years). Comparing MMR-vaccinated with MMR-unvaccinated children yielded a fully adjusted autism hazard ratio of 0.93 (95% CI, 0.85 to 1.02). Similarly, no increased risk for autism after MMR vaccination was consistently observed in subgroups of children defined according to sibling history of autism, autism risk factors (based on a disease risk score) or other childhood vaccinations, or during specified time periods after vaccination.Limitation: No individual medical charts were reviewed.Conclusion: The study strongly supports that MMR vaccination does not increase the risk for autism, does not trigger autism in susceptible children, and is not associated with clustering of autism cases after vaccination. It adds to previous studies through significant additional statistical power and by addressing hypotheses of susceptible subgroups and clustering of cases.Primary Funding Source: Novo Nordisk Foundation and Danish Ministry of Health.

    View details for PubMedID 30831578

  • Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors. Nature genetics Warrington, N. M., Beaumont, R. N., Horikoshi, M., Day, F. R., Helgeland, Ø., Laurin, C., Bacelis, J., Peng, S., Hao, K., Feenstra, B., Wood, A. R., Mahajan, A., Tyrrell, J., Robertson, N. R., Rayner, N. W., Qiao, Z., Moen, G. H., Vaudel, M., Marsit, C. J., Chen, J., Nodzenski, M., Schnurr, T. M., Zafarmand, M. H., Bradfield, J. P., Grarup, N., Kooijman, M. N., Li-Gao, R., Geller, F., Ahluwalia, T. S., Paternoster, L., Rueedi, R., Huikari, V., Hottenga, J. J., Lyytikäinen, L. P., Cavadino, A., Metrustry, S., Cousminer, D. L., Wu, Y., Thiering, E., Wang, C. A., Have, C. T., Vilor-Tejedor, N., Joshi, P. K., Painter, J. N., Ntalla, I., Myhre, R., Pitkänen, N., van Leeuwen, E. M., Joro, R., Lagou, V., Richmond, R. C., Espinosa, A., Barton, S. J., Inskip, H. M., Holloway, J. W., Santa-Marina, L., Estivill, X., Ang, W., Marsh, J. A., Reichetzeder, C., Marullo, L., Hocher, B., Lunetta, K. L., Murabito, J. M., Relton, C. L., Kogevinas, M., Chatzi, L., Allard, C., Bouchard, L., Hivert, M. F., Zhang, G., Muglia, L. J., Heikkinen, J., Morgen, C. S., van Kampen, A. H., van Schaik, B. D., Mentch, F. D., Langenberg, C., Luan, J., Scott, R. A., Zhao, J. H., Hemani, G., Ring, S. M., Bennett, A. J., Gaulton, K. J., Fernandez-Tajes, J., van Zuydam, N. R., Medina-Gomez, C., de Haan, H. G., Rosendaal, F. R., Kutalik, Z., Marques-Vidal, P., Das, S., Willemsen, G., Mbarek, H., Müller-Nurasyid, M., Standl, M., Appel, E. V., Fonvig, C. E., Trier, C., van Beijsterveldt, C. E., Murcia, M., Bustamante, M., Bonas-Guarch, S., Hougaard, D. M., Mercader, J. M., Linneberg, A., Schraut, K. E., Lind, P. A., Medland, S. E., Shields, B. M., Knight, B. A., Chai, J. F., Panoutsopoulou, K., Bartels, M., Sánchez, F., Stokholm, J., Torrents, D., Vinding, R. K., Willems, S. M., Atalay, M., Chawes, B. L., Kovacs, P., Prokopenko, I., Tuke, M. A., Yaghootkar, H., Ruth, K. S., Jones, S. E., Loh, P. R., Murray, A., Weedon, M. N., Tönjes, A., Stumvoll, M., Michaelsen, K. F., Eloranta, A. M., Lakka, T. A., van Duijn, C. M., Kiess, W., Körner, A., Niinikoski, H., Pahkala, K., Raitakari, O. T., Jacobsson, B., Zeggini, E., Dedoussis, G. V., Teo, Y. Y., Saw, S. M., Montgomery, G. W., Campbell, H., Wilson, J. F., Vrijkotte, T. G., Vrijheid, M., de Geus, E. J., Hayes, M. G., Kadarmideen, H. N., Holm, J. C., Beilin, L. J., Pennell, C. E., Heinrich, J., Adair, L. S., Borja, J. B., Mohlke, K. L., Eriksson, J. G., Widén, E. E., Hattersley, A. T., Spector, T. D., Kähönen, M., Viikari, J. S., Lehtimäki, T., Boomsma, D. I., Sebert, S., Vollenweider, P., Sørensen, T. I., Bisgaard, H., Bønnelykke, K., Murray, J. C., Melbye, M., Nohr, E. A., Mook-Kanamori, D. O., Rivadeneira, F., Hofman, A., Felix, J. F., Jaddoe, V. W., Hansen, T., Pisinger, C., Vaag, A. A., Pedersen, O., Uitterlinden, A. G., Järvelin, M. R., Power, C., Hyppönen, E., Scholtens, D. M., Lowe, W. L., Davey Smith, G., Timpson, N. J., Morris, A. P., Wareham, N. J., Hakonarson, H., Grant, S. F., Frayling, T. M., Lawlor, D. A., Njølstad, P. R., Johansson, S., Ong, K. K., McCarthy, M. I., Perry, J. R., Evans, D. M., Freathy, R. M. 2019; 51 (5): 804–14

    Abstract

    Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.

    View details for PubMedID 31043758

  • Increased Risk of Ischemic Stroke After Treatment of Infective Endocarditis: A Danish, Nationwide, Propensity Score-Matched Cohort Study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Klein, C. F., Gørtz, S., Wohlfahrt, J., Nørgaard Munch, T., Melbye, M., Bundgaard, H., Iversen, K. K. 2019

    Abstract

    Several studies have reported a high risk of ischemic stroke (IS) during the acute phase of infective endocarditis (IE). The long-term risk of IS after IE, however, is not fully illuminated.This Danish, nationwide, register-based, propensity score-matched cohort study used Cox regression to estimate hazard ratios (HRs) of IS for persons with vs without a history of left-sided IE, from 1977 to 2015.We followed 9312 patients exposed to a first-time IE and 91 996 nonexposed, matched control persons. Compared to persons without IE, patients with a history of IE had a significantly increased risk of IS; the risk was highest during the first 4 weeks after IE diagnosis (HR 57.20, 95% confidence interval [CI] 45.58-71.78; P < .0001) and a moderately elevated risk persisted until 2 years after IE (4 weeks to 3 months after IE, HR 5.40, 95% CI 4.11-7.19; 3 months to 2 years after IE, HR 1.73, 95% CI 1.48-2.01). Mediation analyses showed that the higher risk of IS the first 2 years after IE could not be explained by atrial fibrillation (AF) or inserted mechanical valves in IE patients. In the period from 4 weeks to 3 months after IE diagnosis, patients treated with anticoagulative therapy had a lower risk of IS (HR 0.30, 95% CI .10-0.96; P = .04).Patients with a history of IE had an increased risk of IS for up to 2 years after IE diagnosis. The increased risk was unrelated to AF and inserted mechanical valves. During the initial phase after IE, patients taking an anticoagulative medication had a lower risk of IS.

    View details for DOI 10.1093/cid/ciz320

    View details for PubMedID 31198927

  • Multiple sclerosis among first- and second-generation immigrants in Denmark: a population-based cohort study. Brain : a journal of neurology Munk Nielsen, N., Corn, G., Frisch, M., Stenager, E., Koch-Henriksen, N., Wohlfahrt, J., Magyari, M., Melbye, M. 2019

    Abstract

    Multiple sclerosis is a disease with a highly variable incidence worldwide. While knowledge about multiple sclerosis risk factors has grown over the years, the aetiology of multiple sclerosis has still not been fully established. We examined multiple sclerosis incidence rates among first-generation immigrants in Denmark, a high-incidence country, and their Danish-born children (second-generation immigrants), to evaluate the importance and timing of exposure to environmental factors in the aetiology of multiple sclerosis. By means of the Danish Civil Registration System we identified 9 121 187 individuals living in Denmark between 1968 and 2015, including 1 176 419 first-generation and 184 282 second-generation immigrants. Study participants were followed for multiple sclerosis in the Danish Multiple Sclerosis Registry from 1968 to 2015. The relative risk (RR) of multiple sclerosis according to immigration status was estimated by means of multiple sclerosis incidence rate ratios obtained in log-linear Poisson regression analysis. Altogether, 16 905 cases of multiple sclerosis were identified in the study cohort, 578 among first-generation and 106 among second-generation immigrants. Multiple sclerosis risk among first-generation immigrants whose parents were born in low, intermediate and high multiple sclerosis risk areas were 21% (RR = 0.21; 95% CI: 0.16-0.28), 43% (RR = 0.43; 95% CI: 0.36-0.50) and 75% (RR = 0.75; 95% CI: 0.67-0.83), respectively, of that among ethnic Danes (test for trend P < 0.0001). First-generation immigrants arriving in Denmark before age 15 years had a multiple sclerosis risk higher than that in their country of birth but lower than that in Denmark, reaching on average 69% of the multiple sclerosis risk among ethnic Danes (RR = 0.69; 95% CI: 0.55-0.87). Multiple sclerosis risk among individuals who came to Denmark at a later age remained closer to that of their country of birth, corresponding to 45% of the multiple sclerosis risk among ethnic Danes (RR = 0.45; 95% CI: 0.41-0.49). Our study supports the idea that environmental factors exerting their role in childhood or adolescence may be of aetiological relevance in multiple sclerosis.

    View details for PubMedID 31081503

  • Use of tumour necrosis factor-α inhibitors and the risk of serious infection in paediatric inflammatory bowel disease in Denmark: a nationwide cohort study. The lancet. Gastroenterology & hepatology Wintzell, V., Svanström, H., Melbye, M., Jess, T., Olén, O., Ludvigsson, J. F., Pasternak, B. 2019

    Abstract

    Studies have shown an association between use of tumour necrosis factor-α (TNFα) inhibitors and increased risk of serious infection in adult inflammatory bowel disease (IBD). However, data on this topic for paediatric patients are scarce and inconclusive. The aim of this study was to investigate whether there is an association between the use of TNFα inhibitors and the risk of serious infection in children with IBD.In this nationwide Danish cohort study, we searched health registers (from Jan 1, 2007, to Dec 31, 2016) to identify episodes of children and adolescents (<18 years) with at least two recorded IBD diagnoses in specialist care. We categorised follow-up time in mutually exclusive episodes of incident TNFα inhibitor use or no TNFα inhibitor use from specialist care records. We used Cox proportional hazards models to estimate hazard ratios (HRs), adjusting using propensity score weighting for demographic characteristics, comorbidities, treatment history, health-care use, and indicators of disease severity. The primary outcome, incident serious infection, was defined as infection requiring a stay in hospital and was identified through hospital records.Among 2817 paediatric patients with IBD, we identified 618 episodes of incident TNFα inhibitor use and 2925 episodes of no TNFα inhibitor use. In the cohort of exposed and not exposed episodes that was propensity-score weighted, 53·9% were of male sex, the mean age was 15·1 (SD 1·7) years, 69·9% had Crohn's disease, and 30·1% had ulcerative colitis or IBD-unclassified; median follow-up was 1·4 years (IQR 0·4-3·0). The weighted incidence of serious infection was 54·6 events per 1000 patient-years for the TNFα inhibitor episodes and 61·9 events per 1000 patient-years for the no-use episodes. The weighted HR of serious infection associated with TNFα inhibitor use was 0·81 (95% CI 0·54-1·21).There was no significant association between use of TNFα inhibitors and the risk of serious infection in children with IBD, and, based on the upper bound of the confidence interval, a relatively small risk increase seems unlikely, contrary to previous findings in adults. Observational data such as these can support paediatric clinical practice.Swedish Research Council, Frimurare Barnhuset Foundation, and the Åke Wiberg Foundation.

    View details for DOI 10.1016/S2468-1253(19)30266-3

    View details for PubMedID 31494100

  • Use of liraglutide and risk of major cardiovascular events: a register-based cohort study in Denmark and Sweden. The lancet. Diabetes & endocrinology Svanstrom, H., Ueda, P., Melbye, M., Eliasson, B., Svensson, A., Franzen, S., Gudbjornsdottir, S., Hveem, K., Jonasson, C., Pasternak, B. 2018

    Abstract

    BACKGROUND: Trial evidence shows that the glucagon-like peptide-1 receptor agonist liraglutide significantly reduces the risk of major cardiovascular events among patients with type 2 diabetes who have established cardiovascular disease or are at high cardiovascular risk. We aimed to assess the cardiovascular effectiveness of liraglutide in routine clinical practice.METHODS: We used data from nationwide registers in Denmark and Sweden for the period from Jan 1, 2010, to Dec 31, 2016, to investigate the risk of major cardiovascular events associated with use of liraglutide, compared with an active comparator drug class, dipeptidyl peptidase-4 (DPP-4) inhibitors, in patients with type 2 diabetes. The cohort included incident users of liraglutide or DPP-4 inhibitors, who were also using metformin at baseline, matched 1:1 on age, sex, and propensity score. The main outcome was major cardiovascular events, a composite outcome consisting of myocardial infarction, stroke, and cardiovascular death. Other outcomes assessed were the individual components of the main composite outcome, heart failure, death from any cause, and an expanded composite major cardiovascular events outcome that also included other ischaemic heart disease, coronary revascularisation, and peripheral arterial disease.FINDINGS: The study population consisted of 23 402 users of liraglutide and 23 402 matched users of DPP-4 inhibitors; patients were followed up for a mean of 3·3 years (SD 2·0). A major cardiovascular event occurred in 1132 users of liraglutide (incidence rate 14·0 per 1000 person-years) and in 1141 users of DPP-4 inhibitors (15·4 per 1000 person-years; hazard ratio [HR] 0·90, 95% CI 0·83-0·98). The HRs were 0·81 (0·71-0·92) for patients with a history of major cardiovascular disease and 0·96 (0·86-1·06) for patients without such a history (p=0·057 [test of homogeneity], suggesting no statistical evidence of heterogeneity). Compared with use of DPP-4 inhibitors, use of liraglutide was associated with a significantly lower risk of cardiovascular death (HR 0·78, 95% CI 0·68-0·91), but no significant differences were identified for risk of myocardial infarction (0·94, 0·84-1·06) or stroke (0·88, 0·77-1·01). Furthermore, use of liraglutide was associated with a significantly lower risk of death from any cause (HR 0·83, 95% CI 0·77-0·90), but no significant differences were identified for risk of heart failure (0·90, 0·80-1·03) or for the expanded major cardiovascular events outcome (0·95, 0·89-1·01).INTERPRETATION: In this large Scandinavian cohort, use of liraglutide, as compared with use of DPP-4 inhibitors, was associated with significantly reduced risk of major cardiovascular events. Patients with history of cardiovascular disease seemed to derive the largest benefit from treatment with liraglutide. These data provide support for the cardiovascular effectiveness of liraglutide in routine clinical practice.FUNDING: Swedish Heart-Lung Foundation, Novo Nordisk Foundation, and Swedish Society for Medical Research.

    View details for PubMedID 30527909

  • Increased risk of inflammatory bowel disease in families with tonsillectomy: A Danish national cohort study. Epidemiology (Cambridge, Mass.) Bager, P., Gortz, S., Feenstra, B., Nyboe Andersen, N., Jess, T., Frisch, M., Melbye, M. 2018

    Abstract

    BACKGROUND: The possible etiologic link between tonsillectomy and inflammatory bowel diseases remains unclear. To investigate the hereditary component, we assessed the risk of inflammatory bowel disease after own tonsillectomy as well as after tonsillectomy among family members.METHODS: A nationwide Danish cohort of 7,045,288 individuals was established and linked to comprehensive national registers with data on kinship, tonsillectomy surgery, and diagnosis of inflammatory bowel disease from all health sectors. We used Poisson regression models to estimate hospital contact rate ratios (RR) for Crohn's disease and ulcerative colitis, with 95% confidence intervals (CI), between individuals with or without tonsillectomy, as well as between individuals with or without tonsillectomized relatives.RESULTS: During 189 million person-years of follow-up between 1977 and 2014, 276,673 individuals were tonsillectomized, 22,015 developed Crohn's disease, and 49,550 developed ulcerative colitis. Rates of inflammatory bowel disease were elevated up to 20 years after own tonsillectomy (Crohn's disease: RR 1.52 (95% CI, 1.43-1.61); ulcerative colitis: RR 1.24 (95% CI, 1.18-1.29)). RRs for Crohn's disease was 1.22 (95% CI, 1.17-1.27) after 1 degree relatives' tonsillectomy, 1.14 (95% CI, 1.08-1.19) after 2 degree relatives' tonsillectomy, and 1.08 (95% CI, 1.01-1.15 after 3 degree relatives' tonsillectomy. Corresponding RRs for ulcerative colitis were 1.10 (95% CI, 1.07-1.13), 1.05 (95% CI, 1.01-1.08), and 1.03 (95% CI, 0.98-1.09).CONCLUSIONS: Even individuals with tonsillectomized family members were at increased risk of inflammatory bowel disease. These findings call into question a direct influence of tonsillectomy on gastrointestinal inflammation and point instead towards shared hereditary or environmental factors.

    View details for DOI 10.1097/EDE.0000000000000946

    View details for PubMedID 30461527

  • Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ (Clinical research ed.) Ueda, P., Svanstrom, H., Melbye, M., Eliasson, B., Svensson, A., Franzen, S., Gudbjornsdottir, S., Hveem, K., Jonasson, C., Pasternak, B. 2018; 363: k4365

    Abstract

    OBJECTIVE: To assess the association between the use of sodium glucose cotransporter 2 (SGLT2) inhibitors and seven serious adverse events of current concern.DESIGN: Register based cohort study.SETTING: Sweden and Denmark from July 2013 to December 2016.PARTICIPANTS: A propensity score matched cohort of 17213 new users of SGLT2 inhibitors (dapagliflozin, 61%; empagliflozin, 38%; canagliflozin, 1%) and 17213 new users of the active comparator, glucagon-like peptide 1 (GLP1) receptor agonists.MAIN OUTCOME MEASURES: The primary outcomes were lower limb amputation, bone fracture, diabetic ketoacidosis, acute kidney injury, serious urinary tract infection, venous thromboembolism, and acute pancreatitis, as identified from hospital records. Hazard ratios and 95% confidence intervals were estimated by using Cox proportional hazards models.RESULTS: Use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation (incidence rate 2.7 v 1.1 events per 1000 person years, hazard ratio 2.32, 95% confidence interval 1.37 to 3.91) and diabetic ketoacidosis (1.3 v 0.6, 2.14, 1.01 to 4.52) but not with bone fracture (15.4 v 13.9, 1.11, 0.93 to 1.33), acute kidney injury (2.3 v 3.2, 0.69, 0.45 to 1.05), serious urinary tract infection (5.4 v 6.0, 0.89, 0.67 to 1.19), venous thromboembolism (4.2 v 4.1, 0.99, 0.71 to 1.38) or acute pancreatitis (1.3 v 1.2, 1.16, 0.64 to 2.12).CONCLUSIONS: In this analysis of nationwide registers from two countries, use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation and diabetic ketoacidosis, but not with other serious adverse events of current concern.

    View details for PubMedID 30429124

  • Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. American journal of human genetics Ligthart, S., Vaez, A., Vosa, U., Stathopoulou, M. G., de Vries, P. S., Prins, B. P., Van der Most, P. J., Tanaka, T., Naderi, E., Rose, L. M., Wu, Y., Karlsson, R., Barbalic, M., Lin, H., Pool, R., Zhu, G., Mace, A., Sidore, C., Trompet, S., Mangino, M., Sabater-Lleal, M., Kemp, J. P., Abbasi, A., Kacprowski, T., Verweij, N., Smith, A. V., Huang, T., Marzi, C., Feitosa, M. F., Lohman, K. K., Kleber, M. E., Milaneschi, Y., Mueller, C., Huq, M., Vlachopoulou, E., Lyytikainen, L., Oldmeadow, C., Deelen, J., Perola, M., Zhao, J. H., Feenstra, B., LifeLines Cohort Study, Amini, M., CHARGE Inflammation Working Group, Lahti, J., Schraut, K. E., Fornage, M., Suktitipat, B., Chen, W., Li, X., Nutile, T., Malerba, G., Luan, J., Bak, T., Schork, N., Del Greco M, F., Thiering, E., Mahajan, A., Marioni, R. E., Mihailov, E., Eriksson, J., Ozel, A. B., Zhang, W., Nethander, M., Cheng, Y., Aslibekyan, S., Ang, W., Gandin, I., Yengo, L., Portas, L., Kooperberg, C., Hofer, E., Rajan, K. B., Schurmann, C., den Hollander, W., Ahluwalia, T. S., Zhao, J., Draisma, H. H., Ford, I., Timpson, N., Teumer, A., Huang, H., Wahl, S., Liu, Y., Huang, J., Uh, H., Geller, F., Joshi, P. K., Yanek, L. R., Trabetti, E., Lehne, B., Vozzi, D., Verbanck, M., Biino, G., Saba, Y., Meulenbelt, I., O'Connell, J. R., Laakso, M., Giulianini, F., Magnusson, P. K., Ballantyne, C. M., Hottenga, J. J., Montgomery, G. W., Rivadineira, F., Rueedi, R., Steri, M., Herzig, K., Stott, D. J., Menni, C., Franberg, M., St Pourcain, B., Felix, S. B., Pers, T. H., Bakker, S. J., Kraft, P., Peters, A., Vaidya, D., Delgado, G., Smit, J. H., GroSSmann, V., Sinisalo, J., Seppala, I., Williams, S. R., Holliday, E. G., Moed, M., Langenberg, C., Raikkonen, K., Ding, J., Campbell, H., Sale, M. M., Chen, Y. I., James, A. L., Ruggiero, D., Soranzo, N., Hartman, C. A., Smith, E. N., Berenson, G. S., Fuchsberger, C., Hernandez, D., Tiesler, C. M., Giedraitis, V., Liewald, D., Fischer, K., Mellstrom, D., Larsson, A., Wang, Y., Scott, W. R., Lorentzon, M., Beilby, J., Ryan, K. A., Pennell, C. E., Vuckovic, D., Balkau, B., Concas, M. P., Schmidt, R., Mendes de Leon, C. F., Bottinger, E. P., Kloppenburg, M., Paternoster, L., Boehnke, M., Musk, A. W., Willemsen, G., Evans, D. M., Madden, P. A., Kahonen, M., Kutalik, Z., Zoledziewska, M., Karhunen, V., Kritchevsky, S. B., Sattar, N., Lachance, G., Clarke, R., Harris, T. B., Raitakari, O. T., Attia, J. R., van Heemst, D., Kajantie, E., Sorice, R., Gambaro, G., Scott, R. A., Hicks, A. A., Ferrucci, L., Standl, M., Lindgren, C. M., Starr, J. M., Karlsson, M., Lind, L., Li, J. Z., Chambers, J. C., Mori, T. A., de Geus, E. J., Heath, A. C., Martin, N. G., Auvinen, J., Buckley, B. M., de Craen, A. J., Waldenberger, M., Strauch, K., Meitinger, T., Scott, R. J., McEvoy, M., Beekman, M., Bombieri, C., Ridker, P. M., Mohlke, K. L., Pedersen, N. L., Morrison, A. C., Boomsma, D. I., Whitfield, J. B., Strachan, D. P., Hofman, A., Vollenweider, P., Cucca, F., Jarvelin, M., Jukema, J. W., Spector, T. D., Hamsten, A., Zeller, T., Uitterlinden, A. G., Nauck, M., Gudnason, V., Qi, L., Grallert, H., Borecki, I. B., Rotter, J. I., Marz, W., Wild, P. S., Lokki, M., Boyle, M., Salomaa, V., Melbye, M., Eriksson, J. G., Wilson, J. F., Penninx, B. W., Becker, D. M., Worrall, B. B., Gibson, G., Krauss, R. M., Ciullo, M., Zaza, G., Wareham, N. J., Oldehinkel, A. J., Palmer, L. J., Murray, S. S., Pramstaller, P. P., Bandinelli, S., Heinrich, J., Ingelsson, E., Deary, I. J., Magi, R., Vandenput, L., van der Harst, P., Desch, K. C., Kooner, J. S., Ohlsson, C., Hayward, C., Lehtimaki, T., Shuldiner, A. R., Arnett, D. K., Beilin, L. J., Robino, A., Froguel, P., Pirastu, M., Jess, T., Koenig, W., Loos, R. J., Evans, D. A., Schmidt, H., Smith, G. D., Slagboom, P. E., Eiriksdottir, G., Morris, A. P., Psaty, B. M., Tracy, R. P., Nolte, I. M., Boerwinkle, E., Visvikis-Siest, S., Reiner, A. P., Gross, M., Bis, J. C., Franke, L., Franco, O. H., Benjamin, E. J., Chasman, D. I., Dupuis, J., Snieder, H., Dehghan, A., Alizadeh, B. Z., Alizadeh, B. Z., Boezen, H. M., Franke, L., van der Harst, P., Navis, G., Rots, M., Snieder, H., Swertz, M., Wolffenbuttel, B. H., Wijmenga, C., Benjamin, E., Chasman, D. I., Dehghan, A., Ahluwalia, T. S., Meigs, J., Tracy, R., Alizadeh, B. Z., Ligthart, S., Bis, J., Eiriksdottir, G., Pankratz, N., Gross, M., Rainer, A., Snieder, H., Wilson, J. G., Psaty, B. M., Dupuis, J., Prins, B., Vaso, U., Stathopoulou, M., Franke, L., Lehtimaki, T., Koenig, W., Jamshidi, Y., Siest, S., Abbasi, A., Uitterlinden, A. G., Abdollahi, M., Schnabel, R., Schick, U. M., Nolte, I. M., Kraja, A., Hsu, Y., Tylee, D. S., Zwicker, A., Uher, R., Davey-Smith, G., Morrison, A. C., Hicks, A., van Duijn, C. M., Ward-Caviness, C., Boerwinkle, E., Rotter, J., Rice, K., Lange, L., Perola, M., de Geus, E., Morris, A. P., Makela, K. M., Stacey, D., Eriksson, J., Frayling, T. M., Slagboom, E. P. 2018; 103 (5): 691–706

    Abstract

    C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5* 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

    View details for PubMedID 30388399

  • Pregnancy duration and breast cancer risk. Nature communications Husby, A., Wohlfahrt, J., Oyen, N., Melbye, M. 2018; 9 (1): 4255

    Abstract

    Full-term pregnancies reduce a woman's long-term breast cancer risk, while abortions have been shown to have no effect. The precise minimal duration of pregnancy necessary to lower a woman's breast cancer risk is, however, unknown. Here we provide evidence which point to the protective effect of pregnancy on breast cancer risk arising precisely at the 34th pregnancy week. Using a cohort of 2.3 million Danish women, we found the reduction in breast cancer risk was not observed for pregnancies lasting 33 weeks or less, but restricted to those pregnancies lasting 34 weeks or longer. We further found that parity, socioeconomic status, and vital status of the child at birth did not explain the association, and also replicated our finding in data from 1.6 million women in Norway. We suggest that a distinct biological effect introduced around week 34 of pregnancy holds the key to understand pregnancy-associated breast cancer protection.

    View details for PubMedID 30353005

  • Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation. Nature communications Ahlberg, G., Refsgaard, L., Lundegaard, P. R., Andreasen, L., Ranthe, M. F., Linscheid, N., Nielsen, J. B., Melbye, M., Haunso, S., Sajadieh, A., Camp, L., Olesen, S., Rasmussen, S., Lundby, A., Ellinor, P. T., Holst, A. G., Svendsen, J. H., Olesen, M. S. 2018; 9 (1): 4316

    Abstract

    A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients (P=1.76*10-6). This finding is replicated in an independent cohort of early-onset lone AF patients (n=399; odds ratio=36.8; P=4.13*10-6). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF.

    View details for PubMedID 30333491

  • Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenstrom macroglobulinemia NATURE COMMUNICATIONS McMaster, M. L., Berndt, S., Zhang, J., Slager, S. L., Li, S., Vajdic, C. M., Smedby, K. E., Yan, H., Birmann, B. M., Brown, E. E., Smith, A., Kleinstern, G., Fansler, M. M., Mayr, C., Zhu, B., Chung, C. C., Park, J., Burdette, L., Hicks, B. D., Hutchinson, A., Teras, L. R., Adami, H., Bracci, P. M., McKay, J., Monnereau, A., Link, B. K., Vermeulen, R. H., Ansell, S. M., Maria, A., Diver, W., Melbye, M., Ojesina, A., Kraft, P., Boffetta, P., Clavel, J., Giovannucci, E., Besson, C. M., Canzia, F., Travis, R. C., Vineis, P., Weiderpass, E., Montalvan, R., Wang, Z., Yeager, M., Becker, N., Benavente, Y., Brennan, P., Foretova, L., Maynadie, M., Nieters, A., de Sanjose, S., Staines, A., Conde, L., Riby, J., Glimelius, B., Hjalgrim, H., Pradhan, N., Feldman, A. L., Novak, A. J., Lawrence, C., Bassig, B. A., Lan, Q., Zheng, T., North, K. E., Tinker, L. F., Cozen, W., Severson, R. K., Hofmann, J. N., Zhang, Y., Jackson, R. D., Morton, L. M., Purdue, M. P., Chatterjee, N., Offit, K., Cerhan, J. R., Chanock, S. J., Rothman, N., Vijai, J., Goldin, L. R., Skibola, C. F., Caporaso, N. E. 2018; 9: 4182

    Abstract

    Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40-31.03, P = 1.36 × 10-54) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45-6.96, P = 8.75 × 10-19). Both risk alleles are observed at a low frequency among controls (~2-3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy.

    View details for PubMedID 30305637

  • Genome-wide meta-analysis identifies BARX1 and EML4-MTA3 as new loci associated with infantile hypertrophic pyloric stenosis. Human molecular genetics Fadista, J., Skotte, L., Geller, F., Bybjerg-Grauholm, J., Gortz, S., Romitti, P. A., Caggana, M., Kay, D. M., Matsson, H., Boyd, H. A., Hougaard, D. M., Nordenskjold, A., Mills, J. L., Melbye, M., Feenstra, B. 2018

    Abstract

    Infantile hypertrophic pyloric stenosis (IHPS) is a disorder of young infants with a population incidence of ~2/1000 live births, caused by hypertrophy of the pyloric sphincter smooth muscle. Reported genetic loci associated with IHPS explain only a minor proportion of IHPS risk. To identify new risk loci, we carried out a genome-wide meta-analysis on 1395 surgery-confirmed cases and 4438 controls, with replication in a set of 2427 cases and 2524 controls. We identified and replicated six independent genomic loci associated with IHPS risk at genome wide significance (P<5x10-8), including novel associations with two SNPs. One of these SNPs, rs6736913 (odds ratio [OR] = 2.32; P = 3.0x10-15), is a low frequency missense variant in EML4 at 2p21. The second SNP, rs1933683 (OR = 1.34; P = 3.1*10-9) is 1 kb downstream of BARX1 at 9q22.32, an essential gene for stomach formation in embryogenesis. Using the genome-wide complex trait analysis (GCTA) method, we estimated the IHPS SNP heritability to be 30%, and using the LD score regression method, we found support for a previously reported genetic correlation of IHPS with lipid metabolism. By combining the largest collection of IHPS cases to date (3822 cases), with results generalized across populations of different ancestry, we elucidate novel mechanistic avenues of IHPS disease architecture.

    View details for PubMedID 30281099

  • Multiple sclerosis among first- and second-generation immigrants in Denmark. A population-based cohort study Nielsen, N. M., Corn, G., Frisch, M., Stenager, E., Koch-Henriksen, N., Wohlfahrt, J., Magyari, M., Melbye, M. SAGE PUBLICATIONS LTD. 2018: 64–65
  • Consortium-based genome-wide meta-analysis for childhood dental caries traits HUMAN MOLECULAR GENETICS Haworth, S., Shungin, D., van der Tas, J. T., Vucic, S., Medina-Gomez, C., Yakimov, V., Feenstra, B., Shaffer, J. R., Lee, M., Standl, M., Thiering, E., Wang, C., Bonnelykke, K., Waage, J., Jessen, L., Norrisgaard, P., Joro, R., Seppala, I., Raitakari, O., Dudding, T., Grgic, O., Ongkosuwito, E., Vierola, A., Eloranta, A., West, N. X., Thomas, S. J., McNeil, D. W., Levy, S. M., Slayton, R., Nohr, E. A., Lehtimaki, T., Lakka, T., Bisgaard, H., Pennell, C., Kuehnisch, J., Marazita, M. L., Melbye, M., Geller, F., Rivadeneira, F., Wolvius, E. B., Franks, P. W., Johansson, I., Timpson, N. J. 2018; 27 (17): 3113–27

    Abstract

    Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from nine contributing centres. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage and the results were combined using fixed-effects meta-analysis. Analysis included up to 19 003 individuals (7530 affected) for primary teeth and 13 353 individuals (5875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth [intronic within ALLC, odds ratio (OR) 0.85, effect allele frequency (EAF) 0.60, P 4.13e-8] and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, P 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low [h2 of 1% (95% CI: 0%: 7%) and 6% (95% CI 0%: 13%) for primary and permanent dentitions, respectively] compared with corresponding within-study estimates [h2 of 28% (95% CI: 9%: 48%) and 17% (95% CI: 2%: 31%)] or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.

    View details for PubMedID 29931343

  • Use of proton pump inhibitors and risk of acute kidney injury among patients with rheumatoid arthritis Svanstrom, H., Lund, M., Melbye, M., Pasternak, B. WILEY. 2018: 453
  • Titin-truncating variants associates with atrial fibrillation, compromises assembly of the sarcomere Olesen, M. S., Lundegaard, P., Ahlberg, G., Refsgaard, L., Andreasen, L., Ranthe, M., Linscheid, N., Nielsen, J. B., Melbye, M., Haunsoe, S., Sajadieh, A., Olesen, S. P., Ellinor, P. T., Holst, A. G., Svendsen, J. H. OXFORD UNIV PRESS. 2018: 16
  • Association between azathioprine use and risk of acute pancreatitis in pediatric inflammatory bowel disease: A nationwide Swedish cohort study Wintzell, V., Svanstrom, H., Olen, O., Melbye, M., Ludvigsson, J. F., Pasternak, B. WILEY. 2018: 196
  • Concomitant use of statins and macrolide antibiotics and risk of serious renal events: A nationwide cohort study. International journal of cardiology Lund, M., Svanstrom, H., Pasternak, B., Hviid, A., Melbye, M. 2018

    Abstract

    BACKGROUND: Concomitant use of statins metabolized by the cytochrome P450 isoenzyme 3A4 (CYP3A4) and CYP3A4-inhibiting macrolide antibiotics may confer an increased risk of renal failure. We investigated the risk of serious renal events associated with concomitant use of such statins and such macrolides.METHODS: In a nationwide register-based cohort study (Denmark, 1999-2017), we identified 906,423 new users (40-79 years old), of CYP3A4-metabolized statins. In propensity score-matched analyses, we compared the risk of serious renal events during episodes of concomitant use of statins and CYP3A4-inhibiting macrolides (n = 71,521) with episodes of use of statins alone (n = 285,488) and, as the primary analysis, with episodes of concomitant use of statins and an active comparator (penicillin V, n = 139,446). Using proportional hazards regression, we estimated hazard ratios (HRs) for serious renal events within 30 days of start of follow-up.RESULTS: We observed 25 serious renal events during concomitant use of statins and macrolides (incidence rate [IR], 4.9 per 1000 person-years). Compared with use of statins alone (50 events; IR, 2.3), concomitant use of statins and macrolides was associated with a significantly increased risk of serious renal events (HR 2.16, 95% confidence interval [CI] 1.33, 3.49). Compared with concomitant use of statins and penicillin V (52 events; IR, 5.3), however, we observed no increased risk (HR 0.93, 95% CI 0.58, 1.49).CONCLUSIONS: In this nationwide cohort study concomitant use of statins and macrolides was not associated with a significantly increased risk of serious renal events.

    View details for PubMedID 30072148

  • HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes CANCER RESEARCH Wang, S. S., Carrington, M., Berndt, S. I., Slager, S. L., Bracci, P. M., Voutsinas, J., Cerhan, J. R., Smedby, K. E., Hjalgrim, H., Vijai, J., Morton, L. M., Vermeulen, R., Paltiel, O., Vajdic, C. M., Linet, M. S., Nieters, A., de Sanjose, S., Cozen, W., Brown, E. E., Turner, J., Spinelli, J. J., Zheng, T., Birmann, B. M., Flowers, C. R., Becker, N., Holly, E. A., Kane, E., Weisenburger, D., Maynadie, M., Cocco, P., Albanes, D., Weinstein, S. J., Teras, L. R., Diver, W., Lax, S. J., Travis, R. C., Kaaks, R., Riboli, E., Benavente, Y., Brennan, P., McKay, J., Delfau-Larue, M., Link, B. K., Magnani, C., Ennas, M., Latte, G., Feldman, A. L., Doo, N., Giles, G. G., Southey, M. C., Milne, R. L., Offit, K., Musinsky, J., Arslan, A. A., Purdue, M. P., Adami, H., Melbye, M., Glimelius, B., Conde, L., Camp, N. J., Glenn, M., Curtin, K., Clavel, J., Monnereau, A., Cox, D. G., Ghesquieres, H., Salles, G., Bofetta, P., Foretova, L., Staines, A., Davis, S., Severson, R. K., Lan, Q., Brooks-Wilson, A., Smith, M. T., Roman, E., Kricker, A., Zhang, Y., Kraft, P., Chanock, S. J., Rothman, N., Hartge, P., Skibola, C. F. 2018; 78 (14): 4086–96

    Abstract

    A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06-1.60; OR MZL = 1.45, 95% CI = 1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24-3.55; OR MZL = 2.10, 95% CI = 0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086-96. ©2018 AACR.

    View details for PubMedID 29735552

    View details for PubMedCentralID PMC6065509

  • Inherited variants at 3q13.33 and 3p24.1 influences risk of diffuse large B-cell lymphoma Kleinstern, G., Hildebrand, M., Joseph, V., Berndt, S. I., Ghesquieres, H., McKay, J., Wang, S. S., Nieters, A., Cox, D., Monnereau, A., Brooks-Wilson, A. R., Lan, Q., Melbye, M., Jackson, R. D., Teras, L. R., Purdue, M. P., Vajdic, C. M., Albanes, D., Zeleniuch-Jacquotte, A., Crouch, S., Zhang, Y., Slager, S. L., Wu, X., Smedby, K. E., Salles, G., Skibola, C. F., Rothman, N., Chanock, S. J., Cerhan, J. R. AMER ASSOC CANCER RESEARCH. 2018
  • Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation. International journal of cardiology Andersson, N. W., Svanstrom, H., Lund, M., Pasternak, B., Melbye, M. 2018

    Abstract

    BACKGROUND: The comparative effectiveness and safety of individual direct oral anticoagulants (DOACs) in clinical practice is largely unknown. The study objectives were to compare effectiveness and safety of DOACs in patients with non-valvular atrial fibrillation (NVAF).METHODS: Based on nationwide registers we established a population-based historical cohort study of 12,638 new users of standard dose DOACs (apixaban 5 mg twice daily, dabigatran 150 mg twice daily and rivaroxaban 20 mg once daily) with NVAF in Denmark, July 2013 to March 2016. Patients were matched on propensity scores in a 1:1 ratio comparing apixaban vs. dabigatran (for a total of 6470 patients), apixaban vs. rivaroxaban (7352 patients), and rivaroxaban vs. dabigatran (5440 patients). Hazard ratios (HRs) for stroke or systemic embolism (effectiveness outcome) and major bleeding (safety outcome) were estimated.RESULTS: In propensity-matched comparisons of the risk of stroke or systemic embolism, the HRs were 1.27 (95% confidence interval [CI], 0.82-1.96) for apixaban vs. dabigatran, 1.25 (95% CI, 0.87-1.79) for apixaban vs. rivaroxaban, and 1.17 (95% CI, 0.69-1.96) for rivaroxaban vs. dabigatran. For the risk of major bleeding, the HRs were 0.94 (95% CI, 0.62-1.41) for apixaban vs. dabigatran, 0.88 (95% CI, 0.64-1.22) for apixaban vs. rivaroxaban, and 1.35 (95% CI, 0.91-2.00) for rivaroxaban vs. dabigatran.CONCLUSIONS: Among patients with NVAF in routine clinical practice, there were no statistically significant differences in risk of stroke or systemic embolism or major bleeding in propensity-matched comparisons between apixaban, dabigatran, and rivaroxaban used in standard doses. While analyses indicate that more than moderate differences can be excluded, smaller differences cannot be ruled out.

    View details for PubMedID 29934230

  • Noninvasive blood tests for fetal development predict gestational age and preterm delivery SCIENCE Ngo, T. M., Moufarrej, M. N., Rasmussen, M. H., Camunas-Soler, J., Pan, W., Okamoto, J., Neff, N. F., Liu, K., Wong, R. J., Downes, K., Tibshirani, R., Shaw, G. M., Skotte, L., Stevenson, D. K., Biggio, J. R., Elovitz, M. A., Melbye, M., Quake, S. R. 2018; 360 (6393): 1133–36

    Abstract

    Noninvasive blood tests that provide information about fetal development and gestational age could potentially improve prenatal care. Ultrasound, the current gold standard, is not always affordable in low-resource settings and does not predict spontaneous preterm birth, a leading cause of infant death. In a pilot study of 31 healthy pregnant women, we found that measurement of nine cell-free RNA (cfRNA) transcripts in maternal blood predicted gestational age with comparable accuracy to ultrasound but at substantially lower cost. In a related study of 38 women (23 full-term and 15 preterm deliveries), all at elevated risk of delivering preterm, we identified seven cfRNA transcripts that accurately classified women who delivered preterm up to 2 months in advance of labor. These tests hold promise for prenatal care in both the developed and developing worlds, although they require validation in larger, blinded clinical trials.

    View details for PubMedID 29880692

  • Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis BLOOD Kleinstern, G., Camp, N. J., Goldin, L. R., Vachon, C. M., Vajdic, C. M., de Sanjose, S., Weinberg, J., Benavente, Y., Casabonne, D., Liebow, M., Nieters, A., Hjalgrim, H., Melbye, M., Glimelius, B., Adami, H., Boffetta, P., Brennan, P., Maynadie, M., McKay, J., Cocco, P., Shanafelt, T. D., Call, T. G., Norman, A. D., Hanson, C., Robinson, D., Chaffee, K. G., Brooks-Wilson, A. R., Monnereau, A., Clavel, J., Glenn, M., Curtin, K., Conde, L., Bracci, P. M., Morton, L. M., Cozen, W., Severson, R. K., Chanock, S. J., Spinelli, J. J., Johnston, J. B., Rothman, N., Skibola, C. F., Leis, J. F., Kay, N. E., Smedby, K. E., Berndt, S. I., Cerhan, J. R., Caporaso, N., Slager, S. L. 2018; 131 (23): 2541–51

    Abstract

    Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P = 4.4 × 10-94). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P = 7.8 × 10-30) and observed high discrimination (c-statistic = 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P = 9.8 × 10-16). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH. The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL.

    View details for PubMedID 29674426

    View details for PubMedCentralID PMC5992865

  • Concomitant use of low-dose methotrexate and NSAIDs and the risk of serious adverse events among patients with rheumatoid arthritis. Pharmacoepidemiology and drug safety Svanstrom, H., Lund, M., Melbye, M., Pasternak, B. 2018

    Abstract

    PURPOSE: Case reports and pharmacokinetic studies have suggested that concomitant use of low-dose methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with increased risk of methotrexate toxicity. This study aimed to investigate the risk of serious adverse events associated with concomitant use of low-dose methotrexate and NSAIDs, compared with use of methotrexate alone, among patients with rheumatoid arthritis.METHODS: The study was conducted as a register-based cohort study in Denmark, 2004 to 2015, including episodes of concomitant use of methotrexate and NSAIDs (n=21536) and control episodes of use of methotrexate alone (n=21725). The primary outcome was the composite end point any serious adverse event, including liver toxicity, acute renal failure, and cytopenia. Secondary outcomes were the individual outcome components. Analyses were conducted using proportional-hazards regression, with adjustment using inverse-probability-of-treatment weighting based on propensity scores.RESULTS: During follow-up, 110 cases of the primary outcome occurred during concomitant use of methotrexate and NSAIDs (unadjusted incidence rate 12.1 per 1000 person-years) and 129 during control episodes (11.0 per 1000 person-years). Concomitant use of methotrexate and NSAIDs was associated with a significantly increased risk of any serious adverse event (weighted hazard ratio 1.40; 95% CI, 1.07-1.82). In secondary analyses, concomitant use of methotrexate and NSAIDs was associated with a significantly increased risk of acute renal failure and cytopenia.CONCLUSIONS: Concomitant use of low-dose methotrexate and NSAIDs was associated with a significantly increased risk of serious adverse events, expanding on the evidence base for current regulatory recommendations that advocate caution when low-dose methotrexate and NSAID are coprescribed.

    View details for PubMedID 29797447

  • Rare and Common Variants Conferring Risk of Tooth Agenesis JOURNAL OF DENTAL RESEARCH Jonsson, L., Magnusson, T. E., Thordarson, A., Jonsson, T., Geller, F., Feenstra, B., Melbye, M., Nohr, E. A., Vucic, S., Dhamo, B., Rivadeneira, F., Ongkosuwito, E. M., Wolvius, E. B., Leslie, E. J., Marazita, M. L., Howe, B. J., Uribe, L., Alonso, I., Santos, M., Pinho, T., Jonsson, R., Audolfsson, G., Gudmundsson, L., Nawaz, M. S., Olafsson, S., Gustafsson, O., Ingason, A., Unnsteinsdottir, U., Bjornsdottir, G., Walters, G. B., Zervas, M., Oddsson, A., Gudbjartsson, D. F., Steinberg, S., Stefansson, H., Stefansson, K. 2018; 97 (5): 515–22

    Abstract

    We present association results from a large genome-wide association study of tooth agenesis (TA) as well as selective TA, including 1,944 subjects with congenitally missing teeth, excluding third molars, and 338,554 controls, all of European ancestry. We also tested the association of previously identified risk variants, for timing of tooth eruption and orofacial clefts, with TA. We report associations between TA and 9 novel risk variants. Five of these variants associate with selective TA, including a variant conferring risk of orofacial clefts. These results contribute to a deeper understanding of the genetic architecture of tooth development and disease. The few variants previously associated with TA were uncovered through candidate gene studies guided by mouse knockouts. Knowing the etiology and clinical features of TA is important for planning oral rehabilitation that often involves an interdisciplinary approach.

    View details for PubMedID 29364747

    View details for PubMedCentralID PMC5958369

  • Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus. European journal of human genetics : EJHG Fadista, J., Lund, M., Skotte, L., Geller, F., Nandakumar, P., Chatterjee, S., Matsson, H., Granstrom, A. L., Wester, T., Salo, P., Virtanen, V., Carstensen, L., Bybjerg-Grauholm, J., Hougaard, D. M., Pakarinen, M., Perola, M., Nordenskjold, A., Chakravarti, A., Melbye, M., Feenstra, B. 2018; 26 (4): 561–69

    Abstract

    Hirschsprung disease (HSCR) is a congenital disorder with a population incidence of ~1/5000 live births, defined by an absence of enteric ganglia along variable lengths of the colon. HSCR genome-wide association studies (GWAS) have found common associated variants at RET, SEMA3, and NRG1, but they still fail to explain all of its heritability. To enhance gene discovery, we performed a GWAS of 170 cases identified from the Danish nationwide pathology registry with 4717 controls, based on 6.2 million variants imputed from the haplotype reference consortium panel. We found a novel low-frequency variant (rs144432435), which, when conditioning on the lead RET single-nucleotide polymorphism (SNP), was of genome-wide significance in the discovery analysis. This conditional association signal was replicated in a Swedish HSCR cohort with discovery plus replication meta-analysis conditional odds ratio of 6.6 (P=7.7*10-10; 322 cases and 4893 controls). The conditional signal was, however, not replicated in two HSCR cohorts from USA and Finland, leading to the hypothesis that rs144432435 tags a rare haplotype present in Denmark and Sweden. Using the genome-wide complex trait analysis method, we estimated the SNP heritability of HSCR to be 88%, close to estimates based on classical family studies. Moreover, by using Lasso (least absolute shrinkage and selection operator) regression we were able to construct a genetic HSCR predictor with a area under the receiver operator characteristics curve of 76% in an independent validation set. In conclusion, we combined the largest collection of sporadic Hirschsprung cases to date (586 cases) to further elucidate HSCR's genetic architecture.

    View details for PubMedID 29379196

  • Histopathologic characteristics in synchronous bilateral breast cancer patients: A nationwide Danish cohort study from 1999-2015 Mejdahl, M. K., Kroman, N., Balslev, E., Wohlfahrt, J., Melbye, M., Tjonneland, A., Holm, M. ELSEVIER SCI LTD. 2018: S157
  • Maternal and fetal genetic contribution to gestational weight gain INTERNATIONAL JOURNAL OF OBESITY Warrington, N. M., Richmond, R., Fenstra, B., Myhre, R., Gaillard, R., Paternoster, L., Wang, C. A., Beaumont, R. N., Das, S., Murcia, M., Barton, S. J., Espinosa, A., Thiering, E., Atalay, M., Pitkanen, N., Ntalla, I., Jonsson, A. E., Freathy, R., Karhunen, V., Tiesler, C. T., Allard, C., Crawford, A., Ring, S. M., Melbye, M., Magnus, P., Rivadeneira, F., Skotte, L., Hansen, T., Marsh, J., Guxens, M., Holloway, J. W., Grallert, H., Jaddoe, V. V., Lowe, W. L., Roumeliotaki, T., Hattersley, A. T., Lindi, V., Pahkala, K., Panoutsopoulou, K., Standl, M., Flexeder, C., Bouchard, L., Aagaard Nohr, E., Santa Marina, L., Kogevinas, M., Niinikoski, H., Dedoussis, G., Heinrich, J., Reynolds, R. M., Lakka, T., Zeggini, E., Raitakari, O. T., Chatzi, L., Inskip, H. M., Bustamante, M., Hivert, M., Jarvelin, M., Sorensen, T. A., Pennell, C., Felix, J. F., Jacobsson, B., Geller, F., Evans, D. M., Lawlor, D. A., Early Growth Genetics EGG Consort 2018; 42 (4): 775–84

    Abstract

    Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG.A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight).Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10-8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG.We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.

    View details for PubMedID 28990592

    View details for PubMedCentralID PMC5784805

  • Long-Term Risk of Cardiovascular Death With Use of Clarithromycin and Roxithromycin: A Nationwide Cohort Study AMERICAN JOURNAL OF EPIDEMIOLOGY Inghammar, M., Nibell, O., Pasternak, B., Melbye, M., Svanstrom, H., Hviid, A. 2018; 187 (4): 777–85

    View details for DOI 10.1093/aje/kwx359

    View details for Web of Science ID 000428867400016

  • Use of Proton Pump Inhibitors and the Risk of Acute Kidney Injury Among Patients with Rheumatoid Arthritis: Cohort Study. Drug safety Svanstrom, H., Lund, M., Melbye, M., Pasternak, B. 2018

    Abstract

    INTRODUCTION: Recent observational studies have indicated that use of proton pump inhibitors may be associated with adverse renal outcomes. The objective of this study was to investigate whether the use of proton pump inhibitors increases the risk of acute kidney injury among patients with rheumatoid arthritis.METHODS: We conducted the study as a historical prospective cohort study, including patients with rheumatoid arthritis, 30-84years of age, during 2004-2015. Among these, we identified and matched episodes of use and non-use of proton pump inhibitors (control episodes) 1:4 on the propensity score, including 24,579 episodes of use of proton pump inhibitors and 98,230 control episodes. The primary outcome was a first diagnosis of acute kidney injury and the secondary outcome was any serious renal event (acute kidney injury or chronic kidney disease). The primary time point for analysis was 120 days after study entry.RESULTS: The incidence rate of acute kidney injury was 2.2 per 1000 person-years during episodes of use of proton pump inhibitors and 0.9 during control episodes. Use of proton pump inhibitors was associated with a significantly increased risk of acute kidney injury (hazard ratio 2.30, 95% confidence interval 1.26-4.20). The absolute risk difference was 40 (95% confidence interval 8-99) events of acute kidney injury per 100,000 episodes of use of proton pump inhibitors. Use of proton pump inhibitors was also associated with a significantly increased risk of the secondary outcome of any serious renal event (hazard ratio 2.61, 95% confidence interval 1.80-3.80).CONCLUSIONS: This cohort study among patients with rheumatoid arthritis found a significantly increased risk of acute kidney injury associated with the use of proton pump inhibitors. These findings may help inform clinical decision making when considering the risks and benefits of proton pump inhibitor treatment in rheumatoid arthritis.

    View details for PubMedID 29603109

  • Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density ANNALS OF THE RHEUMATIC DISEASES Alonso, N., Estrada, K., Albagha, O. E., Herrera, L., Reppe, S., Olstad, O. K., Gautvik, K. M., Ryan, N. M., Evans, K. L., Nielson, C. M., Hsu, Y., Kiel, D. P., Markozannes, G., Ntzani, E. E., Evangelou, E., Feenstra, B., Liu, X., Melbye, M., Masi, L., Brandi, M., Riches, P., Daroszewska, A., Olmos, J., Valero, C., Castillo, J., Riancho, J. A., Husted, L. B., Langdahl, B. L., Brown, M. A., Duncan, E. L., Kaptoge, S., Khaw, K., Usategui-Martin, R., Del Pino-Montes, J., Gonzalez-Sarmiento, R., Lewis, J. R., Prince, R. L., D'Amelio, P., Garcia-Giralt, N., Nogues, X., Mencej-Bedrac, S., Marc, J., Wolstein, O., Eisman, J. A., Oei, L., Medina-Gomez, C., Schraut, K. E., Navarro, P., Wilson, J. F., Davies, G., Starr, J., Deary, I., Tanaka, T., Ferrucci, L., Gianfrancesco, F., Gennari, L., Lucas, G., Elosua, R., Uitterlinden, A. G., Rivadeneira, F., Ralston, S. H. 2018; 77 (3)
  • Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics HUMAN MOLECULAR GENETICS Beaumont, R. N., Warrington, N. M., Cavadino, A., Tyrrell, J., Nodzenski, M., Horikoshi, M., Geller, F., Myhre, R., Richmond, R. C., Paternoster, L., Bradfield, J. P., Kreiner-Moller, E., Huikari, V., Metrustry, S., Lunetta, K. L., Painter, J. N., Hottenga, J., Allard, C., Barton, S. J., Espinosa, A., Marsh, J. A., Potter, C., Zhang, G., Ang, W., Berry, D. J., Bouchard, L., Das, S., Hakonarson, H., Heikkinen, J., Helgeland, O., Hocher, B., Hofman, A., Inskip, H. M., Jones, S. E., Kogevinas, M., Lind, P. A., Marullo, L., Medland, S. E., Murray, A., Murray, J. C., Njolstad, P. R., Nohr, E. A., Reichetzeder, C., Ring, S. M., Ruth, K. S., Santa-Marina, L., Scholtens, D. M., Sebert, S., Sengpiel, V., Tuke, M. A., Vaudel, M., Weedon, M. N., Willemsen, G., Wood, A. R., Yaghootkar, H., Muglia, L. J., Bartels, M., Relton, C. L., Pennell, C. E., Chatzi, L., Estivill, X., Holloway, J. W., Boomsma, D. I., Montgomery, G. W., Murabito, J. M., Spector, T. D., Power, C., Jarvelin, M., Bisgaard, H., Grant, S. A., Sorensen, T. A., Jaddoe, V. W., Jacobsson, B., Melbye, M., McCarthy, M. I., Hattersley, A. T., Hayes, M., Frayling, T. M., Hivert, M., Felix, J. F., Hypponen, E., Lowe, W. L., Evans, D. M., Lawlor, D. A., Feenstra, B., Freathy, R. M., Early Growth Genetics EGG 2018; 27 (4): 742–56

    View details for DOI 10.1093/hmg/ddx429

    View details for Web of Science ID 000424137500014

  • Genetic Associations With Gestational Duration and Spontaneous Preterm Birth OBSTETRICAL & GYNECOLOGICAL SURVEY Zhang, G., Feenstra, B., Bacelis, J., Liu, X., Muglia, L. M., Juodakis, J., Miller, D. E., Litterman, N., Jiang, P., Russell, L., Hinds, D. A., Hu, Y., Weirauch, M. T., Chen, X., Chavan, A. R., Wagner, G. P., Pavlicev, M., Nnamani, M. C., Maziarz, J., Karjalainen, M. K., Ramet, M., Sengpiel, V., Geller, F., Boyd, H. A., Palotie, A., Momany, A., Bedell, B., Ryckman, K. K., Huusko, J. M., Forney, C. R., Kottyan, L. C., Hallman, M., Teramo, K., Nohr, E. A., Smith, G., Melbye, M., Jacobsson, B., Muglia, L. J. 2018; 73 (2): 83–85
  • Familial aggregation of tonsillectomy in early childhood and adolescence CLINICAL EPIDEMIOLOGY Bager, P., Corn, G., Wohlfahrt, J., Boyd, H. A., Feenstra, B., Melbye, M. 2018; 10: 97–105
  • Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks. Nature genetics Demenais, F., Margaritte-Jeannin, P., Barnes, K. C., Cookson, W. O., Altmüller, J., Ang, W., Barr, R. G., Beaty, T. H., Becker, A. B., Beilby, J., Bisgaard, H., Bjornsdottir, U. S., Bleecker, E., Bønnelykke, K., Boomsma, D. I., Bouzigon, E., Brightling, C. E., Brossard, M., Brusselle, G. G., Burchard, E., Burkart, K. M., Bush, A., Chan-Yeung, M., Chung, K. F., Couto Alves, A., Curtin, J. A., Custovic, A., Daley, D., de Jongste, J. C., Del-Rio-Navarro, B. E., Donohue, K. M., Duijts, L., Eng, C., Eriksson, J. G., Farrall, M., Fedorova, Y., Feenstra, B., Ferreira, M. A., Freidin, M. B., Gajdos, Z., Gauderman, J., Gehring, U., Geller, F., Genuneit, J., Gharib, S. A., Gilliland, F., Granell, R., Graves, P. E., Gudbjartsson, D. F., Haahtela, T., Heckbert, S. R., Heederik, D., Heinrich, J., Heliövaara, M., Henderson, J., Himes, B. E., Hirose, H., Hirschhorn, J. N., Hofman, A., Holt, P., Hottenga, J., Hudson, T. J., Hui, J., Imboden, M., Ivanov, V., Jaddoe, V. W., James, A., Janson, C., Jarvelin, M. R., Jarvis, D., Jones, G., Jonsdottir, I., Jousilahti, P., Kabesch, M., Kähönen, M., Kantor, D. B., Karunas, A. S., Khusnutdinova, E., Koppelman, G. H., Kozyrskyj, A. L., Kreiner, E., Kubo, M., Kumar, R., Kumar, A., Kuokkanen, M., Lahousse, L., Laitinen, T., Laprise, C., Lathrop, M., Lau, S., Lee, Y. A., Lehtimäki, T., Letort, S., Levin, A. M., Li, G., Liang, L., Loehr, L. R., London, S. J., Loth, D. W., Manichaikul, A., Marenholz, I., Martinez, F. J., Matheson, M. C., Mathias, R. A., Matsumoto, K., Mbarek, H., McArdle, W. L., Melbye, M., Melén, E., Meyers, D., Michel, S., Mohamdi, H., Musk, A. W., Myers, R. A., Nieuwenhuis, M. A., Noguchi, E., O'Connor, G. T., Ogorodova, L. M., Palmer, C. D., Palotie, A., Park, J. E., Pennell, C. E., Pershagen, G., Polonikov, A., Postma, D. S., Probst-Hensch, N., Puzyrev, V. P., Raby, B. A., Raitakari, O. T., Ramasamy, A., Rich, S. S., Robertson, C. F., Romieu, I., Salam, M. T., Salomaa, V., Schlünssen, V., Scott, R., Selivanova, P. A., Sigsgaard, T., Simpson, A., Siroux, V., Smith, L. J., Solodilova, M., Standl, M., Stefansson, K., Strachan, D. P., Stricker, B. H., Takahashi, A., Thompson, P. J., Thorleifsson, G., Thorsteinsdottir, U., Tiesler, C. M., Torgerson, D. G., Tsunoda, T., Uitterlinden, A. G., van der Valk, R. J., Vaysse, A., Vedantam, S., von Berg, A., von Mutius, E., Vonk, J. M., Waage, J., Wareham, N. J., Weiss, S. T., White, W. B., Wickman, M., Widén, E., Willemsen, G., Williams, L. K., Wouters, I. M., Yang, J. J., Zhao, J. H., Moffatt, M. F., Ober, C., Nicolae, D. L. 2018; 50 (1): 42–53

    Abstract

    We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

    View details for PubMedID 29273806

  • Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics. Human molecular genetics Beaumont, R. N., Warrington, N. M., Cavadino, A., Tyrrell, J., Nodzenski, M., Horikoshi, M., Geller, F., Myhre, R., Richmond, R. C., Paternoster, L., Bradfield, J. P., Kreiner-Møller, E., Huikari, V., Metrustry, S., Lunetta, K. L., Painter, J. N., Hottenga, J. J., Allard, C., Barton, S. J., Espinosa, A., Marsh, J. A., Potter, C., Zhang, G., Ang, W., Berry, D. J., Bouchard, L., Das, S., Hakonarson, H., Heikkinen, J., Helgeland, Ø., Hocher, B., Hofman, A., Inskip, H. M., Jones, S. E., Kogevinas, M., Lind, P. A., Marullo, L., Medland, S. E., Murray, A., Murray, J. C., Njølstad, P. R., Nohr, E. A., Reichetzeder, C., Ring, S. M., Ruth, K. S., Santa-Marina, L., Scholtens, D. M., Sebert, S., Sengpiel, V., Tuke, M. A., Vaudel, M., Weedon, M. N., Willemsen, G., Wood, A. R., Yaghootkar, H., Muglia, L. J., Bartels, M., Relton, C. L., Pennell, C. E., Chatzi, L., Estivill, X., Holloway, J. W., Boomsma, D. I., Montgomery, G. W., Murabito, J. M., Spector, T. D., Power, C., Järvelin, M. R., Bisgaard, H., Grant, S. F., Sørensen, T. I., Jaddoe, V. W., Jacobsson, B., Melbye, M., McCarthy, M. I., Hattersley, A. T., Hayes, M. G., Frayling, T. M., Hivert, M. F., Felix, J. F., Hyppönen, E., Lowe, W. L., Evans, D. M., Lawlor, D. A., Feenstra, B., Freathy, R. M. 2018; 27 (4): 742–56

    Abstract

    Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.

    View details for PubMedID 29309628

    View details for PubMedCentralID PMC5886200

  • Associations between vitamin D status and atherosclerosis among Inuit in Greenland. Atherosclerosis Gjødesen, C. U., Jørgensen, M. E., Bjerregaard, P., Dahl-Petersen, I. K., Larsen, C. V., Noël, M., Melbye, M., Cohen, A. S., Lundqvist, M., Hougaard, D. M., Helge, J. W., Nielsen, N. O. 2018; 268: 145–51

    Abstract

    Low levels of vitamin D are suspected to be a risk factor for cardiovascular disease and atherosclerosis. The aim of this study was to assess the prevalence of subclinical atherosclerosis among Inuit in Greenland, and to evaluate the association with vitamin D status. We hypothesized that low vitamin D status could be associated with higher carotid intima-media thickness (IMT) as a marker of atherosclerosis.756 adults from the Inuit Health in Transition (IHIT) study carried out in Greenland in the period 2005-2010 were included. A blood sample donated in 1987 was available for a sub-sample of 102 individuals. Serum 25(OH)D3 from the IHIT study and the 1987 survey was used as a measure of vitamin D status. IMT measurements were conducted by ultrasound scanning. The prevalence of atherosclerosis was estimated, and the association between serum 25(OH)D3 and IMT measurements was examined by linear regression.The overall prevalence of subclinical atherosclerosis was 20.1% (n = 152). The linear regression analyses indicated a weak positive association between serum 25(OH)D3 level and IMT measurements from the IHIT study, though not statistically significant after adjustment for potential confounders (β = 0.35% per 10 nmoL/L 25(OH)D3, p = 0.06). Linear regression analyses of the association between serum 25(OH)D3 level in the 1987 survey and IMT measurements also indicated a positive, though not statistically significant, association after adjustment (β = 0.07% per 10 nmoL/L 25(OH)D3, p = 0.86).Our findings did not support the hypothesis of an association between low vitamin D levels and risk of atherosclerosis.

    View details for PubMedID 29227867

  • School performance in children with infantile hydrocephalus: a nationwide cohort study CLINICAL EPIDEMIOLOGY Schmidt, L., Corn, G., Wohlfahrt, J., Melbye, M., Munch, T. 2018; 10: 1721–31
  • Long-Term Risk of Cardiovascular Death With Use of Clarithromycin and Roxithromycin: A Nationwide Cohort Study. American journal of epidemiology Inghammar, M., Nibell, O., Pasternak, B., Melbye, M., Svanström, H., Hviid, A. 2018; 187 (4): 777–85

    Abstract

    Recent studies have raised concern that macrolide antibiotics may be associated with an increased long-term risk of cardiovascular death. We examined the 1-year risk associated with treatment with clarithromycin (n = 187,887) or roxithromycin (n = 698,899) compared with penicillin V (n = 3,473,081), matched 1:4 on propensity score, in a nationwide, registry-based cohort study in Danish outpatients, 1997-2011. Among clarithromycin courses, the rate ratio for cardiovascular death was 1.24 (95% confidence interval (CI): 0.96, 1.59). Among roxithromycin courses, the rate ratio was 0.99 (95% CI: 0.86, 1.16). In analyses by time after treatment start, the rate ratio associated with clarithromycin was 1.66 (95% CI: 0.98, 2.79) during days 0-7. This was attenuated in later time periods (days 8-89, rate ratio = 1.30, 95% CI: 0.88, 1.94; and days 90-364, rate ratio = 0.96, 95% CI: 0.63, 1.47). For roxithromycin, the rate ratios were 0.88 (95% CI: 0.59, 1.32) during days 0-7, 1.17 (95% CI: 0.92, 1.48) during days 8-89, and 0.88 (95% CI: 0.70, 1.10) during days 90-364. We found no increased risk of cardiovascular death in a general outpatient population. With clarithromycin, we observed a transient increased risk during days 0-7 after treatment start, which corresponds to the period of active treatment. This association was absent in later time periods, which is consistent with no long-term toxicity resulting in cardiovascular death.

    View details for PubMedID 29155931

  • School performance in children with infantile hydrocephalus: a nationwide cohort study. Clinical epidemiology Schmidt, L. B., Corn, G., Wohlfahrt, J., Melbye, M., Munch, T. N. 2018; 10: 1721–31

    Abstract

    Little is known about the prognosis for school performance among children with all-cause infantile hydrocephalus (IHC). Using detailed educational data, we investigated the school performance for IHC patients compared to other children in Denmark.We conducted a population-based cohort study of all live-born children in Denmark (1977-2015) based on data from the Danish national health registers and the Danish educational register. The cumulative chance of completing school at age 18 years was estimated using the Aalen-Johansen estimator. The relative risks presented as ORs for not completing school, obtaining grades, or obtaining a grade point average below the national mean value were estimated using a logistic regression model.The cohort included 2,381,413 children, and of these, 2,573 were diagnosed with IHC. A total of 86% of IHC children completed compulsory school compared to 96% among other children; only 62% of IHC children who completed school received marks vs 96% among other children. Mediation analyses indicated that one-third of these poorer performances in IHC children could be attributable to their higher prevalence of epilepsy, spasticity, visual disturbances, autism, and attention-deficit hyperactivity disorder. Completion rates were similar for isolated and non-isolated hydrocephalus, and did not vary by age at diagnosis or number of surgeries. Of the children with isolated IHC, 73% obtained grades vs 58% of the children with non-isolated IHC. Poorer school performance in IHC children was also observed when considering age at school start, grade point average, and completion of further education.The poorer school performance among IHC children is particularly reflected by the larger proportion not obtaining grades compared to other children. However, the performance of the IHC children obtaining grades is comparable to that of other children.

    View details for PubMedID 30538576

    View details for PubMedCentralID PMC6254655

  • Study of correlation between the NAT2 phenotype and genotype status among Greenlandic Inuit. EXCLI journal Birch Kristensen, E., Yakimov, V., Bjorn-Mortensen, K., Soborg, B., Koch, A., Andersson, M., Birch Kristensen, K., Michelsen, S. W., Skotte, L., Ahrendt Bjerregaard, A., Blaszkewicz, M., Golka, K., Hengstler, J. G., Feenstra, B., Melbye, M., Geller, F. 2018; 17: 1043–53

    Abstract

    N-acetyltransferase 2 (NAT2) is the main enzyme metabolizing isoniazid and genotype-based treatment has been studied for years without becoming common practice. To investigate whether genotype-based isoniazid treatment is feasible in Greenland, we sequenced the coding sequence of NAT2 and determined the NAT2 enzyme-activity by caffeine test. No additional genetic variants were identified in the coding sequence of NAT2, so that genotype status in 260 study participants could be assessed by a well-established 7-SNP panel. Studying the enzyme activity by the ratio of the two caffeine metabolites AFMU and 1X in 260 participants showed a high rate of slow phenotypes with intermediate or rapid genotype. These misclassifications were mainly observed in urine samples with pH<3, a deviation from the standard protocol due to the field work character of the study, where immediate pH adjustment to pH=3.5 was not possible. We excluded these samples. For the remaining 143 individuals with pH>3, we observed a moderate level of discrepancies (19 of the 116 individuals with intermediate or rapid genotype status having a slow phenotype). Further investigation showed that drinking coffee and not tea or cola was the most important factor for high levels of both metabolites. The concordance between phenotype and genotype status with regard to slow metabolism supported the recommendation of lower isoniazid doses in individuals with slow genotype status in order to avoid liver injury, a frequent side effect. The phenotypical variation observed for individuals with intermediate or rapid genotype status warrants further research before increased dosing of isoniazid can be recommended.

    View details for PubMedID 30564082

    View details for PubMedCentralID PMC6295636

  • STUDY OF CORRELATION BETWEEN THE NAT2 PHENOTYPE AND GENOTYPE STATUS AMONG GREENLANDIC INUIT EXCLI JOURNAL Kristensen, E., Yakimov, V., Bjorn-Mortensen, K., Soborg, B., Koch, A., Andersson, M., Kristensen, K., Michelsen, S., Skotte, L., Bjerregaard, A., Blaszkewicz, M., Golka, K., Hengstler, J. G., Feenstra, B., Melbye, M., Geller, F. 2018; 17: 1043–53
  • Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks NATURE GENETICS Demenais, F., Margaritte-Jeannin, P., Barnes, K. C., Cookson, W. C., Altmueller, J., Ang, W., Barr, R., Beaty, T. H., Becker, A. B., Beilby, J., Bisgaard, H., Bjornsdottir, U., Bleecker, E., Bonnelykke, K., Boomsma, D. I., Bouzigon, E., Brightling, C. E., Brossard, M., Brusselle, G. G., Burchard, E., Burkart, K. M., Bush, A., Chan-Yeung, M., Chung, K., Alves, A., Curtin, J. A., Custovic, A., Daley, D., de Jongste, J. C., Del-Rio-Navarro, B. E., Donohue, K. M., Duijts, L., Eng, C., Eriksson, J. G., Farrall, M., Fedorova, Y., Feenstra, B., Ferreira, M. A., Freidin, M. B., Gajdos, Z., Gauderman, J., Gehring, U., Geller, F., Genuneit, J., Gharib, S. A., Gilliland, F., Granell, R., Graves, P. E., Gudbjartsson, D. F., Haahtela, T., Heckbert, S. R., Heederik, D., Heinrich, J., Heliovaara, M., Henderson, J., Himes, B. E., Hirose, H., Hirschhorn, J. N., Hofman, A., Holt, P., Hottenga, J., Hudson, T. J., Hui, J., Imboden, M., Ivanov, V., Jaddoe, V. V., James, A., Janson, C., Jarvelin, M., Jarvis, D., Jones, G., Jonsdottir, I., Jousilahti, P., Kabesch, M., Kahonen, M., Kantor, D. B., Karunas, A. S., Khusnutdinova, E., Koppelman, G. H., Kozyrskyj, A. L., Kreiner, E., Kubo, M., Kumar, R., Kumar, A., Kuokkanen, M., Lahousse, L., Laitinen, T., Laprise, C., Lathrop, M., Lau, S., Lee, Y., Lehtimaki, T., Letort, S., Levin, A. M., Li, G., Liang, L., Loehr, L. R., London, S. J., Loth, D. W., Manichaikul, A., Marenholz, I., Martinez, F. J., Matheson, M. C., Mathias, R. A., Matsumoto, K., Mbarek, H., McArdle, W. L., Melbye, M., Melen, E., Meyers, D., Michel, S., Mohamdi, H., Musk, A. W., Myers, R. A., Nieuwenhuis, M. E., Noguchi, E., O'Connor, G. T., Ogorodova, L. M., Palmer, C. D., Palotie, A., Park, J. E., Pennell, C. E., Pershagen, G., Polonikov, A., Postma, D. S., Probst-Hensch, N., Puzyrev, V. P., Raby, B. A., Raitakari, O. T., Ramasamy, A., Rich, S. S., Robertson, C. F., Romieu, I., Salam, M. T., Salomaa, V., Schlunssen, V., Scott, R., Selivanova, P. A., Sigsgaard, T., Simpson, A., Siroux, V., Smith, L. J., Solodilova, M., Standl, M., Stefansson, K., Strachan, D. P., Stricker, B. H., Takahashi, A., Thompson, P. J., Thorleifsson, G., Thorsteinsdottir, U., Tiesler, C. T., Torgerson, D. G., Tsunoda, T., Uitterlinden, A. G., van der Valk, R. P., Vaysse, A., Vedantam, S., von Berg, A., von Mutius, E., Vonk, J. M., Waage, J., Wareham, N. J., Weiss, S. T., White, W. B., Wickman, M., Widen, E., Willemsen, G., Williams, L., Wouters, I. M., Yang, J. J., Zhao, J., Moffatt, M. F., Ober, C., Nicolae, D. L., Australian Asthma Genetics Consort 2018; 50 (1): 42-+
  • Associations between vitamin D status and atherosclerosis among Inuit in Greenland ATHEROSCLEROSIS Gjodesen, C. U., Jorgensen, M. E., Bjerregaard, P., Dahl-Petersen, I. K., Larsen, C. L., Noel, M., Melbye, M., Cohen, A. S., Lundqvist, M., Hougaard, D. M., Helge, J. W., Nielsen, N. O. 2018; 268: 145–51
  • Strabismus Incidence in a Danish Population-Based Cohort of Children JAMA OPHTHALMOLOGY Torp-Pedersen, T., Boyd, H. A., Skotte, L., Haargaard, B., Wohlfahrt, J., Holmes, J. M., Melbye, M. 2017; 135 (10): 1047–53
  • CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits NATURE COMMUNICATIONS Mace, A., Tuke, M. A., Deelen, P., Kristiansson, K., Mattsson, H., Noukas, M., Sapkota, Y., Schick, U., Porcu, E., Rueger, S., McDaid, A. F., Porteous, D., Winkler, T. W., Salvi, E., Shrine, N., Liu, X., Ang, W. Q., Zhang, W., Feitosa, M. F., Venturini, C., van der Most, P. J., Rosengren, A., Wood, A. R., Beaumont, R. N., Jones, S. E., Ruth, K. S., Yaghootkar, H., Tyrrell, J., Havulinna, A. S., Boers, H., Magi, R., Kriebel, J., Mueller-Nurasyid, M., Perola, M., Nieminen, M., Lokki, M., Kahonen, M., Viikari, J. S., Geller, F., Lahti, J., Palotie, A., Koponen, P., Lundqvist, A., Rissanen, H., Bottinger, E. P., Afaq, S., Wojczynski, M. K., Lenzini, P., Nolte, I. M., Sparso, T., Schupf, N., Christensen, K., Perls, T. T., Newman, A. B., Werge, T., Snieder, H., Spector, T. D., Chambers, J. C., Koskinen, S., Melbye, M., Raitakari, O. T., Lehtimaki, T., Tobin, M. D., Wain, L. V., Sinisalo, J., Peters, A., Meitinger, T., Martin, N. G., Wray, N. R., Montgomery, G. W., Medland, S. E., Swertz, M. A., Vartiainen, E., Borodulin, K., Mannisto, S., Murray, A., Bochud, M., Jacquemont, S., Rivadeneira, F., Hansen, T. F., Oldehinkel, A. J., Mangino, M., Province, M. A., Deloukas, P., Kooner, J. S., Freathy, R. M., Pennell, C., Feenstra, B., Strachan, D. P., Lettre, G., Hirschhorn, J., Cusi, D., Heid, I. M., Hayward, C., Mannik, K., Beckmann, J. S., Loos, R. F., Nyholt, D. R., Metspalu, A., Eriksson, J. G., Weedon, M. N., Salomaa, V., Franke, L., Reymond, A., Frayling, T. M., Kutalik, Z. 2017; 8: 744

    Abstract

    There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01-0.2%), with large effects on height (>2.4 cm), weight (>5 kg), and body mass index (BMI) (>3.5 kg/m2). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m2 for each Mb of total deletion burden (P = 2.5 × 10-10, 6.0 × 10-5, and 2.9 × 10-3). Our study provides evidence that the same genes (e.g., MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders.Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.

    View details for PubMedID 28963451

  • Genetic Associations with Gestational Duration and Spontaneous Preterm Birth NEW ENGLAND JOURNAL OF MEDICINE Zhang, G., Feenstra, B., Bacelis, J., Liu, X., Muglia, L. M., Juodakis, J., Miller, D. E., Litterman, N., Jiang, P., Russell, L., Hinds, D. A., Hu, Y., Weirauch, M. T., Chen, X., Chavan, A. R., Wagner, G. P., Pavlicev, M., Nnamani, M. C., Maziarz, J., Karjalainen, M. K., Ramet, M., Sengpiel, V., Geller, F., Boyd, H. A., Palotie, A., Momany, A., Bedell, B., Ryckman, K. K., Huusko, J. M., Forney, C. R., Kottyan, L. C., Hallman, M., Teramo, K., Nohr, E. A., Smith, G., Melbye, M., Jacobsson, B., Muglia, L. J. 2017; 377 (12): 1156–67
  • Risk, treatment duration, and recurrence risk of postpartum affective disorder in women with no prior psychiatric history: A population-based cohort study. PLoS medicine Rasmussen, M. H., Strom, M., Wohlfahrt, J., Videbech, P., Melbye, M. 2017; 14 (9): e1002392

    Abstract

    BACKGROUND: Some 5%-15% of all women experience postpartum depression (PPD), which for many is their first psychiatric disorder. The purpose of this study was to estimate the incidence of postpartum affective disorder (AD), duration of treatment, and rate of subsequent postpartum AD and other affective episodes in a nationwide cohort of women with no prior psychiatric history.METHODS AND FINDINGS: Linking information from several Danish national registers, we constructed a cohort of 457,317 primiparous mothers with first birth (and subsequent births) from 1 January 1996 to 31 December 2013 (a total of 789,068 births) and no prior psychiatric hospital contacts and/or use of antidepressants. These women were followed from 1 January 1996 to 31 December 2014. Postpartum AD was defined as use of antidepressants and/or hospital contact for PPD within 6 months after childbirth. The main outcome measures were risk of postpartum AD, duration of treatment, and recurrence risk. We observed 4,550 (0.6%) postpartum episodes of AD. The analyses of treatment duration showed that 1 year after the initiation of treatment for their first episode, 27.9% of women were still in treatment; after 4 years, 5.4%. The recurrence risk of postpartum AD for women with a PPD hospital contact after first birth was 55.4 per 100 person-years; for women with postpartum antidepressant medication after first birth, it was 35.0 per 100 person-years. The rate of postpartum AD after second birth for women with no history of postpartum AD was 1.2 per 100 person-years. After adjusting for year of birth and mother's age, women with PPD hospital contact after first birth had a 46.4 times higher rate (95% CI 31.5-68.4) and women with postpartum antidepressant medication after their first birth had a 26.9 times higher rate (95% CI 21.9-33.2) of a recurrent postpartum episode after their second birth compared to women with no postpartum AD history. Limitations include the use of registry data to identify cases and limited confounder control.CONCLUSIONS: In this study, an episode of postpartum AD was observed for 0.6% of childbirths among women with no prior psychiatric history. The observed episodes were characterized by a relatively short treatment duration, yet the women had a notably high rate of later AD and recurrent episodes of postpartum AD. The recurrence risk of postpartum AD was markedly higher among women with PPD hospital contact after first birth compared to women with postpartum antidepressant medication after first birth. Our results underline the necessity of measures targeted at specific vulnerable groups, such as women who experience PPD as a first psychiatric episode.

    View details for PubMedID 28949960

  • Risk of post-pregnancy hypertension in women with a history of hypertensive disorders of pregnancy: nationwide cohort study BMJ-BRITISH MEDICAL JOURNAL Behrens, I., Basit, S., Melbye, M., Lykke, J. A., Wohlfahrt, J., Bundgaard, H., Thilaganathan, B., Boyd, H. A. 2017; 358

    View details for DOI 10.1136/bmj.j3078

    View details for Web of Science ID 000405770400003

  • SPONTANEOUS PREMATURE BIRTH: PROGRESS REPORT ON GENOMIC STUDIES Haapalainen, A., Karjalainen, M., Huusko, J., Ojaniemi, M., Marttila, R., Melbye, M., Jacobsson, B., Muglia, L., Ramet, M., Hallman, M. WILEY. 2017: 13–14
  • Sequence variants in ARHGAP15, COLQ and FAM155A associate with diverticular disease and diverticulitis. Nature communications Sigurdsson, S., Alexandersson, K. F., Sulem, P., Feenstra, B., Gudmundsdottir, S., Halldorsson, G. H., Olafsson, S., Sigurdsson, A., Rafnar, T., Thorgeirsson, T., Sørensen, E., Nordholm-Carstensen, A., Burcharth, J., Andersen, J., Jørgensen, H. S., Possfelt-Møller, E., Ullum, H., Thorleifsson, G., Masson, G., Thorsteinsdottir, U., Melbye, M., Gudbjartsson, D. F., Stefansson, T., Jonsdottir, I., Stefansson, K. 2017; 8: 15789-?

    Abstract

    Diverticular disease is characterized by pouches (that is, diverticulae) due to weakness in the bowel wall, which can become infected and inflamed causing diverticulitis, with potentially severe complications. Here, we test 32.4 million sequence variants identified through whole-genome sequencing (WGS) of 15,220 Icelanders for association with diverticular disease (5,426 cases) and its more severe form diverticulitis (2,764 cases). Subsequently, 16 sequence variants are followed up in a diverticular disease sample from Denmark (5,970 cases, 3,020 controls). In the combined Icelandic and Danish data sets we observe significant association of intronic variants in ARHGAP15 (Rho GTPase-activating protein 15; rs4662344-T: P=1.9 × 10(-18), odds ratio (OR)=1.23) and COLQ (collagen-like tail subunit of asymmetric acetylcholinesterase; rs7609897-T: P=1.5 × 10(-10), OR=0.87) with diverticular disease and in FAM155A (family with sequence similarity 155A; rs67153654-A: P=3.0 × 10(-11), OR=0.82) with diverticulitis. These are the first loci shown to associate with diverticular disease in a genome-wide study.

    View details for DOI 10.1038/ncomms15789

    View details for PubMedID 28585551

  • CPT1A Missense Mutation Associated With Fatty Acid Metabolism and Reduced Height in Greenlanders. Circulation. Cardiovascular genetics Skotte, L., Koch, A., Yakimov, V., Zhou, S., Soborg, B., Andersson, M., Michelsen, S. W., Navne, J. E., Mistry, J. M., Dion, P. A., Pedersen, M. L., Borresen, M. L., Rouleau, G. A., Geller, F., Melbye, M., Feenstra, B. 2017; 10 (3)

    Abstract

    BACKGROUND: Inuit have lived for thousands of years in an extremely cold environment on a diet dominated by marine-derived fat. To investigate how this selective pressure has affected the genetic regulation of fatty acid metabolism, we assessed 233 serum metabolic phenotypes in a population-based sample of 1570 Greenlanders.METHODS AND RESULTS: Using array-based and targeted genotyping, we found that rs80356779, a p.Pro479Leu variant in CPT1A, was strongly associated with markers of n-3 fatty acid metabolism, including degree of unsaturation (P=1.16*10-34), levels of polyunsaturated fatty acids, n-3 fatty acids, and docosahexaoenic acid relative to total fatty acid levels (P=2.35*10-15, P=4.02*10-19, and P=7.92*10-27). The derived allele (L479) occurred at a frequency of 76.2% in our sample while being absent in most other populations, and we found strong signatures of positive selection at the locus. Furthermore, we found that each copy of L479 reduced height by an average of 2.1 cm (P=1.04*10-9). In exome sequencing data from a sister population, the Nunavik Inuit, we found no other likely causal candidate variant than rs80356779.CONCLUSION: Our study shows that a common CPT1A missense mutation is strongly associated with a range of metabolic phenotypes and reduced height in Greenlanders. These findings are important from a public health perspective and highlight the usefulness of complex trait genetic studies in isolated populations.

    View details for PubMedID 28611031

  • Genome-wide association study identifies variants in HORMAD2 associated with tonsillectomy JOURNAL OF MEDICAL GENETICS Feenstra, B., Bager, P., Liu, X., Hjalgrim, H., Nohr, E. A., Hougaard, D. M., Geller, F., Melbye, M. 2017; 54 (5): 358-364
  • Prevalence of atopic dermatitis in infants by domestic water hardness and season of birth: Cohort study JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Engebretsen, K. A., Bager, P., Wohlfahrt, J., Skov, L., Zachariae, C., Andersen, A. N., Melbye, M., Thyssen, J. P. 2017; 139 (5): 1568-?

    Abstract

    Atopic dermatitis (AD) appears to be more common in regions with hard domestic water and in children with a fall/winter birth. However, it is unknown whether a synergistic effect exists.We sought to evaluate the association between domestic water hardness and season of birth, respectively, with onset of AD within the first 18 months of life in a large Danish birth cohort.Of children from the Danish National Birth Cohort, 52,950 were included. History of physician-diagnosed AD and population characteristics were obtained from interviews. Birth data were obtained from the Civil Registration System, and domestic water hardness data were obtained from the Geological Survey of Denmark and Greenland. The relative prevalence (RP) of AD was calculated by using log-linear binomial regression.The prevalence of AD was 15.0% (7,942/52,950). The RP of AD was 5% (RPtrend, 1.05; 95% CI, 1.03-1.07) higher for each 5° increase in domestic water hardness (range, 6.60-35.90 German degrees of hardness [118-641 mg/L]). Although the RP of AD was higher in children with a fall (RP, 1.24; 95% CI, 1.17-1.31) or winter (RP, 1.18; 95% CI, 1.11-1.25) birth, no significant interaction was observed with domestic water hardness. The population attributable risk of hard domestic water on AD was 2%.We observed that early exposure to hard domestic water and a fall/winter birth was associated with an increase in the relative prevalence of AD within the first 18 months of life. Although the 2 exposures did not interact synergistically, a dose-response relationship was observed between domestic water hardness and AD.

    View details for DOI 10.1016/j.jaci.2016.11.021

    View details for Web of Science ID 000400465300017

  • Association Between Fetal Congenital Heart Defects and Maternal Risk of Hypertensive Disorders of Pregnancy in the Same Pregnancy and Across Pregnancies. Circulation Boyd, H. A., Basit, S., Behrens, I., Leirgul, E., Bundgaard, H., Wohlfahrt, J., Melbye, M., Øyen, N. 2017

    Abstract

    Background -Pregnant women carrying fetuses with heart defects and women with hypertensive disorders of pregnancy both often exhibit angiogenic imbalances, suggesting that the same mechanisms are involved in the etiology of the former and the pathophysiology of the latter. We conducted a register-based cohort study to determine whether offspring congenital heart defects are associated with an increased risk of hypertensive disorders of pregnancy, and whether the mechanisms driving any association are primarily maternal or fetal. Methods -Among singleton pregnancies without chromosomal abnormalities lasting ≥20 weeks in Denmark, 1978-2011 (N= 1,972,857), we identified pregnancies complicated by offspring congenital heart defects and/or early preterm preeclampsia, late preterm preeclampsia, term preeclampsia, and gestational hypertension. We used polytomous logistic regression to estimate odds ratios (ORs) for associations between offspring congenital heart defects and maternal hypertensive disorders of pregnancy, overall and for specific heart defects. Results -Offspring congenital heart defects were strongly associated with early preterm preeclampsia (OR 7.00, 95% confidence interval [CI] 6.11-8.03) and late preterm preeclampsia (OR 2.82, 95% CI 2.38-3.34) in the same pregnancy and weakly associated with term preeclampsia (OR 1.16, 95% CI 1.06-1.27), but were not associated with gestational hypertension (OR 1.07, 95% CI 0.92-1.25). Association strengths were consistent across heart defect types. Offspring congenital heart defects in a previous pregnancy were also strongly associated with preterm preeclampsia in subsequent pregnancies (early preterm preeclampsia: OR 2.37, 95% CI 1.68-3.34; late preterm preeclampsia OR 2.04, 95% CI 1.52-2.75), but only modestly associated with term preeclampsia and not associated with gestational hypertension. Similarly, preterm preeclampsia in a previous pregnancy, but not term preeclampsia or gestational hypertension, was associated with offspring congenital heart defects in later pregnancies (early preterm preeclampsia: OR 7.91, 95% CI 6.06-10.3; late preterm preeclampsia: OR 2.83, 95% CI 2.11-3.79; term preeclampsia: OR 0.98, 95% CI 0.88-1.10; gestational hypertension: OR 1.13, 95% CI 0.92-1.38). Conclusions -Linked pathophysiological mechanisms may be involved in some congenital heart defects and preterm preeclampsia. The strong associations across pregnancies support a predominantly maternal origin-of-effect.

    View details for DOI 10.1161/CIRCULATIONAHA.116.024600

    View details for PubMedID 28424221

  • Non-specific effects of BCG vaccination on morbidity among children in Greenland-an answer to a relevant question. International journal of epidemiology Haahr, S., Michelsen, S. W., Andersson, M., Bjorn-Mortensen, K., Soborg, B., Wohlfahrt, J., Melbye, M., Koch, A. 2017

    View details for DOI 10.1093/ije/dyx044

    View details for PubMedID 28402471

  • Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia NATURE COMMUNICATIONS Law, P. J., Berndt, S. I., Speedy, H. E., Camp, N. J., Sava, G. P., Skibola, C. F., Holroyd, A., Joseph, V., Sunter, N. J., Nieters, A., Bea, S., Monnereau, A., Martin-Garcia, D., Goldin, L. R., Clot, G., Teras, L. R., Quintela, I., Birmann, B. M., Jayne, S., Cozen, W., Majid, A., Smedby, K. E., Lan, Q., Dearden, C., Brooks-Wilson, A. R., Hall, A. G., Purdue, M. P., Mainou-Fowler, T., Vajdic, C. M., Jackson, G. H., Cocco, P., Marr, H., Zhang, Y., Zheng, T., Giles, G. G., Lawrence, C., Call, T. G., Liebow, M., Melbye, M., Glimelius, B., Mansouri, L., Glenn, M., Curtin, K., Diver, W. R., Link, B. K., Conde, L., Bracci, P. M., Holly, E. A., Jackson, R. D., Tinker, L. F., Benavente, Y., Boffetta, P., Brennan, P., Maynadie, M., McKay, J., Albanes, D., Weinstein, S., Wang, Z., Caporaso, N. E., Morton, L. M., Severson, R. K., Riboli, E., Vineis, P., Vermeulen, R. C., Southey, M. C., Milne, R. L., Clavel, J., Topka, S., Spinelli, J. J., Kraft, P., Ennas, M. G., Summerfield, G., Ferri, G. M., Harris, R. J., Miligi, L., Pettitt, A. R., North, K. E., Allsup, D. J., Fraumeni, J. F., Bailey, J. R., Offit, K., Pratt, G., Hjalgrim, H., Pepper, C., Chanock, S. J., Fegan, C., Rosenquist, R., de Sanjose, S., Carracedo, A., Dyer, M. J., Catovsky, D., Campo, E., Cerhan, J. R., Allan, J. M., Rothman, N., Houlston, R., Slager, S. L. 2017; 8

    Abstract

    Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10(-13)), 1q42.13 (rs41271473, P=1.06 × 10(-10)), 4q24 (rs71597109, P=1.37 × 10(-10)), 4q35.1 (rs57214277, P=3.69 × 10(-8)), 6p21.31 (rs3800461, P=1.97 × 10(-8)), 11q23.2 (rs61904987, P=2.64 × 10(-11)), 18q21.1 (rs1036935, P=3.27 × 10(-8)), 19p13.3 (rs7254272, P=4.67 × 10(-8)) and 22q13.33 (rs140522, P=2.70 × 10(-9)). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response.

    View details for DOI 10.1038/ncomms14175

    View details for PubMedID 28165464

  • Effect of the 13-valent pneumococcal conjugate vaccine on nasopharyngeal carriage by respiratory pathogens among Greenlandic children. International journal of circumpolar health Navne, J. E., Koch, A., Slotved, H., Andersson, M., Melbye, M., Ladefoged, K., Børresen, M. 2017; 76 (1): 1309504-?

    Abstract

    In 2010, Greenland introduced the 13-valent pneumococcal conjugate vaccine (Prevnar 13®- PCV-13) in the childhood immunisation program. The authors aimed to evaluate the impact of PCV-13 on nasopharyngeal carriage of bacteria frequently associated with respiratory infections in children.In 2013 a cross-sectional population-based study of nasopharyngeal carriage was conducted among Greenlandic children aged 0-6 years and results were compared with an equivalent study from 2011. Nasopharyngeal swab samples were tested for Streptococcus pneumoniae, non-typeable Haemophilus influenzae, Moraxella catarrhalis and Staphylococcus aureus. Pneumococcal serotyping was performed by Quellung reaction and serotype-specific antisera. Statistical analysis included logistic regression models, adjusting for known risk factors.A total of 377 nasopharyngeal samples were collected. Overall carriage rate of S. pneumoniae remained unchanged from 2011 to 2013 (51% and 56%, p=0.13), but significant serotype shifts were observed among both vaccinated and unvaccinated children with marked reductions in carriage of vaccine-type pneumococci, counterbalanced by increasing carriage of non-vaccine types. Carriage rate of S. aureus decreased significantly among vaccinated children whereas that of M. catarrhalis increased.PCV-13 introduction in Greenland is associated with significant changes in nasopharyngeal bacterial carriage. Continued surveillance is warranted to clarify whether these changes are persistent, and affect the pattern of respiratory and invasive diseases in Greenland.

    View details for DOI 10.1080/22423982.2017.1309504

    View details for PubMedID 28467237

  • Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma LUPUS SCIENCE & MEDICINE Bernatsky, S., Garcia, H., Spinelli, J. J., Gaffney, P., Smedby, K. E., Ramsey-Goldman, R., Wang, S. S., Adami, H., Albanes, D., Angelucci, E., Ansell, S. M., Asmann, Y. W., Becker, N., Benavente, Y., Berndt, S. I., Bertrand, K. A., Birmann, B. M., Boeing, H., Boffetta, P., Bracci, P. M., Brennan, P., Brooks-Wilson, A. R., Cerhan, J. R., Chanock, S. J., Clavel, J., Conde, L., Cotenbader, K. H., Cox, D. G., Cozen, W., Crouch, S., De Roos, A. J., de Sanjose, S., Di Lollo, S., Diver, W., Dogan, A., Foretova, L., Ghesquieres, H., Giles, G. G., Glimelius, B., Habermann, T. M., Haioun, C., Hartge, P., Hjalgrim, H., Holford, T. R., Holly, E. A., Jackson, R. D., Kaaks, R., Kane, E., Kelly, R. S., Klein, R. J., Kraft, P., Kricker, A., Lan, Q., Lawrence, C., Liebow, M., Lightfoot, T., Link, B. K., Maynadie, M., Mckay, J., Melbye, M., Molina, T. J., Monnereau, A., Morton, L. M., Nieters, A., North, K. E., Novak, A. J., Offit, K., Purdue, M. P., Rais, M., Riby, J., Roman, E., Rothman, N., Salles, G., Severi, G., Severson, R. K., Skibola, C. F., Slager, S. L., Smith, A., Smith, M. T., Southey, M. C., Staines, A., Teras, L. R., Thompson, C. A., Tilly, H., Tinker, L. F., Tjonneland, A., Turner, J., Vajdic, C. M., Vermeulen, R. H., Vijai, J., Vineis, P., Virtamo, J., Wang, Z., Weinstein, S., Witzig, T. E., Zelenetz, A., Zeleniuch-Jacquotte, A., Zhang, Y., Zheng, T., Zucca, M., Clarke, A. E. 2017; 4 (1): e000187

    Abstract

    Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL.GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis.Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765.These data suggest several plausible genetic links between DLBCL and SLE.

    View details for DOI 10.1136/lupus-2016-000187

    View details for Web of Science ID 000447607600007

    View details for PubMedID 29214033

    View details for PubMedCentralID PMC5715504

  • Genetic Associations with Gestational Duration and Spontaneous Preterm Birth. The New England journal of medicine Zhang, G., Feenstra, B., Bacelis, J., Liu, X., Muglia, L. M., Juodakis, J., Miller, D. E., Litterman, N., Jiang, P. P., Russell, L., Hinds, D. A., Hu, Y., Weirauch, M. T., Chen, X., Chavan, A. R., Wagner, G. P., Pavličev, M., Nnamani, M. C., Maziarz, J., Karjalainen, M. K., Rämet, M., Sengpiel, V., Geller, F., Boyd, H. A., Palotie, A., Momany, A., Bedell, B., Ryckman, K. K., Huusko, J. M., Forney, C. R., Kottyan, L. C., Hallman, M., Teramo, K., Nohr, E. A., Davey Smith, G., Melbye, M., Jacobsson, B., Muglia, L. J. 2017; 377 (12): 1156–67

    Abstract

    Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations.We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0×10-8) or an association with suggestive significance (P<1.0×10-6) in the discovery set.In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother-infant dyads suggested that these variants act at the level of the maternal genome.In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement. (Funded by the March of Dimes and others.).

    View details for PubMedID 28877031

  • The dynamics of immune responses to Mycobacterium tuberculosis during different stages of natural infection: A longitudinal study among Greenlanders. PloS one Michelsen, S. W., Soborg, B., Diaz, L. J., Hoff, S. T., Agger, E. M., Koch, A., Rosenkrands, I., Wohlfahrt, J., Melbye, M. 2017; 12 (6)

    Abstract

    Understanding human immunity to Mycobacterium tuberculosis (Mtb) during different stages of infection is important for development of an effective tuberculosis (TB) vaccine. We aimed to evaluate immunity to Mtb infection by measuring immune responses to selected Mtb antigens expressed during different stages of infection over time and to observe sustainability of immunity.In a cohort study comprising East Greenlanders aged 17-22 years (2012 to 2014) who had either; undetectable Mtb infection, ongoing or prior Mtb infection at enrolment, we measured immunity to 15 antigens over a one-year period. Quantiferon-TB Gold testing (QFT) defined Mtb infection status (undetected/detected). The eligible study population of East Greenlanders aged 17-22 years was identified from the entire population using the Civil Registration System. From the source population 65 participants were selected by stratified random sampling according to information on Mtb infection stage. Retrospective and prospective information on notified TB (including treatment) was obtained through the mandatory TB notification system and was used to characterise Mtb infection stage (ongoing/prior). Immunity to 15 antigens including two QFT antigens, PPD and 12 non-QFT antigens (representing early, constitutive and latent Mtb infection) was assessed by measuring immune responses using whole-blood antigen stimulation and interferon gamma measurement.Of 65 participants, 54 were considered Mtb-infected. Immunity to Mtb infection fluctuated with high annual risk of conversion (range: 6-69%) and reversion (range: 5-95%). During follow-up, five (8%) participants were notified with TB; neither conversion nor reversion was associated with an increased risk of progressing to TB.Our findings suggest that human immunity to natural Mtb infection over time is versatile with fluctuations, resulting in high levels of conversion and reversion of immunity, thus human immunity to Mtb is much more dynamic than anticipated. The study findings suggest future use of longitudinal assessment of immune responses when searching for TB vaccine candidate antigens.

    View details for DOI 10.1371/journal.pone.0177906

    View details for PubMedID 28570574

  • Prevalence of atopic dermatitis in infants by domestic water hardness and season of birth: Cohort study. journal of allergy and clinical immunology Engebretsen, K. A., Bager, P., Wohlfahrt, J., Skov, L., Zachariae, C., Nybo Andersen, A., Melbye, M., Pontoppidan Thyssen, J. 2016

    Abstract

    Atopic dermatitis (AD) appears to be more common in regions with hard domestic water and in children with a fall/winter birth. However, it is unknown whether a synergistic effect exists.We sought to evaluate the association between domestic water hardness and season of birth, respectively, with onset of AD within the first 18 months of life in a large Danish birth cohort.Of children from the Danish National Birth Cohort, 52,950 were included. History of physician-diagnosed AD and population characteristics were obtained from interviews. Birth data were obtained from the Civil Registration System, and domestic water hardness data were obtained from the Geological Survey of Denmark and Greenland. The relative prevalence (RP) of AD was calculated by using log-linear binomial regression.The prevalence of AD was 15.0% (7,942/52,950). The RP of AD was 5% (RPtrend, 1.05; 95% CI, 1.03-1.07) higher for each 5° increase in domestic water hardness (range, 6.60-35.90 German degrees of hardness [118-641 mg/L]). Although the RP of AD was higher in children with a fall (RP, 1.24; 95% CI, 1.17-1.31) or winter (RP, 1.18; 95% CI, 1.11-1.25) birth, no significant interaction was observed with domestic water hardness. The population attributable risk of hard domestic water on AD was 2%.We observed that early exposure to hard domestic water and a fall/winter birth was associated with an increase in the relative prevalence of AD within the first 18 months of life. Although the 2 exposures did not interact synergistically, a dose-response relationship was observed between domestic water hardness and AD.

    View details for DOI 10.1016/j.jaci.2016.11.021

    View details for PubMedID 28017882

  • Genome-wide association study identifies variants in HORMAD2 associated with tonsillectomy. Journal of medical genetics Feenstra, B., Bager, P., Liu, X., Hjalgrim, H., Nohr, E. A., Hougaard, D. M., Geller, F., Melbye, M. 2016

    Abstract

    Inflammation of the tonsils is a normal response to infection, but some individuals experience recurrent, severe tonsillitis and massive hypertrophy of the tonsils in which case surgical removal of the tonsils may be considered.To identify common genetic variants associated with tonsillectomy.We used tonsillectomy information from Danish health registers and carried out a genome-wide association study comprising 1464 patients and 12 019 controls of Northwestern European ancestry, with replication in an independent sample set of 1575 patients and 1367 controls.The variant rs2412971, intronic in HORMAD2 at chromosome 22q12.2, was robustly associated with tonsillectomy (OR=1.22; p=1.48×10(-9)) and is highly correlated with SNPs previously found to be associated with IgA nephropathy, Crohn's disease (CD) and early onset inflammatory bowel disease (IBD). The risk allele for tonsillectomy corresponded to increased risk of IgA nephropathy and decreased risk of CD and IBD. We further performed lookup analyses of the top SNP for outcomes related to tonsillectomy in the combined discovery and replication sample and found that rs2412971 was associated with acute tonsillitis (OR=1.19; p=7.82×10(-4)), chronic disease of the tonsils (OR=1.19; p=2.32×10(-6)) and appendectomy (OR=1.18; p=1.13×10(-3)).We identified and replicated a genetic association at 22q12.2 with tonsillectomy. Further functional investigation is required to illuminate whether the molecular mechanisms underlying the genetic association involve general lymphoid hyper-reaction throughout the mucosa-associated lymphoid tissue system.

    View details for DOI 10.1136/jmedgenet-2016-104304

    View details for PubMedID 27941131

  • Non-specific effects of BCG vaccination on morbidity among children in Greenland: a population-based cohort study INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Haahr, S., Michelsen, S. W., Andersson, M., Bjorn-Mortensen, K., Soborg, B., Wohlfahrt, J., Melbye, M., Koch, A. 2016; 45 (6): 2122-2130

    Abstract

    The potential non-specific effects of BCG (Bacillus Calmette-Guérin) vaccination, with reported reduction of infectious disease morbidity among vaccinated children, in addition to the protective effect against tuberculosis (TB), are highly debated. In Greenland, BCG vaccination was introduced in 1955, but temporarily discontinued from 1991 to 1996 due to nationwide policy changes. Using the transient vaccination stop, we aimed to investigate possible non-specific effects of BCG vaccination by measuring nation-wide hospitalization rates due to infectious diseases other than TB among vaccinated and unvaccinated children.A retrospective cohort study including all children born in Greenland aged 3 months to 3 years from 1989 to 2004. A personal identification number assigned at birth allowed for follow-up through national registers. Information on hospitalization due to infectious diseases was obtained from the Greenlandic inpatient register using ICD-8 and ICD-10 codes. Participants with notified TB were censored. Incidence rate ratios (IRR) were estimated using Poisson regression.Overall, 19 363 children, hereof 66% BCG-vaccinated, were followed for 44 065 person-years and had 2069 hospitalizations due to infectious diseases. IRRs of hospitalization in BCG-vaccinated as compared with BCG-unvaccinated children were 1.07 [95% confidence interval (CI) 0.96-1.20] for infectious diseases overall, and specifically 1.10 (95% CI 0.98-1.24) for respiratory tract infections. Among BCG-vaccinated children aged 3 to 11 months, the IRR of hospitalization due to infectious diseases was 1.00 (95% CI 0.84-1.19) as compared with BCG-unvaccinated children.Our results do not support the hypothesis that neonatal BCG vaccination reduces morbidity in children caused by infectious diseases other than TB.

    View details for DOI 10.1093/ije/dyw244

    View details for Web of Science ID 000398261100051

    View details for PubMedID 28338723

  • Host immunity to Mycobacterium tuberculosis and risk of tuberculosis: A longitudinal study among Greenlanders VACCINE Michelsen, S. W., Soborg, B., Agger, E. M., Diaz, L. J., Hoff, S. T., Koch, A., Sorensen, H. C., Andersen, P., Wohlfahrt, J., Melbye, M. 2016; 34 (48): 5975-5983

    Abstract

    Human immune responses to latent Mycobacterium tuberculosis (Mtb) infection (LTBI) may enable individuals to control Mtb infection and halt progression to tuberculosis (TB), a hypothesis applied in several novel TB vaccines. We aimed to evaluate whether immune responses to selected LTBI antigens were associated with subsequent reduced risk of progression to TB.We conducted a population-based cohort study in East Greenland (2012-2014) including individuals aged 5-31years. A personal identifier allowed follow-up in national registers including the TB notification register. Mtb infection was defined by a positive Quantiferon test. Immune responses to LTBI antigens were assessed by whole blood antigen stimulation and interferon gamma measurement.Among 978 participants, 67 previously had TB. LTBI antigen (Rv1284, Rv2659, Rv2660c) immune response prevalence was 18%, 50%, 2% among Mtb-infected and 7%, 40%, 4% among non-infected (Quantiferon negative) participants. Among 911 participants without prior notified TB, 31 were notified with TB during study follow-up. Immune responses to LTBI antigens were not associated with reduced risk of subsequent TB; Rv1284 HR 0.92 (95%CI 0.28-3.04), Rv2659 HR 1.05 (95%CI 0.51-2.13), Rv2660c HR 3.06 (95%CI 0.70-13.37).In this large population-based study, human immune responses to selected LTBI antigens were not found to be strongly associated with reduced risk of subsequent TB.

    View details for DOI 10.1016/j.vaccine.2016.09.047

    View details for Web of Science ID 000388059800024

    View details for PubMedID 27997344

  • Recurrent Intracerebral Hemorrhage: Associations with Comorbidities and Medicine with Antithrombotic Effects PLOS ONE Schmidt, L. B., Goertz, S., Wohlfahrt, J., Melbye, M., Munch, T. N. 2016; 11 (11)

    Abstract

    Intracerebral hemorrhage (ICH) is a disease with high mortality and a substantial risk of recurrence. However, the recurrence risk is poorly documented and the knowledge of potential predictors for recurrence among co-morbidities and medicine with antithrombotic effect is limited.1) To estimate the short- and long-term cumulative risks of recurrent intracerebral hemorrhage (ICH). 2) To investigate associations between typical comorbid diseases, surgical treatment, use of medicine with antithrombotic effects, including antithrombotic treatment (ATT), selective serotonin reuptake inhibitors (SSRI's), and nonsteroidal anti-inflammatory drugs (NSAID's) with recurrent ICH.The cohort consisted of all individuals diagnosed with a primary ICH in Denmark 1996-2011. Information on comorbidities, surgical treatment for the primary ICH, and the use of ATT, SSRI's and NSAID's was retrieved from the Danish national health registers. The cumulative recurrence risk of ICH was estimated using the Aalen-Johansen estimator, thus taking into account the competing risk of death. Associations with potential predictors of recurrent ICH were estimated as rate ratios (RR's) using Poisson regression. Propensity score matching was used for the analyses of medicine with antithrombotic effects.Among 15,270 individuals diagnosed with a primary ICH, 2,053 recurrences were recorded, resulting in cumulative recurrence risk of 8.9% after one year and 13.7% after five years. Surgical treatment and renal insufficiency were associated with increased recurrence risks (RR 1.64, 95% CI 1.39-1.93 and RR 1.72, 95% CI 1.34-2.17, respectively), whereas anti-hypertensive treatment was associated with a reduced risk (RR 0.82, 95% CI 0.74-0.91). We observed non-significant associations between the use of any of the investigated medicines with antithrombotic effect (ATT, SSRI's, NSAID's) and recurrent ICH.The substantial short-and long-term recurrence risks warrant aggressive management of hypertension following a primary ICH, particularly in patients treated surgically for the primary ICH, and patients with renal insufficiency.

    View details for DOI 10.1371/journal.pone.0166223

    View details for Web of Science ID 000387725000077

    View details for PubMedID 27832176

    View details for PubMedCentralID PMC5104445

  • Nasopharyngeal bacterial carriage in young children in Greenland: a population at high risk of respiratory infections. Epidemiology and infection Navne, J. E., Børresen, M. L., Slotved, H. C., Andersson, M., Melbye, M., Ladefoged, K., Koch, A. 2016; 144 (15): 3226-3236

    Abstract

    The incidence of childhood respiratory infections in Greenland is among the highest globally. We performed a population-based study of 352 Greenlandic children aged 0-6 years aiming to describe rates and risk factors for carriage of four key bacteria associated with respiratory infections, their antimicrobial susceptibility and inter-bacterial associations. Nasopharyngeal swabs were tested for Streptococcus pneumoniae grouped by serotypes included (VT) or not included (NVT) in the 13-valent pneumococcal conjugate vaccine, non-typable Haemophilus influenzae (NTHi), Staphylococcus aureus and Moraxella catarrhalis. S. pneumoniae was detected from age 2 weeks with a peak carriage rate of 60% in 2-year-olds. Young age and having siblings attending a daycare institution were associated with pneumococcal carriage. Overall co-colonization with ⩾2 of the studied bacteria was 52%. NTHi showed a positive association with NVT pneumococci and M. catarrhalis, respectively, M. catarrhalis was positively associated with S. pneumoniae, particular VT pneumococci, whereas S. aureus were negatively associated with NTHi and M. catarrhalis. Nasopharyngeal bacterial carriage was present unusually early in life and with frequent co-colonization. Domestic crowding increased odds of carriage. Due to important bacterial associations we suggest future surveillance of pneumococcal conjugate vaccine's impact on carriage in Greenland to also include other pathogens.

    View details for PubMedID 27405603

  • ABO blood group and risk of cancer: A register-based cohort study of 1.6 million blood donors. Cancer epidemiology Vasan, S. K., Hwang, J., Rostgaard, K., Nyrén, O., Ullum, H., Pedersen, O. B., Erikstrup, C., Melbye, M., Hjalgrim, H., Pawitan, Y., Edgren, G. 2016; 44: 40-43

    Abstract

    The associations between ABO blood group and cancer risk have been studied repeatedly, but results have been variable. Consistent associations have only been reported for pancreatic and gastric cancers.We estimated associations between different ABO blood groups and site-specific cancer risk in a large cohort of healthy blood donors from Sweden and Denmark.A total of 1.6 million donors were followed over 27 million person-years (20 million in Sweden and 7 million in Denmark). We observed 119,584 cancer cases. Blood groups A, AB and B were associated either with increased or decreased risk of cancer at 13 anatomical sites (p≤0.05), compared to blood group O. Consistent with assessment using a false discovery rate approach, significant associations with ABO blood group were observed for cancer of the pancreas, breast, and upper gastrointestinal tract (mouth, salivary glands, pharynx, esophageal adenocarcinoma and stomach).Our study reconfirms the association between ABO blood group and cancer risk and exact underlying mechanisms involved needs further research.

    View details for DOI 10.1016/j.canep.2016.06.005

    View details for PubMedID 27459465

  • Distribution of HLA-G extended haplotypes and one HLA-E polymorphism in a large-scale study of mother-child dyads with and without severe preeclampsia and eclampsia. HLA Nilsson, L. L., DJURISIC, S., Andersen, A. N., Melbye, M., Bjerre, D., Ferrero-Miliani, L., Hackmon, R., Geraghty, D. E., Hviid, T. V. 2016; 88 (4): 172-186

    Abstract

    The etiological pathways and pathogenesis of preeclampsia have rendered difficult to disentangle. Accumulating evidence points toward a maladapted maternal immune system, which may involve aberrant placental expression of immunomodulatory human leukocyte antigen (HLA) class Ib molecules during pregnancy. Several studies have shown aberrant or reduced expression of HLA-G in the placenta and in maternal blood in cases of preeclampsia compared with controls. Unlike classical HLA class Ia loci, the nonclassical HLA-G has limited polymorphic variants. Most nucleotide variations are clustered in the 5'-upstream regulatory region (5'URR) and 3'-untranslated regulatory region (3'UTR) of HLA-G and reflect a stringent expressional control. Based on genotyping and full gene sequencing of HLA-G in a large number of cases and controls (n > 900), the present study, which to our knowledge is the largest and most comprehensive performed, investigated the association between the HLA-G 14-bp ins/del (rs66554220) and HLA-E polymorphisms in mother and newborn dyads from pregnancies complicated by severe preeclampsia/eclampsia and from uncomplicated pregnancies. Furthermore, results from extended HLA-G haplotyping in the newborns are presented in order to assess whether a combined contribution of nucleotide variations spanning the 5'URR, coding region, and 3'UTR of HLA-G describes the genetic association with severe preeclampsia more closely. In contrast to earlier findings, the HLA-G 14-bp ins/del polymorphism was not associated with severe preeclampsia. Furthermore, the polymorphism (rs1264457) defining the two nonsynonymous HLA-E alleles, HLA-E*01:01:xx:xx and HLA-E*01:03:xx:xx, were not associated with severe preeclampsia. Finally, no specific HLA-G haplotypes were significantly associated with increased risk of developing severe preeclampsia/eclampsia.

    View details for DOI 10.1111/tan.12871

    View details for PubMedID 27596021

  • Genome-wide associations for birth weight and correlations with adult disease. Nature Horikoshi, M., Beaumont, R. N., Day, F. R., Warrington, N. M., Kooijman, M. N., Fernandez-Tajes, J., Feenstra, B., Van Zuydam, N. R., Gaulton, K. J., Grarup, N., Bradfield, J. P., Strachan, D. P., Li-Gao, R., Ahluwalia, T. S., Kreiner, E., Rueedi, R., Lyytikäinen, L., Cousminer, D. L., Wu, Y., Thiering, E., Wang, C. A., Have, C. T., Hottenga, J., Vilor-Tejedor, N., Joshi, P. K., Boh, E. T., Ntalla, I., Pitkänen, N., Mahajan, A., van Leeuwen, E. M., Joro, R., Lagou, V., Nodzenski, M., Diver, L. A., Zondervan, K. T., Bustamante, M., Marques-Vidal, P., Mercader, J. M., Bennett, A. J., Rahmioglu, N., Nyholt, D. R., Ma, R. C., Tam, C. H., Tam, W. H., Ganesh, S. K., van Rooij, F. J., Jones, S. E., Loh, P., Ruth, K. S., Tuke, M. A., Tyrrell, J., Wood, A. R., Yaghootkar, H., Scholtens, D. M., Paternoster, L., Prokopenko, I., Kovacs, P., Atalay, M., Willems, S. M., Panoutsopoulou, K., Wang, X., Carstensen, L., Geller, F., Schraut, K. E., Murcia, M., van Beijsterveldt, C. E., Willemsen, G., Appel, E. V., Fonvig, C. E., Trier, C., Tiesler, C. M., Standl, M., Kutalik, Z., Bonàs-Guarch, S., Hougaard, D. M., Sánchez, F., Torrents, D., Waage, J., Hollegaard, M. V., de Haan, H. G., Rosendaal, F. R., Medina-Gomez, C., Ring, S. M., Hemani, G., McMahon, G., Robertson, N. R., Groves, C. J., Langenberg, C., Luan, J., Scott, R. A., Zhao, J. H., Mentch, F. D., MacKenzie, S. M., Reynolds, R. M., Lowe, W. L., Tönjes, A., Stumvoll, M., Lindi, V., Lakka, T. A., van Duijn, C. M., Kiess, W., Körner, A., Sørensen, T. I., Niinikoski, H., Pahkala, K., Raitakari, O. T., Zeggini, E., Dedoussis, G. V., Teo, Y., Saw, S., Melbye, M., Campbell, H., Wilson, J. F., Vrijheid, M., de Geus, E. J., Boomsma, D. I., Kadarmideen, H. N., Holm, J., Hansen, T., Sebert, S., Hattersley, A. T., Beilin, L. J., Newnham, J. P., Pennell, C. E., Heinrich, J., Adair, L. S., Borja, J. B., Mohlke, K. L., Eriksson, J. G., Widén, E., Kähönen, M., Viikari, J. S., Lehtimäki, T., Vollenweider, P., Bønnelykke, K., Bisgaard, H., Mook-Kanamori, D. O., Hofman, A., Rivadeneira, F., Uitterlinden, A. G., Pisinger, C., Pedersen, O., Power, C., Hyppönen, E., Wareham, N. J., Hakonarson, H., Davies, E., Walker, B. R., Jaddoe, V. W., Järvelin, M., Grant, S. F., Vaag, A. A., Lawlor, D. A., Frayling, T. M., Smith, G. D., Morris, A. P., Ong, K. K., Felix, J. F., Timpson, N. J., Perry, J. R., Evans, D. M., McCarthy, M. I., Freathy, R. M. 2016; 538 (7624): 248-252

    Abstract

    Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10(-8)). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10(-13)), T2D (Rg = -0.27, P = 1.1 × 10(-6)) and coronary artery disease (Rg = -0.30, P = 6.5 × 10(-9)). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10(-4)). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.

    View details for DOI 10.1038/nature19806

    View details for PubMedID 27680694

    View details for PubMedCentralID PMC5164934

  • Transmission of Neurodegenerative Disorders Through Blood Transfusion A Cohort Study ANNALS OF INTERNAL MEDICINE Edgren, G., Hjalgrim, H., Rostgaard, K., Lambert, P., Wikman, A., Norda, R., Titlestad, K., Erikstrup, C., Ullum, H., Melbye, M., Busch, M. P., Nyren, O. 2016; 165 (5): 316-?

    Abstract

    The aggregation of misfolded proteins in the brain occurs in several neurodegenerative disorders. Aberrant protein aggregation is inducible in rodents and primates by intracerebral inoculation. Possible transfusion transmission of neurodegenerative diseases has important public health implications.To investigate possible transfusion transmission of neurodegenerative disorders.Retrospective cohort study.Nationwide registers of transfusions in Sweden and Denmark.1 465 845 patients who received transfusions between 1968 and 2012.Multivariable Cox regression models were used to estimate hazard ratios for dementia of any type, Alzheimer disease, and Parkinson disease in patients receiving blood transfusions from donors who were later diagnosed with any of these diseases versus patients who received blood from healthy donors. Whether excess occurrence of neurodegenerative disease occurred among recipients of blood from a subset of donors was also investigated. As a positive control, transmission of chronic hepatitis before and after implementation of hepatitis C virus screening was assessed.Among included patients, 2.9% received a transfusion from a donor diagnosed with one of the studied neurodegenerative diseases. No evidence of transmission of any of these diseases was found, regardless of approach. The hazard ratio for dementia in recipients of blood from donors with dementia versus recipients of blood from healthy donors was 1.04 (95% CI, 0.99 to 1.09). Corresponding estimates for Alzheimer disease and Parkinson disease were 0.99 (CI, 0.85 to 1.15) and 0.94 (CI, 0.78 to 1.14), respectively. Hepatitis transmission was detected before but not after implementation of hepatitis C virus screening.Observational study design, underascertainment of the outcome, and possible insufficient statistical power.The data provide no evidence for the transmission of neurodegenerative diseases and suggest that if transmission does occur, it is rare.Swedish Research Council, Swedish Heart-Lung Foundation, Swedish Society for Medical Research, and Danish Council for Independent Research.

    View details for DOI 10.7326/M15-2421

    View details for Web of Science ID 000382795000002

    View details for PubMedID 27368068

  • E1. Risk of chronic hypertension in women with a history of hypertensive disorders of pregnancy - a nationwide cohort study. journal of maternal-fetal & neonatal medicine Behrens, I., Basit, S., Melbye, M., Lykke, J. A., Wohlfahrt, J., Bundgaard, H., Thilaganathan, B., Boyd, H. A. 2016; 29 (sup2): 21-?

    Abstract

    Women with a history of hypertensive disorders of pregnancy (HDP) are known to have an increased risk of hypertension years after their pregnancy. However, how soon after an affected pregnancy the risk of hypertension increases and how/whether this risk evolves over time, is unclear.Using national health register data, we identified all women giving birth in Denmark from 1978 to 2011. Cox regression analysis was used to compare the rates of incident post-pregnancy hypertension requiring treatment with medication after pregnancy in women with and without a history of HDP, by the number of years since pregnancy.In the first 3 years after a woman's latest pregnancy, rates of chronic hypertension were 4- to 9-fold higher in women with an HDP in that pregnancy than in women with a normotensive pregnancy. The difference in rates between the two groups declined progressively with time, but even after ≥20 years, rates of chronic hypertension were twice as high among women with an HDP in their latest pregnancy. Gestational hypertension was associated with significantly higher rates of later hypertension than preeclampsia, while moderate and severe preeclampsia were associated with similar increases in risk of later hypertension. Women with HDP-affected pregnancies in their 20s, 30s and 40s, respectively had 10-year cumulative incidences of chronic hypertension between 10% and 30%, whereas for women with normotensive pregnancies in their 20s, 30s and 40s, the corresponding cumulative incidences fell between 4% and 12% (for all three age groups, the cumulative incidences for the HDP and non-HDP groups were statistically significantly different).The increased risk of chronic hypertension associated with a previous HDP is already present soon after delivery, and is substantial in all age groups. Women with an HDP affected pregnancy in their 20s had the same post-pregnancy 10-year cumulative risk of chronic hypertension as women with normotensive pregnancies who were 20 years older. These findings suggest that blood pressure monitoring in women with a history of HDP should be initiated soon after the affected pregnancy.

    View details for PubMedID 27680802

  • Hypertensive disorders of pregnancy and subsequent risk of solid cancerA nationwide cohort study INTERNATIONAL JOURNAL OF CANCER Behrens, I., Basit, S., Jensen, A., Lykke, J. A., Nielsen, L. P., Wohlfahrt, J., Kjaer, S. K., Melbye, M., Boyd, H. A. 2016; 139 (1): 58-64

    Abstract

    Women with hypertensive disorders of pregnancy (HDP) have higher levels of antiangiogenic growth factors during pregnancy than women with normotensive pregnancies. Since angiogenesis is necessary for solid cancer growth and spread, we hypothesized that women with a history of HDP might have a reduced risk of solid cancers (cancers other than lymphomas, hematologic cancers and nonmelanoma skin cancers) later in life. In a register-based cohort study of 1.08 million women giving birth at least once between 1978 and 2011, we used Cox regression to estimate hazard ratios (HRs) comparing solid cancer rates for women with and without a history of HDP. In this cohort, 68,236 women (6.3%) had ≥1 pregnancy complicated by HDP and 42,236 women (3.9%) developed solid tumors during follow-up. A history of HDP was not associated with a clinically meaningful reduction in the overall rate of solid cancer (HR 0.96, 95% confidence interval 0.92-1.00), regardless of HDP severity or time since HDP, nor was there a general tendency toward reduced solid cancer rates across organ sites. A history of HDP was only significantly associated with decreased rates of breast and lung cancers and with increased rates of endometrial and urinary tract cancers. Overall, our results do not support the hypothesis that women with a history of HDP have a reduced overall risk of solid cancer due to a persistent post-HDP antiangiogenic state or an innate tendency toward antiangiogenesis. Observed associations with specific cancers may instead be due to other pregnancy-related mechanisms or to residual/unmeasured confounding.

    View details for DOI 10.1002/ijc.30065

    View details for Web of Science ID 000374381400009

    View details for PubMedID 26919086

  • Association Between Hypertensive Disorders of Pregnancy and Later Risk of Cardiomyopathy EDITORIAL COMMENT OBSTETRICAL & GYNECOLOGICAL SURVEY Behrens, I., Basit, S., Lykke, J., Ranthe, M., Wohlfahrt, J., Bundgaard, H., Melbye, M., Boyd, H. A. 2016; 71 (7): 387–89
  • Prepregnancy Diabetes and Offspring Risk of Congenital Heart Disease A Nationwide Cohort Study CIRCULATION Oyen, N., Diaz, L. J., Leirgul, E., Boyd, H. A., Priest, J., Mathiesen, E. R., Quertermous, T., Wohlfahrt, J., Melbye, M. 2016; 133 (23): 2243-2253

    Abstract

    Maternal diabetes mellitus is associated with an increased risk of offspring congenital heart defects (CHD); however, the causal mechanism is poorly understood. We further investigated this association in a Danish nationwide cohort.In a national cohort study, we identified 2 025 727 persons born from 1978 to 2011; among them were 7296 (0.36%) persons exposed to maternal pregestational diabetes mellitus. Pregestational diabetes mellitus was identified by using the National Patient Register and individual-level information on all prescriptions filled in Danish pharmacies. Persons with CHD (n=16 325) were assigned to embryologically related cardiac phenotypes. The CHD prevalence in the offspring of mothers with pregestational diabetes mellitus was 318 per 10 000 live births (n=232) in comparison with a baseline risk of 80 per 10 000; the adjusted relative risk for CHD was 4.00 (95% confidence interval, 3.51-4.53). The association was not modified by year of birth, maternal age at diabetes onset, or diabetes duration, and CHD risks associated with type 1 (insulin-dependent) and type 2 (insulin-independent) diabetes mellitus did not differ significantly. Persons born to women with previous acute diabetes complications had a higher CHD risk than those exposed to maternal diabetes mellitus without complications (relative risk, 7.62; 95% confidence interval, 5.23-10.6, and relative risk, 3.49; 95% confidence interval, 2.91-4.13, respectively; P=0.0004). All specific CHD phenotypes were associated with maternal pregestational diabetes mellitus (relative risk range, 2.74-13.8).The profoundly increased CHD risk conferred by maternal pregestational diabetes mellitus neither changed over time nor differed by diabetes subtype. The association with acute pregestational diabetes complications was particularly strong, suggesting a role for glucose in the causal pathway.

    View details for DOI 10.1161/CIRCULATIONAHA.115.017465

    View details for Web of Science ID 000377439900007

    View details for PubMedID 27166384

    View details for PubMedCentralID PMC4890838

  • Meta-analysis of genome-wide association studies reveals genetic overlap between Hodgkin lymphoma and multiple sclerosis INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Khankhanian, P., Cozen, W., Himmelstein, D. S., Madireddy, L., Din, L., van den Berg, A., Matsushita, T., Glaser, S. L., More, J. M., Smedby, K. E., Baranzini, S. E., Mack, T. M., Lizee, A., de Sanjose, S., Gourraud, P., Nieters, A., Hauser, S. L., Cocco, P., Maynadie, M., Foretova, L., Staines, A., Delahaye-Sourdeix, M., Li, D., Bhatia, S., Melbye, M., Onel, K., Jarrett, R., McKay, J. D., Oksenberg, J. R., Hjalgrim, H. 2016; 45 (3): 728-740

    Abstract

    Based on epidemiological commonalities, multiple sclerosis (MS) and Hodgkin lymphoma (HL), two clinically distinct conditions, have long been suspected to be aetiologically related. MS and HL occur in roughly the same age groups, both are associated with Epstein-Barr virus infection and ultraviolet (UV) light exposure, and they cluster mutually in families (though not in individuals). We speculated if in addition to sharing environmental risk factors, MS and HL were also genetically related. Using data from genome-wide association studies (GWAS) of 1816 HL patients, 9772 MS patients and 25 255 controls, we therefore investigated the genetic overlap between the two diseases.From among a common denominator of 404 K single nucleotide polymorphisms (SNPs) studied, we identified SNPs and human leukocyte antigen (HLA) alleles independently associated with both diseases. Next, we assessed the cumulative genome-wide effect of MS-associated SNPs on HL and of HL-associated SNPs on MS. To provide an interpretational frame of reference, we used data from published GWAS to create a genetic network of diseases within which we analysed proximity of HL and MS to autoimmune diseases and haematological and non-haematological malignancies.SNP analyses revealed genome-wide overlap between HL and MS, most prominently in the HLA region. Polygenic HL risk scores explained 4.44% of HL risk (Nagelkerke R(2)), but also 2.36% of MS risk. Conversely, polygenic MS risk scores explained 8.08% of MS risk and 1.94% of HL risk. In the genetic disease network, HL was closer to autoimmune diseases than to solid cancers.HL displays considerable genetic overlap with MS and other autoimmune diseases.

    View details for DOI 10.1093/ije/dyv364

    View details for Web of Science ID 000384653200027

    View details for PubMedID 26971321

    View details for PubMedCentralID PMC5005944

  • Maternal and fetal human leukocyte antigen class Ia and II alleles in severe preeclampsia and eclampsia GENES AND IMMUNITY Emmery, J., Hachmon, R., Pyo, C. W., Nelson, W. C., Geraghty, D. E., Andersen, A. M., Melbye, M., Hviid, T. V. 2016; 17 (4): 251-260

    Abstract

    A line of investigations indicate that genes in the human leukocyte antigen (HLA) complex are involved in a successful acceptance of the semiallogeneic fetus during pregnancy. In this study, associations between specific HLA class Ia (HLA-A and -B) and class II (HLA-DRB1, -DQA1, -DQB1, -DPA1 and -DPB1) alleles and the risk of developing severe preeclampsia/eclampsia were investigated in a detailed and large-scale study. In total, 259 women diagnosed with severe preeclampsia or eclampsia and 260 matched control women with no preeclampsia, together with their neonates, were included in the study. HLA genotyping for mothers and neonates was performed using next-generation sequencing. The HLA-DPB1*04:01:01G allele was significantly more frequent (Pc=0.044) among women diagnosed with severe preeclampsia/eclampsia compared with controls, and the DQA1*01:02:01G allele frequency was significantly lower (Pc=0.042) among newborns born by women with severe preeclampsia/eclampsia compared with controls. In mothers with severe preeclampsia/eclampsia, homozygosity was significantly more common compared with controls at the HLA-DPB1 locus (Pc=0.0028). Although the current large study shows some positive results, more studies, also with a functional focus, are needed to further clarify a possible role of the classical HLA genes in preeclampsia.

    View details for DOI 10.1038/gene.2016.20

    View details for Web of Science ID 000377451500007

    View details for PubMedID 27121092

  • The role of filaggrin mutations during pregnancy and postpartum: atopic dermatitis and genital skin diseases ALLERGY Bager, P., Wohlfahrt, J., Boyd, H., Thyssen, J. P., Melbye, M. 2016; 71 (5): 724-727

    Abstract

    Mutations in the epidermal filaggrin gene (FLG) are associated with skin barrier dysfunction (dry skin, less acidic skin, and fissured skin), and atopic dermatitis (AD) with a severe and persistent course. Because pregnancy and delivery further impairs normal skin barrier functions (immune suppression, mechanical stress), we studied the possible role of FLG mutations on the risk of AD flares, genital infections, and postpartum problems related to perineal trauma. FLG-genotyping was performed in a population-based sample of 1837 women interviewed in the 12th and 30th weeks of pregnancy and 6 months postpartum as part of the Danish National Birth Cohort study 1996-2002. We found that FLG mutations also influence pregnancy-related skin disease; thus, women with FLG mutations had an increased risk of AD flares during pregnancy (OR 10.5, 95% CI 3.6-30.5) and of enduring postpartum physical problems linked to perineal trauma during delivery (OR 11.1, 95% CI 1.1-107.7).

    View details for DOI 10.1111/all.12849

    View details for Web of Science ID 000374989800017

    View details for PubMedID 26835886

  • Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes. Human molecular genetics Machiela, M. J., Lan, Q., Slager, S. L., Vermeulen, R. C., Teras, L. R., Camp, N. J., Cerhan, J. R., Spinelli, J. J., Wang, S. S., Nieters, A., Vijai, J., Yeager, M., Wang, Z., Ghesquières, H., McKay, J., Conde, L., de Bakker, P. I., Cox, D. G., Burdett, L., Monnereau, A., Flowers, C. R., De Roos, A. J., Brooks-Wilson, A. R., Giles, G. G., Melbye, M., Gu, J., Jackson, R. D., Kane, E., Purdue, M. P., Vajdic, C. M., Albanes, D., Kelly, R. S., Zucca, M., Bertrand, K. A., Zeleniuch-Jacquotte, A., Lawrence, C., Hutchinson, A., Zhi, D., Habermann, T. M., Link, B. K., Novak, A. J., Dogan, A., Asmann, Y. W., Liebow, M., Thompson, C. A., Ansell, S. M., Witzig, T. E., Tilly, H., Haioun, C., Molina, T. J., Hjalgrim, H., Glimelius, B., Adami, H., Roos, G., Bracci, P. M., Riby, J., Smith, M. T., Holly, E. A., Cozen, W., Hartge, P., Morton, L. M., Severson, R. K., Tinker, L. F., North, K. E., Becker, N., Benavente, Y., Boffetta, P., Brennan, P., Foretova, L., Maynadie, M., Staines, A., Lightfoot, T., Crouch, S., Smith, A., Roman, E., Diver, W. R., Offit, K., Zelenetz, A., Klein, R. J., Villano, D. J., Zheng, T., Zhang, Y., Holford, T. R., Turner, J., Southey, M. C., Clavel, J., Virtamo, J., Weinstein, S., Riboli, E., Vineis, P., Kaaks, R., Boeing, H., Tjønneland, A., Angelucci, E., di Lollo, S., Rais, M., De Vivo, I., Giovannucci, E., Kraft, P., Huang, J., Ma, B., Ye, Y., Chiu, B. C., Liang, L., Park, J., Chung, C. C., Weisenburger, D. D., Fraumeni, J. F., Salles, G., Glenn, M., Cannon-Albright, L., Curtin, K., Wu, X., Smedby, K. E., de Sanjose, S., Skibola, C. F., Berndt, S. I., Birmann, B. M., Chanock, S. J., Rothman, N. 2016; 25 (8): 1663-1676

    Abstract

    Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 × 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 × 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.

    View details for DOI 10.1093/hmg/ddw027

    View details for PubMedID 27008888

  • Associations between Vitamin D Status and Type 2 Diabetes Measures among Inuit in Greenland May Be Affected by Other Factors PLOS ONE Nielsen, N. O., Bjerregaard, P., Ronn, P. F., Friis, H., Andersen, S., Melbye, M., Lundqvist, M., Cohen, A. S., Hougaard, D. M., Jorgensen, M. E. 2016; 11 (4)

    Abstract

    Epidemiological studies have provided evidence of an association between vitamin D insufficiency and type 2 diabetes. Vitamin D levels have decreased among Inuit in Greenland, and type 2 diabetes is increasing. We hypothesized that the decline in vitamin D could have contributed to the increase in type 2 diabetes, and therefore investigated associations between serum 25(OH)D3 as a measure of vitamin D status and glucose homeostasis and glucose intolerance in an adult Inuit population.2877 Inuit (≥18 years) randomly selected for participation in the Inuit Health in Transition study were included. Fasting- and 2hour plasma glucose and insulin, C-peptide and HbA1c were measured, and associations with serum 25(OH)D3 were analysed using linear and logistic regression. A subsample of 330 individuals who also donated a blood sample in 1987, were furthermore included.After adjustment, increasing serum 25(OH)D3 (per 10 nmol/L) was associated with higher fasting plasma glucose (0.02 mmol/L, p = 0.004), 2hour plasma glucose (0.05 nmol/L, p = 0.002) and HbA1c (0.39%, p<0.001), and with lower beta-cell function (-1.00 mmol/L, p<0.001). Serum 25(OH)D3 was positively associated with impaired fasting glycaemia (OR: 1.08, p = 0.001), but not with IGT or type 2 diabetes.Our results did not support an association between low vitamin D levels and risk of type 2 diabetes. Instead, we found weak positive associations between vitamin D levels and fasting- and 2hour plasma glucose levels, HbA1c and impaired fasting glycaemia, and a negative association with beta-cell function, underlining the need for determination of the causal relationship.

    View details for DOI 10.1371/journal.pone.0152763

    View details for Web of Science ID 000374131200036

    View details for PubMedID 27073876

    View details for PubMedCentralID PMC4830590

  • ABO Blood Group and Risk of Thromboembolic and Arterial Disease A Study of 1.5 Million Blood Donors CIRCULATION Vasan, S. K., Rostgaard, K., Majeed, A., Ullum, H., Titlestad, K., Pedersen, O. B., Erikstrup, C., Nielsen, K. R., Melbye, M., Nyren, O., Hjalgrim, H., Edgren, G. 2016; 133 (15): 1449-1457

    Abstract

    ABO blood groups have been shown to be associated with increased risks of venous thromboembolic and arterial disease. However, the reported magnitude of this association is inconsistent and is based on evidence from small-scale studies.We used the SCANDAT2 (Scandinavian Donations and Transfusions) database of blood donors linked with other nationwide health data registers to investigate the association between ABO blood groups and the incidence of first and recurrent venous thromboembolic and arterial events. Blood donors in Denmark and Sweden between 1987 and 2012 were followed up for diagnosis of thromboembolism and arterial events. Poisson regression models were used to estimate incidence rate ratios as measures of relative risk. A total of 9170 venous and 24 653 arterial events occurred in 1 112 072 individuals during 13.6 million person-years of follow-up. Compared with blood group O, non-O blood groups were associated with higher incidence of both venous and arterial thromboembolic events. The highest rate ratios were observed for pregnancy-related venous thromboembolism (incidence rate ratio, 2.22; 95% confidence interval, 1.77-2.79), deep vein thrombosis (incidence rate ratio, 1.92; 95% confidence interval, 1.80-2.05), and pulmonary embolism (incidence rate ratio, 1.80; 95% confidence interval, 1.71-1.88).In this healthy population of blood donors, non-O blood groups explain >30% of venous thromboembolic events. Although ABO blood groups may potentially be used with available prediction systems for identifying at-risk individuals, its clinical utility requires further comparison with other risk markers.

    View details for DOI 10.1161/CIRCULATIONAHA.115.017563

    View details for Web of Science ID 000373933400004

    View details for PubMedID 26939588

  • Determination of NAT2 acetylation status in the Greenlandic population ARCHIVES OF TOXICOLOGY Geller, F., Soborg, B., Koch, A., Michelsen, S. W., Bjorn-Mortensen, K., Carstensen, L., Birch, E., Nordholm, A. C., Johansen, M. M., Borresen, M. L., Feenstra, B., Melbye, M. 2016; 90 (4): 883-889

    Abstract

    N-acetyltransferase 2 (NAT2) is a well-studied phase II xenobiotic metabolizing enzyme relevant in drug metabolism and cancerogenesis. NAT2 activity is largely determined by genetic polymorphisms in the coding region of the corresponding gene. We investigated NAT2 acetylation status in 1556 individuals from Greenland based on four different single nucleotide polymorphism (SNP) panels and the tagging SNP rs1495741. There was good concordance between the NAT2 status inferred by the different SNP combinations. Overall, the fraction of slow acetylators was low with 17.5 % and varied depending on the degree of Inuit ancestry; in individuals with <50 % Inuit ancestry, we observed more than 25 % slow acetylators reflecting European ancestry. Greenland has a high incidence of tuberculosis, and individual dosing of isoniazid according to NAT2 status has been shown to improve treatment and reduce side effects. Our findings could be a first step in pharmacogenetics-based tuberculosis therapy in Greenland.

    View details for DOI 10.1007/s00204-015-1501-1

    View details for Web of Science ID 000372427900011

    View details for PubMedID 25794903

  • Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Tyrrell, J., Richmond, R. C., Palmer, T. M., Feenstra, B., Rangarajan, J., Metrustry, S., Cavadino, A., Paternoster, L., Armstrong, L. L., De Silva, N. M., Wood, A. R., Horikoshi, M., Geller, F., Myhre, R., Bradfield, J. P., Kreiner-Moller, E., Huikari, V., Painter, J. N., Hottenga, J., Allard, C., Berry, D. J., Bouchard, L., Das, S., Evans, D. M., Hakonarson, H., Hayes, M. G., Heikkinen, J., Hofman, A., Knight, B., Lind, P. A., McCarthy, M. I., McMahon, G., Medland, S. E., Melbye, M., Morris, A. P., Nodzenski, M., Reichetzeder, C., Ring, S. M., Sebert, S., Sengpiel, V., Sorensen, T. I., Willemsen, G., de Geus, E. J., Martin, N. G., Spector, T. D., Power, C., Jarvelin, M., Bisgaard, H., Grant, S. F., Nohr, E. A., Jaddoe, V. W., Jacobsson, B., Murray, J. C., Hocher, B., Hattersley, A. T., Scholtens, D. M., Smith, G. D., Hivert, M., Felix, J. F., Hypponen, E., Lowe, W. L., Frayling, T. M., Lawlor, D. A., Freathy, R. M. 2016; 315 (11): 1129-1140

    Abstract

    Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included.Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level.Offspring birth weight from 18 studies.Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions.In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.

    View details for DOI 10.1001/jama.2016.1975

    View details for Web of Science ID 000372159800018

    View details for PubMedID 26978208

    View details for PubMedCentralID PMC4811305

  • Association between pregnancy losses in women and risk of atherosclerotic disease in their relatives: a nationwide cohort study EUROPEAN HEART JOURNAL Ranthe, M. F., Diaz, L. J., Behrens, I., Bundgaard, H., Simonsen, J., Melbye, M., Boyd, H. A. 2016; 37 (11): 900-907

    Abstract

    A common underlying mechanism with a genetic component could link pregnancy losses with vascular disease. We examined whether pregnancy losses (miscarriages and stillbirths) and atherosclerotic outcomes co-aggregated in families.Using Danish registers, we identified women with pregnancies in 1977-2008, and their parents (>1 million) and brothers (>435 000). We followed parents for incident ischaemic heart disease (IHD), myocardial infarction (MI), and cerebrovascular infarction (CVI), and brothers for a broader combined atherosclerotic endpoint. Using Cox regression, we estimated hazard ratios (HRs) for each outcome by history of pregnancy loss in daughters/sisters. Overall, parents whose daughters had 1, 2, and ≥3 miscarriages had 1.01 [95% confidence interval (CI) 0.99-1.04], 1.07 (95% CI 1.02-1.11), and 1.10 (95% CI 1.02-1.19) times the rate of MI, respectively, as parents whose daughters had no miscarriages. For parents with ≥3 daughters, the HRs were 1.12 (95% CI 1.02-1.24), 1.29 (95% CI 1.13-1.48), and 1.33 (95% CI 1.12-1.57). Effect magnitudes did not differ for fathers and mothers. We observed similar patterns for IHD and CVI (parents) and the atherosclerotic endpoint (brothers). Parents whose daughters had stillbirths had 1.14 (95% CI 1.05-1.24) and 1.07 (95% CI 0.96-1.18) times the rates of MI and CVI, respectively, as parents whose daughters had no stillbirths.Certain pregnancy losses and atherosclerotic diseases in both heart and brain may have a common aetiologic mechanism. Women in families with atherosclerotic disease may be predisposed to pregnancy loss; conversely, pregnancy losses in first-degree relatives may have implications for atherosclerotic disease risk.

    View details for DOI 10.1093/eurheartj/ehv549

    View details for Web of Science ID 000372400400013

    View details for PubMedID 26497162

  • Association Between Hypertensive Disorders of Pregnancy and Later Risk of Cardiomyopathy JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Behrens, I., Basit, S., Lykke, J. A., Ranthe, M. F., Wohlfahrt, J., Bundgaard, H., Melbye, M., Boyd, H. A. 2016; 315 (10): 1026-1033

    Abstract

    Women with hypertensive disorders of pregnancy, preeclampsia in particular, have an increased risk of cardiomyopathy during the peripartum period. Whether hypertensive disorders of pregnancy are also associated with cardiomyopathy later in life is unknown.To determine whether hypertensive disorders of pregnancy are associated with cardiomyopathy beyond the peripartum period.Nationwide register-based cohort study using Cox regression to compare rates of cardiomyopathy in women with and without a history of hypertensive disorders of pregnancy in a cohort of 1,075,763 women with at least 1 pregnancy ending in live birth or stillbirth in Denmark, 1978-2012, with follow-up through December 31, 2012.A hypertensive disorder of pregnancy (severe or moderate preeclampsia or gestational hypertension) registered in the National Patient Register.Cardiomyopathy more than 5 months after delivery (outside the peripartum period) up to 34 years 7 months.The women in the primary cohort had 2,067,633 eligible pregnancies during the study period, 76,108 of which were complicated by a hypertensive disorder of pregnancy. During follow-up, 1577 women (mean age, 48.5 years at cardiomyopathy diagnosis; 2.6% with multiple pregnancies) developed cardiomyopathy. Compared with women with normotensive pregnancies (18,211,603 person-years of follow-up; n = 1408 cardiomyopathy events, 7.7/100,000 person-years [95% CI, 7.3-8.2]), women with a history of hypertensive disorders of pregnancy had significantly increased rates of cardiomyopathy (in 173,062 person-years of follow-up among women with severe preeclampsia, n = 27 cardiomyopathy events; 15.6/100,000 person-years [95% CI, 10.7-22.7]; adjusted hazard ratio [HR], 2.20 [95% CI, 1.50-3.23]; in 697,447 person-years of follow-up among women with moderate preeclampsia, n = 102 cardiomyopathy events; 14.6/100,000 person-years [95% CI, 12.0-17.8]; adjusted HR, 1.89 [95% CI, 1.55-2.23]; in 213,197 person-years of follow-up among women with gestational hypertension, n = 40 cardiomyopathy events; 17.3/100,000 person-years [95% CI, 12.7-23.6]; adjusted HR, 2.06 [95% CI, 1.50-2.82]). These increases persisted more than 5 years after the latest pregnancy. Mediation analyses suggested that only about 50% of the association was an indirect association through postpregnancy chronic hypertension. In this cohort, 11% of all cardiomyopathy events occurred in women with a history of hypertensive disorders of pregnancy.Women with a history of hypertensive disorders of pregnancy, compared with women without such a history, had a small but statistically significant increased risk of cardiomyopathy more than 5 months after delivery. Further research is necessary to understand whether there is a causal mechanism behind this association.

    View details for DOI 10.1001/jama.2016.1869

    View details for Web of Science ID 000371540200015

    View details for PubMedID 26954411

  • Filaggrin genotype and skin diseases independent of atopic dermatitis in childhood PEDIATRIC ALLERGY AND IMMUNOLOGY Bager, P., Wohlfahrt, J., Thyssen, J. P., Melbye, M. 2016; 27 (2): 162-168

    Abstract

    Filaggrin gene (FLG) mutations compromise skin barrier functions and increase risk of atopic dermatitis. We aimed to study effects on other skin diseases using unique data from the Danish registers.FLG genotyping of a population-based sample of 1547 children with extracted DNA and information on skin diseases from the Danish National Birth Cohort and Health Register, with 18 years follow-up during years 1996-2013. Odds ratios (OR) and hazard ratios (HR) were estimated using logistic regression and Cox regression, respectively, and adjusted for physician-diagnosed atopic dermatitis.FLG mutations were associated with increased risk of dry skin (OR 1.9, CI 1.1-3.1), and a decreased risk of fungal skin infections at age <18 months (OR 0.2, CI 0.1-0.8). There was no association with wart treatments (HR 1.0, CI 0.6-1.7). FLG mutations were associated with an increased risk of atopic dermatitis (OR 3.3, CI 2.1-5.3), dermatology consultations for allergy or rash (HR 2.2, CI 1.4-3.5), basic dermatology consultations at age <5 years (HR 2.2, CI 1.7-2.9), urticaria at age <18 months (OR 2.9, CI 1.0-7.9), and other rash at age <18 months (OR 2.1, CI 1.2-3.8).FLG mutations may predispose to skin disease in young children including urticaria, and rash not recognized as atopic dermatitis although equally frequent. In clinical practice, FLG genotyping may help indicate the use of moisturizers to reduce skin problems.

    View details for DOI 10.1111/pai.12511

    View details for Web of Science ID 000371506900009

    View details for PubMedID 26594040

  • Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia NATURE COMMUNICATIONS Berndt, S. I., Camp, N. J., Skibola, C. F., Vijai, J., Wang, Z., Gu, J., Nieters, A., Kelly, R. S., Smedby, K. E., Monnereau, A., Cozen, W., Cox, A., Wang, S. S., Lan, Q., Teras, L. R., Machado, M., Yeager, M., Brooks-Wilson, A. R., Hartge, P., Purdue, M. P., Birmann, B. M., Vajdic, C. M., Cocco, P., Zhang, Y., Giles, G. G., Zeleniuch-Jacquotte, A., Lawrence, C., Montalvan, R., Burdett, L., Hutchinson, A., Ye, Y., Call, T. G., Shanafelt, T. D., Novak, A. J., Kay, N. E., Liebow, M., Cunningham, J. M., Allmer, C., Hjalgrim, H., Adami, H., Melbye, M., Glimelius, B., Chang, E. T., Glenn, M., Curtin, K., Cannon-Albright, L. A., Diver, W. R., Link, B. K., Weiner, G. J., Conde, L., Bracci, P. M., Riby, J., Arnett, D. K., Zhi, D., Leach, J. M., Holly, E. A., Jackson, R. D., Tinker, L. F., Benavente, Y., Sala, N., Casabonne, D., Becker, N., Boffetta, P., Brennan, P., Foretova, L., Maynadie, M., McKay, J., Staines, A., Chaffee, K. G., Achenbach, S. J., Vachon, C. M., Goldin, L. R., Strom, S. S., Leis, J. F., Weinberg, J. B., Caporaso, N. E., Norman, A. D., De Roos, A. J., Morton, L. M., Severson, R. K., Riboli, E., Vineis, P., Kaaks, R., Masala, G., Weiderpass, E., Chirlaque, M., Vermeulen, R. C., Travis, R. C., Southey, M. C., Milne, R. L., Albanese, D., Virtamo, J., Weinstein, S., Clavel, J., Zheng, T., Holford, T. R., Villano, D. J., Maria, A., Spinelli, J. J., Gascoyne, R. D., Connors, J. M., Bertrand, K. A., Giovannucci, E., Kraft, P., Kricker, A., Turner, J., Ennas, M. G., Ferri, G. M., Miligi, L., Liang, L., Ma, B., Huang, J., Crouch, S., Park, J., Chatterjee, N., North, K. E., Snowden, J. A., Wright, J., Fraumeni, J. F., Offit, K., Wu, X., de Sanjose, S., Cerhan, J. R., Chanock, S. J., Rothman, N., Slager, S. L. 2016; 7

    Abstract

    Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10(-11)), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10(-8)) and 3q28 (rs9815073, LPP, P=3.62 × 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10(-11)) in the combined analysis. We find suggestive evidence (P<5 × 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.

    View details for DOI 10.1038/ncomms10933

    View details for PubMedID 26956414

  • Oral fluoroquinolone use and serious arrhythmia: bi-national cohort study BMJ-BRITISH MEDICAL JOURNAL Inghammar, M., Svanstrom, H., Melbye, M., Pasternak, B., Hviid, A. 2016; 352

    Abstract

    To evaluate if oral fluoroquinolone use is associated with an increased risk of serious arrhythmia.Bi-national cohort study, linking register data on filled prescriptions, cases of serious arrhythmia, and patient characteristics.Denmark, 1997-2011; Sweden, 2006-13.The study cohort was derived from a source population of all Danish and Swedish adults, aged 40 to 79 years. 909,656 courses of fluoroquinolone use (ciprofloxacin 82.6%, norfloxacin 12.1%, ofloxacin 3.2%, moxifloxacin 1.2%, and other fluoroquinolones 0.9%) and 909,656 courses of penicillin V use, matched 1:1 on propensity score, were included.The main outcome was risk of serious arrhythmia (fatal and non-fatal), comparing courses of fluoroquinolone use with courses of penicillin V use (an antibiotic with no pro-arrhythmic effect). The risk period of interest was current use, defined as days 0-7 of treatment. Subgroup analyses were conducted according to country, sex, age, underlying cardiovascular disease, concomitant use of drugs known to increase the risk of torsades de pointes, fluoroquinolone type, and levels of arrhythmia risk score.144 cases of serious arrhythmia occurred during follow-up, 66 among current fluoroquinolone users (incidence rate 3.4 per 1000 person years) and 78 among current penicillin users (4.0 per 1000 person years); comparing oral fluoroquinolone treatment with penicillin V, the rate ratio was 0.85 (95% confidence interval 0.61 to 1.18). Compared with penicillin V, the absolute risk difference was -13 (95% confidence interval -35 to 16) cases of serious arrhythmia per 1,000,000 courses of fluoroquinolones. The risk of serious arrhythmia was not statistically significantly increased in any of the subgroups, including analyses by fluoroquinolone type.Contrary to previous reports, oral fluoroquinolone treatment was not associated with an increased risk of serious arrhythmia in the general adult populations of Denmark and Sweden. Given the statistical power of the study, even small increases in relative and absolute risk could be ruled out. Since ciprofloxacin was the most commonly used fluoroquinolone in our study, we cannot exclude that intraclass differences influence the risk of serious arrhythmia associated with other less frequently used fluoroquinolones.

    View details for DOI 10.1136/bmj.i843

    View details for Web of Science ID 000371116900002

    View details for PubMedID 26920666

    View details for PubMedCentralID PMC4770814

  • Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index. Human molecular genetics Felix, J. F., Bradfield, J. P., Monnereau, C., van der Valk, R. J., Stergiakouli, E., Chesi, A., Gaillard, R., Feenstra, B., Thiering, E., Kreiner-Møller, E., Mahajan, A., Pitkänen, N., Joro, R., Cavadino, A., Huikari, V., Franks, S., Groen-Blokhuis, M. M., Cousminer, D. L., Marsh, J. A., Lehtimäki, T., Curtin, J. A., Vioque, J., Ahluwalia, T. S., Myhre, R., Price, T. S., Vilor-Tejedor, N., Yengo, L., Grarup, N., Ntalla, I., Ang, W., Atalay, M., Bisgaard, H., Blakemore, A. I., Bonnefond, A., Carstensen, L., Eriksson, J., Flexeder, C., Franke, L., Geller, F., Geserick, M., Hartikainen, A., Haworth, C. M., Hirschhorn, J. N., Hofman, A., Holm, J., Horikoshi, M., Hottenga, J. J., Huang, J., Kadarmideen, H. N., Kähönen, M., Kiess, W., Lakka, H., Lakka, T. A., Lewin, A. M., Liang, L., Lyytikäinen, L., Ma, B., Magnus, P., McCormack, S. E., McMahon, G., Mentch, F. D., Middeldorp, C. M., Murray, C. S., Pahkala, K., Pers, T. H., Pfäffle, R., Postma, D. S., Power, C., Simpson, A., Sengpiel, V., Tiesler, C. M., Torrent, M., Uitterlinden, A. G., van Meurs, J. B., Vinding, R., Waage, J., Wardle, J., Zeggini, E., Zemel, B. S., Dedoussis, G. V., Pedersen, O., Froguel, P., Sunyer, J., Plomin, R., Jacobsson, B., Hansen, T., Gonzalez, J. R., Custovic, A., Raitakari, O. T., Pennell, C. E., Widén, E., Boomsma, D. I., Koppelman, G. H., Sebert, S., Järvelin, M., Hyppönen, E., McCarthy, M. I., Lindi, V., Harri, N., Körner, A., Bønnelykke, K., Heinrich, J., Melbye, M., Rivadeneira, F., Hakonarson, H., Ring, S. M., Smith, G. D., Sørensen, T. I., Timpson, N. J., Grant, S. F., Jaddoe, V. W. 2016; 25 (2): 389-403

    Abstract

    A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.

    View details for DOI 10.1093/hmg/ddv472

    View details for PubMedID 26604143

    View details for PubMedCentralID PMC4854022

  • Supplemental folic acid in pregnancy and childhood cancer risk BRITISH JOURNAL OF CANCER Mortensen, J. H., Oyen, N., Fomina, T., Melbye, M., Tretli, S., Vollset, S. E., Bjorge, T. 2016; 114 (1): 71-75
  • Maternal use of oral contraceptives and risk of birth defects in Denmark: prospective, nationwide cohort study BMJ-BRITISH MEDICAL JOURNAL Charlton, B. M., Molgaard-Nielsen, D., Svanstroem, H., Wohlfahrt, J., Pasternak, B., Melbye, M. 2016; 352

    Abstract

    Is oral contraceptive use around the time of pregnancy onset associated with an increased risk of major birth defects?In a prospective observational cohort study, data on oral contraceptive use and major birth defects were collected among 880,694 live births from Danish registries between 1997 and 2011. We conservatively assumed that oral contraceptive exposure lasted up to the most recently filled prescription. The main outcome measure was the number of major birth defects throughout one year follow-up (defined according to the European Surveillance of Congenital Anomalies classification). Logistic regression estimated prevalence odds ratios of any major birth defect as well as categories of birth defect subgroups.Prevalence of major birth defects (per 1000 births) was consistent across each oral contraceptive exposure group (25.1, never users; 25.0, use >3 months before pregnancy onset (reference group); 24.9, use 0-3 months before pregnancy onset (that is, recent use); 24.8, use after pregnancy onset). No increase in prevalence of major birth defects was seen with oral contraceptive exposure among women with recent use before pregnancy (prevalence odds ratio 0.98 (95% confidence interval 0.93 to 1.03)) or use after pregnancy onset (0.95 (0.84 to 1.08)), compared with the reference group. There was also no increase in prevalence of any birth defect subgroup (for example, limb defects). It is unknown whether women took oral contraceptives up to the date of their most recently filled prescription. Also, the rarity of birth defects made disaggregation of the results difficult. Residual confounding was possible, and the analysis lacked information on folate, one of the proposed mechanisms.Oral contraceptive exposure just before or during pregnancy does not appear to be associated with an increased risk of major birth defects.BMC was funded by the Harvard T H Chan School of Public Health's Maternal Health Task Force and Department of Epidemiology Rose Traveling Fellowship; training grant T32HD060454 in reproductive, perinatal, and paediatric epidemiology and award F32HD084000 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development; and grant T32CA09001 from the National Cancer Institute. The authors have no competing interests or additional data to share.

    View details for DOI 10.1136/bmj.h6712

    View details for Web of Science ID 000368059200012

    View details for PubMedID 26738512

    View details for PubMedCentralID PMC4703703

  • Association Between Use of Oral Fluconazole During Pregnancy and Risk of Spontaneous Abortion and Stillbirth JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Molgaard-Nielsen, D., Svanstrom, H., Melbye, M., Hviid, A., Pasternak, B. 2016; 315 (1): 58-67

    Abstract

    Vaginal candidiasis is common during pregnancy. Although intravaginal formulations of topical azole antifungals are first-line treatment for pregnant women, oral fluconazole is often used despite limited safety information.To study the association between oral fluconazole exposure during pregnancy and the risk of spontaneous abortion and stillbirth.Nationwide register-based cohort study in Denmark, 1997-2013. From a cohort of 1,405,663 pregnancies, oral fluconazole-exposed pregnancies were compared with up to 4 unexposed pregnancies matched on propensity score, maternal age, calendar year, and gestational age (based on gestational age at first day of treatment with eligible controls surviving through this date). To test for confounding by indication, pregnancies exposed to intravaginal formulations of topical azoles were used as an additional comparator group.Filled prescriptions for oral fluconazole were obtained from the National Prescription Register.Hazard ratios (HRs) for spontaneous abortion and stillbirth, estimated using proportional hazards regression.Among 3315 women exposed to oral fluconazole from 7 through 22 weeks' gestation, 147 experienced a spontaneous abortion, compared with 563 among 13,246 unexposed matched women. There was a significantly increased risk of spontaneous abortion associated with fluconazole exposure (HR, 1.48; 95% CI, 1.23-1.77). Among 5382 women exposed to fluconazole from gestational week 7 to birth, 21 experienced a stillbirth, compared with 77 among 21,506 unexposed matched women. There was no significant association between fluconazole exposure and stillbirth (HR, 1.32 [95% CI, 0.82-2.14]). Using topical azole exposure as the comparison, 130 of 2823 women exposed to fluconazole vs 118 of 2823 exposed to topical azoles had a spontaneous abortion (HR, 1.62 [95% CI, 1.26-2.07]); 20 of 4301 women exposed to fluconazole vs 22 of 4301 exposed to topical azoles had a stillbirth (HR, 1.18 [95% CI, 0.64-2.16]).In this nationwide cohort study in Denmark, use of oral fluconazole in pregnancy was associated with a statistically significant increased risk of spontaneous abortion compared with risk among unexposed women and women with topical azole exposure in pregnancy. Until more data on the association are available, cautious prescribing of fluconazole in pregnancy may be advisable. Although the risk of stillbirth was not significantly increased, this outcome should be investigated further.

    View details for DOI 10.1001/jama.2015.17844

    View details for Web of Science ID 000367523000015

    View details for PubMedID 26746458

  • Common variants upstream of KDR encoding VEGFR2 and in TTC39B associate with endometriosis. Nature communications Steinthorsdottir, V., Thorleifsson, G., Aradottir, K., Feenstra, B., Sigurdsson, A., Stefansdottir, L., Kristinsdottir, A. M., Zink, F., Halldorsson, G. H., Munk Nielsen, N., Geller, F., Melbye, M., Gudbjartsson, D. F., Geirsson, R. T., Thorsteinsdottir, U., Stefansson, K. 2016; 7: 12350-?

    Abstract

    We conducted a genome-wide association scan (GWAS) of endometriosis using 25.5 million sequence variants detected through whole-genome sequencing (WGS) of 8,453 Icelanders and imputed into 1,840 cases and 129,016 control women, followed by testing of associated variants in Danish samples. Here we report the discovery of a new endometriosis susceptibility locus on 4q12 (rs17773813[G], OR=1.28; P=3.8 × 10(-11)), upstream of KDR encoding vascular endothelial growth factor receptor 2 (VEGFR2). The variant correlates with disease severity (P=0.0046) when moderate/severe endometriosis cases are tested against minimal/mild cases. We further report association of rs519664[T] in TTC39B on 9p22 with endometriosis (P=4.8 × 10(-10); OR=1.29). The involvement of KDR in endometriosis risk highlights the importance of the VEGF pathway in the pathogenesis of the disease.

    View details for DOI 10.1038/ncomms12350

    View details for PubMedID 27453397

    View details for PubMedCentralID PMC4962463

  • Supplemental folic acid in pregnancy and childhood cancer risk. British journal of cancer Mortensen, J. H., Øyen, N., Fomina, T., Melbye, M., Tretli, S., Vollset, S. E., Bjørge, T. 2016; 114 (1): 71–75

    Abstract

    We investigated the association between supplemental folic acid in pregnancy and childhood cancer in a nation-wide study of 687 406 live births in Norway, 1999-2010, and 799 children diagnosed later with cancer.Adjusted hazard ratios (HRs) compared cancer risk in children by approximated periconceptional folic acid levels (folic acid tablets and multivitamins (0.6 mg), only folic acid (0.4 mg), only multivitamins (0.2 mg)) and cancer risk in unexposed.Any folic acid levels were not associated with leukemia (e.g., high-level folic acid HR 1.25; 95% CI 0.89-1.76, PTrend 0.20), lymphoma (HR 0.96; 95% CI 0.42-2.21, PTrend 0.51), central nervous system tumours (HR 0.68; 95% CI 0.42-1.10, PTrend 0.32), neuroblastoma (HR 1.05; 95% CI 0.53-2.06, PTrend 0.85), Wilms' tumour (HR 1.16; 95% CI 0.52-2.58, PTrend 0.76), or soft-tissue tumours (HR 0.77; 95% CI 0.34-1.75, PTrend 0.90).Folic acid supplementation was not associated with risk of major childhood cancers.

    View details for PubMedID 26757423

    View details for PubMedCentralID PMC4716548

  • Effect of the 13-valent pneumococcal conjugate vaccine on nasopharyngeal carriage by respiratory pathogens among Greenlandic children Navne, J., Borresen, M., Slotved, H., Melbye, M., Ladefoged, K., Koch, A. TAYLOR & FRANCIS LTD. 2016: 38
  • Determination of NAT2 acetylation status in the Greenlandic population - an enzyme related to tuberculosis therapy Geller, F., Soborg, B., Koch, A., Michelsen, S., Feenstra, B., Melbye, M. TAYLOR & FRANCIS LTD. 2016: 82
  • Supplemental folic acid in pregnancy and maternal cancer risk CANCER EPIDEMIOLOGY Mortensen, J. H., Oyen, N., Fomina, T., Melbye, M., Tretli, S., Vollset, S. E., Bjorge, T. 2015; 39 (6): 805-811

    Abstract

    There is evidence that increased intake of folate protects against the development of several types of cancer. Some studies have, however, raised concern about the safety of folate in relation to cancer risk. Here we examined the risk of maternal cancer after intake of supplemental folic acid in pregnancy.This is a population-based cohort study comprising 429,004 women with data from the Medical Birth Registry of Norway, the Cancer Registry of Norway, and other national registries from 1999 to 2010. Altogether 3781 cancer cases were identified during follow-up (average 7 years). Cox proportional hazards regression models were used to estimate hazard ratios of maternal cancer according to folic acid use prior to and during one or two or more pregnancies as compared to no supplement use.Folic acid supplementation use had no overall effect on cancer risk in women using folic acid supplementation in one (HR 1.08; 95% CI 1.00-1.18) or two or more pregnancies (HR 1.06; 95% CI 0.91-1.22) (ptrend=0.12). Analyses of 13 cancer types revealed no associations between folic acid and cancer.Folic acid supplementation before and during pregnancy had no overall effect on maternal cancer risk.Folic acid substitution before and/or during pregnancy does not increase the short-term overall maternal cancer risk.

    View details for DOI 10.1016/j.canep.2015.10.009

    View details for Web of Science ID 000367444300003

  • A Novel Risk Locus at 6p21.3 for Epstein-Barr Virus-Positive Hodgkin Lymphoma CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Delahaye-Sourdeix, M., Urayama, K. Y., Gaborieau, V., Veenstra, R., Foll, M., Chabrier, A., Benavente, Y., Nieters, A., Becker, N., Foretova, L., Maynadie, M., Staines, A., Smedby, K. E., Glimelius, I., Lightfoot, T., Cocco, P., Galan, P., Vatten, L. J., Duell, E. J., Kiemeney, L., Roman, E., de Sanjose, S., Lathrop, M., Melbye, M., Brennan, P., Diepstra, A., van den Berg, A., Hjalgrim, H., Jarrett, R. F., McKay, J. D. 2015; 24 (12): 1838-1843

    Abstract

    A proportion of the genetic variants involved in susceptibility to Hodgkin lymphoma differ by the tumor's Epstein-Barr virus (EBV) status, particularly within the MHC region.We have conducted an SNP imputation study of the MHC region, considering tumor EBV status in 1,200 classical Hodgkin lymphoma (cHL) cases and 5,726 control subjects of European origin. Notable findings were genotyped in an independent study population of 468 cHL cases and 551 controls.We identified and subsequently replicated a novel association between a common genetic variant rs6457715 and cHL. Although strongly associated with EBV-positive cHL [OR, 2.33; 95% confidence interval (CI), 1.83-2.97; P = 7 × 10(-12)], there was little evidence for association between rs6457715 and the EBV-negative subgroup of cHL (OR, 1.06; 95% CI, 0.92-1.21), indicating that this association was specific to the EBV-positive subgroup (Phet < P = 10(-8)). Furthermore, the association was limited to EBV-positive cHL subgroups within mixed cell (MCHL) and nodular sclerosis subtypes (NSHL), suggesting that the association is independent of histologic subtype of cHL.rs6457715, located near the HLA-DPB1 gene, is associated with EBV-positive cHL and suggests this region as a novel susceptibility locus for cHL.This expands the number of genetic variants that are associated with cHL and provides additional evidence for a critical and specific role of EBV in the etiology of this disease.

    View details for DOI 10.1158/1055-9965.EPI-15-0534

    View details for Web of Science ID 000366129100004

    View details for PubMedID 26404960

  • Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Sampson, J. N., Wheeler, W. A., Yeager, M., Panagiotou, O., Wang, Z., Berndt, S. I., Lan, Q., Abnet, C. C., Amundadottir, L. T., Figueroa, J. D., Landi, M. T., Mirabello, L., Savage, S. A., Taylor, P. R., De Vivo, I., McGlynn, K. A., Purdue, M. P., Rajaraman, P., Adami, H., Ahlbom, A., Albanes, D., Amary, M. F., An, S., Andersson, U., Andriole, G., Andrulis, I. L., Angelucci, E., Ansell, S. M., Arici, C., Armstrong, B. K., Arslan, A. A., Austin, M. A., Baris, D., Barkauskas, D. A., Bassig, B. A., Becker, N., Benavente, Y., Benhamou, S., Berg, C., Van Den Berg, D., Bernstein, L., Bertrand, K. A., Birmann, B. M., Black, A., Boeing, H., Boffetta, P., Boutron-Ruault, M., Bracci, P. M., Brinton, L., Brooks-Wilson, A. R., Bueno-de-Mesquita, H. B., Burdett, L., Buring, J., Butler, M. A., Cai, Q., Cancel-Tassin, G., Canzian, F., Carrato, A., Carreon, T., Carta, A., Chan, J. K., Chang, E. T., Chang, G., Chang, I., Chang, J., Chang-Claude, J., Chen, C., Chen, C., Chen, C., Chen, C., Chen, C., Chen, H., Chen, K., Chen, K., Chen, K., Chen, Y., Chen, Y., Chen, Y., Chen, Y., Chien, L., Chirlaque, M., Choi, J. E., Choi, Y. Y., Chow, W., Chung, C. C., Clavel, J., Clavel-Chapelon, F., Cocco, P., Colt, J. S., Comperat, E., Conde, L., Connors, J. M., Conti, D., Cortessis, V. K., Cotterchio, M., Cozen, W., Crouch, S., Crous-Bou, M., Cussenot, O., Davis, F. G., Ding, T., Diver, W. R., Dorronsoro, M., Dossus, L., Duell, E. J., Ennas, M. G., Erickson, R. L., Feychting, M., Flanagan, A. M., Foretova, L., Fraumeni, J. F., Freedman, N. D., Freeman, L. E., Fuchs, C., Gago-Dominguez, M., Gallinger, S., Gao, Y., Gapstur, S. M., Garcia-Closas, M., Garcia-Closas, R., Gascoyne, R. D., Gastier-Foster, J., Gaudet, M. M., Gaziano, J. M., Giffen, C., Giles, G. G., Giovannucci, E., Glimelius, B., Goggins, M., Gokgoz, N., Goldstein, A. M., Gorlick, R., Gross, M., Grubb, R., Gu, J., Guan, P., Gunter, M., Guo, H., Habermann, T. M., Haiman, C. A., Halai, D., Hallmans, G., Hassan, M., Hattinger, C., He, Q., He, X., Helzlsouer, K., Henderson, B., Henriksson, R., Hjalgrim, H., Hoffman-Bolton, J., Hohensee, C., Holford, T. R., Holly, E. A., Hong, Y., Hoover, R. N., Horn-Ross, P. L., Hosain, G. M., Hosgood, H. D., Hsiao, C., Hu, N., Hu, W., Hu, Z., Huang, M., Huerta, J., Hung, J., Hutchinson, A., Inskip, P. D., Jackson, R. D., Jacobs, E. J., Jenab, M., Jeon, H., Ji, B., Jin, G., Jin, L., Johansen, C., Johnson, A., Jung, Y. J., Kaaks, R., Kamineni, A., Kane, E., Kang, C. H., Karagas, M. R., Kelly, R. S., Khaw, K., Kim, C., Kim, H. N., Kim, J. H., Kim, J. S., Kim, Y. H., Kim, Y. T., Kim, Y., Kitahara, C. M., Klein, A. P., Klein, R. J., Kogevinas, M., Kohno, T., Kolonel, L. N., Kooperberg, C., Kricker, A., Krogh, V., Kunitoh, H., Kurtz, R. C., Kweon, S., LaCroix, A., Lawrence, C., Lecanda, F., Lee, V. H., Li, D., Li, H., Li, J., Li, Y., Li, Y., Liao, L. M., Liebow, M., Lightfoot, T., Lim, W., Lin, C., Lin, D., Lindstrom, S., Linet, M. S., Link, B. K., Liu, C., Liu, J., Liu, L., Ljungberg, B., Lloreta, J., di Lollo, S., Lu, D., Lund, E., Malats, N., Mannisto, S., Le Marchand, L., Marina, N., Masala, G., Mastrangelo, G., Matsuo, K., Maynadie, M., McKay, J., McKean-Cowdin, R., Melbye, M., Melin, B. S., Michaud, D. S., Mitsudomi, T., Monnereau, A., Montalvan, R., Moore, L. E., Mortensen, L. M., Nieters, A., North, K. E., Novak, A. J., Oberg, A. L., Offit, K., Oh, I., Olson, S. H., Palli, D., Pao, W., Park, I. K., Park, J. Y., Park, K. H., Patino-Garcia, A., Pavanello, S., Peeters, P. H., Perng, R., Peters, U., Petersen, G. M., Picci, P., Pike, M. C., Porru, S., Prescott, J., Prokunina-Olsson, L., Qian, B., Qiao, Y., Rais, M., Riboli, E., Riby, J., Risch, H. A., Rizzato, C., Rodabough, R., Roman, E., Roupret, M., Ruder, A. M., de Sanjose, S., Scelo, G., Schned, A., Schumacher, F., Schwartz, K., Schwenn, M., Scotlandi, K., Seow, A., Serra, C., Serra, M., Sesso, H. D., Setiawan, V. W., Severi, G., Severson, R. K., Shanafelt, T. D., Shen, H., Shen, W., Shin, M., Shiraishi, K., Shu, X., Siddiq, A., Sierrasesumaga, L., Sihoe, A. D., Skibola, C. F., Smith, A., Smith, M. T., Southey, M. C., Spinelli, J. J., Staines, A., Stampfer, M., Stern, M. C., Stevens, V. L., Stolzenberg-Solomon, R. S., Su, J., Su, W., Sund, M., Sung, J. S., Sung, S. W., Tan, W., Tang, W., Tardon, A., Thomas, D., Thompson, C. A., Tinker, L. F., Tirabosco, R., Tjonneland, A., Travis, R. C., Trichopoulos, D., Tsai, F., Tsai, Y., Tucker, M., Turner, J., Vajdic, C. M., Vermeulen, R. C., Villano, D. J., Vineis, P., Virtamo, J., Visvanathan, K., Wactawski-Wende, J., Wang, C., Wang, C., Wang, J., Wang, J., Wei, F., Weiderpass, E., Weiner, G. J., Weinstein, S., Wentzensen, N., White, E., Witzig, T. E., Wolpin, B. M., Wong, M. P., Wu, C., Wu, G., Wu, J., Wu, T., Wu, W., Wu, X., Wu, Y., Wunder, J. S., Xiang, Y., Xu, J., Xu, P., Yang, P., Yang, T., Ye, Y., Yin, Z., Yokota, J., Yoon, H., Yu, C., Yu, H., Yu, K., Yuan, J., Zelenetz, A., Zeleniuch-Jacquotte, A., Zhang, X., Zhang, Y., Zhao, X., Zhao, Z., Zheng, H., Zheng, T., Zheng, W., Zhou, B., Zhu, M., Zucca, M., Boca, S. M., Cerhan, J. R., Ferri, G. M., Hartge, P., Hsiung, C. A., Magnani, C., Miligi, L., Morton, L. M., Smedby, K. E., Teras, L. R., Vijai, J., Wang, S. S., Brennan, P., Caporaso, N. E., Hunter, D. J., Kraft, P., Rothman, N., Silverman, D. T., Slager, S. L., Chanock, S. J., Chatterjee, N. 2015; 107 (12)

    Abstract

    Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

    View details for DOI 10.1093/jnci/djv279

    View details for Web of Science ID 000366970900015

    View details for PubMedID 26464424

    View details for PubMedCentralID PMC4806328

  • Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis NATURE GENETICS Paternoster, L., Standl, M., Waage, J., Baurecht, H., Hotze, M., Strachan, D. P., Curtin, J. A., Bonnelykke, K., Tian, C., Takahashi, A., Esparza-Gordillo, J., Alves, A. C., Thyssen, J. P., den Dekker, H. T., Ferreira, M. A., Altmaier, E., Sleiman, P. M., Xiao, F. L., Gonzalez, J. R., Marenholz, I., Kalb, B., Pino-Yanes, M., Xu, C., Carstensen, L., Groen-Blokhuis, M. M., Venturini, C., Pennell, C. E., Barton, S. J., Levin, A. M., Curjuric, I., Bustamante, M., Kreiner-Moller, E., Lockett, G. A., Bacelis, J., Bunyavanich, S., Myers, R. A., Matanovic, A., Kumar, A., Tung, J. Y., Hirota, T., Kubo, M., McArdle, W. L., Henderson, A. J., Kemp, J. P., Zheng, J., Smith, G. D., Rueschendorf, F., Bauerfeind, A., Lee-Kirsch, M. A., Arnold, A., Homuth, G., Schmidt, C. O., Mangold, E., Cichon, S., Keil, T., Rodriguez, E., Peters, A., Franke, A., Lieb, W., Novak, N., Foelster-Holst, R., Horikoshi, M., Pekkanen, J., Sebert, S., Husemoen, L. L., Grarup, N., de Jongste, J. C., Rivadeneira, F., Hofman, A., Jaddoe, V. W., Pasmans, S. G., Elbert, N. J., Uitterlinden, A. G., Marks, G. B., Thompson, P. J., Matheson, M. C., Robertson, C. F., Ried, J. S., Li, J., Zuo, X. B., Zheng, X. D., Yin, X. Y., Sun, L. D., McAleer, M. A., O'Regan, G. M., Fahy, C. M., Campbell, L. E., Macek, M., Kurek, M., Hu, D., Eng, C., Postma, D. S., Feenstra, B., Geller, F., Hottenga, J. J., Middeldorp, C. M., Hysi, P., Bataille, V., Spector, T., Tiesler, C. M., Thiering, E., Pahukasahasram, B., Yang, J. J., Imboden, M., Huntsman, S., Vilor-Tejedor, N., Relton, C. L., Myhre, R., Nystad, W., Custovic, A., Weiss, S. T., Meyers, D. A., Soederhaell, C., Melen, E., Ober, C., Raby, B. A., Simpson, A., Jacobsson, B., Holloway, J. W., Bisgaard, H., Sunyer, J., Probst-Hensch, N. M., Williams, L. K., Godfrey, K. M., Wang, C. A., Boomsma, D. I., Melbye, M., Koppelman, G. H., Jarvis, D., McLean, W. H., Irvine, A. D., Zhang, X. J., Hakonarson, H., Gieger-, C., Burchard, E. G., Martin, N. G., Duijts, L., Linneberg, A., Jarvelin, M., Noethen, M. M., Lau, S., Huebner, N., Lee, Y., Tamari, M., Hinds, D. A., Glass, D., Brown, S. J., Heinrich, J., Evans, D. M., Weidinger, S. 2015; 47 (12): 1449-?

    Abstract

    Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.

    View details for DOI 10.1038/ng.3424

    View details for Web of Science ID 000365813200017

    View details for PubMedID 26482879

    View details for PubMedCentralID PMC4753676

  • Trichuris suis ova therapy in relapsing multiple sclerosis is safe but without signals of beneficial effect MULTIPLE SCLEROSIS JOURNAL Voldsgaard, A., Bager, P., Garde, E., Akeson, P., Leffers, A. M., Madsen, C. G., Kapel, C., Roepstorff, A., Thamsborg, S. M., Melbye, M., Siebner, H., Sondergaard, H. B., Sellebjerg, F., Sorensen, P. S. 2015; 21 (13): 1723-1729

    Abstract

    An observational study has suggested that relapsing-remitting multiple sclerosis patients with helminth infections have lower disease activity and progression than uninfected multiple sclerosis patients.To evaluate the safety and efficacy on MRI activity of treatment with TSO in relapsing MS.The study was an open-label, magnetic resonance imaging assessor-blinded, baseline-to-treatment study including ten patients with relapsing forms of multiple sclerosis. Median (range) age was 41 (24-55) years, disease duration 9 (4-34) years, Expanded Disability Status Scale score 2.5 (1-5.0), and number of relapses within the last two years 3 (2-5). Four patients received no disease modifying therapy, while six patients received IFN-β. After an observational period of 8 weeks, patients received 2500 ova from the helminth Trichuris suis orally every second week for 12 weeks. Patients were followed with serial magnetic resonance imaging, neurological examinations, laboratory safety tests and expression of immunological biomarker genes.Treatment with Trichuris suis orally was well-tolerated apart from some gastrointestinal symptoms. Magnetic resonance imaging revealed 6 new or enlarged T2 lesions in the run-in period, 7 lesions in the early period and 21 lesions in the late treatment period. Two patients suffered a relapse before treatment and two during treatment. Eight patients developed eosinophilia. The expression of cytokines and transcription factors did not change.In a small group of relapsing multiple sclerosis patients, Trichuris suis oral therapy was well tolerated but without beneficial effect.

    View details for DOI 10.1177/1352458514568173

    View details for Web of Science ID 000364161000013

    View details for PubMedID 25698173

  • No evidence of transmission of chronic lymphocytic leukemia through blood transfusion BLOOD Hjalgrim, H., Rostgaard, K., Vasan, S. K., Ullum, H., Erikstrup, C., Pedersen, O. B., Nielsen, K. R., Titlestad, K., Melbye, M., Nyren, O., Edgren, G. 2015; 126 (17): 2059-2061

    Abstract

    Monoclonal B-cell lymphocytosis (MBL) is a precursor of chronic lymphocytic leukemia (CLL). Observations of MBL in blood donors raise concern that transmitted MBL may cause recipient CLL. Using a database with health information on 1.5 million donors and 2.1 million recipients, we compared CLL occurrence among 7413 recipients of blood from 796 donors diagnosed with CLL after donation cessation, and among 80, 431 recipients of blood from 7477 matched CLL-free donors. During follow-up, 12 and 107 cases of CLL occurred among the exposed and unexposed recipients, respectively, yielding a relative risk of 0.94 (95% confidence interval, 0.52-1.71). Analyses using the entire database showed no evidence of CLL clustering among recipients of blood from individual donors. In conclusion, when donor MBL was approximated by subsequent donor CLL diagnosis, data from 2 countries' entire computerized transfusion experience over more than 30 years indicate that MBL/CLL transmission does not contribute importantly to recipient CLL risk.

    View details for DOI 10.1182/blood-2015-03-632844

    View details for Web of Science ID 000366389200017

    View details for PubMedID 26302757

  • Recurrence of Subdural Haematoma in a Population-Based Cohort - Risks and Predictive Factors PLOS ONE Schmidt, L., Gortz, S., Wohlfahrt, J., Melbye, M., Munch, T. N. 2015; 10 (10)

    Abstract

    To estimate the risks of and identify predictors for recurrent subdural haematoma in surgically and conservatively treated patients.The cohort comprised all individuals diagnosed with a first-time subdural hematoma in Denmark 1996-2011. Information on potential predictors was retrieved from the Danish health registers. Cumulative recurrence risks were estimated using the Aalen-Johansen estimator. Rate ratios (RR) were estimated using Poisson regression.Among 10,158 individuals with a subdural hematoma, 1,555 had a recurrent event. The cumulative risk of recurrent subdural hematoma was 9% at 4 weeks after the primary bleeding, increasing to and stabilising at 14% after one year. Predictors associated with recurrence were: Male sex (RR 1.60, 95% CI:1.43-1.80), older age (>70 years compared to 20-49 years; RR 1.41, 95% CI: 1.21-1.65), alcohol addiction (RR 1.20, 95% CI:1.04-1.37), surgical treatment (RR 1.76, 95% CI:1.58-1.96), trauma diagnoses (RR 1.14, 95% CI:1.03-1.27), and diabetes mellitus (RR 1.40, 95% CI:1.11-1.74). Out of a selected combination of risk factors, the highest cumulative 1-year recurrence risks for subdural hematoma of 25% (compared to 14% for all patients) was found in surgically treated males with diabetes mellitus.The recurrence risk of subdural hematoma is largely limited to the first year. Patient characteristics including co-morbidities greatly influence the recurrence risk of SDH, suggesting that individualized prognostic guidance and follow-up is needed.

    View details for DOI 10.1371/journal.pone.0140450

    View details for Web of Science ID 000363183100125

    View details for PubMedID 26465602

    View details for PubMedCentralID PMC4605528

  • Blood donation and blood donor mortality after adjustment for a healthy donor effect TRANSFUSION Ullum, H., Rostgaard, K., Kamper-Jorgensen, M., Reilly, M., Melbye, M., Nyren, O., Norda, R., Edgren, G., Hjalgrim, H. 2015; 55 (10): 2479-2485

    Abstract

    Studies have repeatedly demonstrated that blood donors experience lower mortality than the general population. While this may suggest a beneficial effect of blood donation, it may also reflect the selection of healthy persons into the donor population. To overcome this bias, we investigated the relation between blood donation frequency and mortality within a large cohort of blood donors. In addition, our analyses also took into consideration the effects of presumed health differences linked to donation behavior.Using the Scandinavian Donation and Transfusion database (SCANDAT), we assessed the association between annual number of donations in 5-year windows and donor mortality by means of Poisson regression analysis. The analyses included adjustment for demographic characteristics and for an internal healthy donor effect, estimated among elderly donors exempted from continued donation because of age criteria.Statistical analyses included 1,182,495 donors of whom 15,401 died during 9,526,627 person-years of follow-up. Analyses adjusted only for demographic characteristics showed a 18.6% reduction in mortality per additional annual donation (95% confidence interval [CI], 16.8%-20.4%). After additional adjustment for the internal healthy donor effect, each additional annual donation was associated with a 7.5% decreased mortality risk 7.5% (95% CI, 5.7%-9.4%).We observed an inverse relationship between donation frequency and mortality. The magnitude of the association was reduced after adjustment for an estimate of self-selection in the donor population. Our observations indicate that repeated blood donation is not associated with premature death, but cannot be interpreted as conclusive evidence of a beneficial health effect.

    View details for DOI 10.1111/trf.13205

    View details for Web of Science ID 000362914500024

    View details for PubMedID 26098293

  • The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study. PLoS genetics Winkler, T. W., Justice, A. E., Graff, M., Barata, L., Feitosa, M. F., Chu, S., Czajkowski, J., Esko, T., Fall, T., Kilpeläinen, T. O., Lu, Y., Mägi, R., Mihailov, E., Pers, T. H., Rüeger, S., Teumer, A., Ehret, G. B., Ferreira, T., Heard-Costa, N. L., Karjalainen, J., Lagou, V., Mahajan, A., Neinast, M. D., Prokopenko, I., Simino, J., Teslovich, T. M., Jansen, R., Westra, H., White, C. C., Absher, D., Ahluwalia, T. S., Ahmad, S., Albrecht, E., Alves, A. C., Bragg-Gresham, J. L., de Craen, A. J., Bis, J. C., Bonnefond, A., Boucher, G., Cadby, G., Cheng, Y., Chiang, C. W., Delgado, G., Demirkan, A., Dueker, N., Eklund, N., Eiriksdottir, G., Eriksson, J., Feenstra, B., Fischer, K., Frau, F., Galesloot, T. E., Geller, F., Goel, A., Gorski, M., Grammer, T. B., Gustafsson, S., Haitjema, S., Hottenga, J., Huffman, J. E., Jackson, A. U., Jacobs, K. B., Johansson, Å., Kaakinen, M., Kleber, M. E., Lahti, J., Mateo Leach, I., Lehne, B., Liu, Y., Lo, K. S., Lorentzon, M., Luan, J., Madden, P. A., Mangino, M., McKnight, B., Medina-Gomez, C., Monda, K. L., Montasser, M. E., Müller, G., Müller-Nurasyid, M., Nolte, I. M., Panoutsopoulou, K., Pascoe, L., Paternoster, L., Rayner, N. W., Renström, F., Rizzi, F., Rose, L. M., Ryan, K. A., Salo, P., Sanna, S., Scharnagl, H., Shi, J., Smith, A. V., Southam, L., Stancáková, A., Steinthorsdottir, V., Strawbridge, R. J., Sung, Y. J., Tachmazidou, I., Tanaka, T., Thorleifsson, G., Trompet, S., Pervjakova, N., Tyrer, J. P., Vandenput, L., van der Laan, S. W., van der Velde, N., van Setten, J., van Vliet-Ostaptchouk, J. V., Verweij, N., Vlachopoulou, E., Waite, L. L., Wang, S. R., Wang, Z., Wild, S. H., Willenborg, C., Wilson, J. F., Wong, A., Yang, J., Yengo, L., Yerges-Armstrong, L. M., Yu, L., Zhang, W., Zhao, J. H., Andersson, E. A., Bakker, S. J., Baldassarre, D., Banasik, K., Barcella, M., Barlassina, C., Bellis, C., Benaglio, P., Blangero, J., Blüher, M., Bonnet, F., Bonnycastle, L. L., Boyd, H. A., Bruinenberg, M., Buchman, A. S., Campbell, H., Chen, Y. I., Chines, P. S., Claudi-Boehm, S., Cole, J., Collins, F. S., de Geus, E. J., de Groot, L. C., Dimitriou, M., Duan, J., Enroth, S., Eury, E., Farmaki, A., Forouhi, N. G., Friedrich, N., Gejman, P. V., Gigante, B., Glorioso, N., Go, A. S., Gottesman, O., Gräßler, J., Grallert, H., Grarup, N., Gu, Y., Broer, L., Ham, A. C., Hansen, T., Harris, T. B., Hartman, C. A., Hassinen, M., Hastie, N., Hattersley, A. T., Heath, A. C., Henders, A. K., Hernandez, D., Hillege, H., Holmen, O., Hovingh, K. G., Hui, J., Husemoen, L. L., Hutri-Kähönen, N., Hysi, P. G., Illig, T., De Jager, P. L., Jalilzadeh, S., Jørgensen, T., Jukema, J. W., Juonala, M., Kanoni, S., Karaleftheri, M., Khaw, K. T., Kinnunen, L., Kittner, S. J., Koenig, W., Kolcic, I., Kovacs, P., Krarup, N. T., Kratzer, W., Krüger, J., Kuh, D., Kumari, M., Kyriakou, T., Langenberg, C., Lannfelt, L., Lanzani, C., Lotay, V., Launer, L. J., Leander, K., Lindström, J., Linneberg, A., Liu, Y., Lobbens, S., Luben, R., Lyssenko, V., Männistö, S., Magnusson, P. K., McArdle, W. L., Menni, C., Merger, S., Milani, L., Montgomery, G. W., Morris, A. P., Narisu, N., Nelis, M., Ong, K. K., Palotie, A., Pérusse, L., Pichler, I., Pilia, M. G., Pouta, A., Rheinberger, M., Ribel-Madsen, R., Richards, M., Rice, K. M., Rice, T. K., Rivolta, C., Salomaa, V., Sanders, A. R., Sarzynski, M. A., Scholtens, S., Scott, R. A., Scott, W. R., Sebert, S., Sengupta, S., Sennblad, B., Seufferlein, T., Silveira, A., Slagboom, P. E., Smit, J. H., Sparsø, T. H., Stirrups, K., Stolk, R. P., Stringham, H. M., Swertz, M. A., Swift, A. J., Syvänen, A., Tan, S., Thorand, B., Tönjes, A., Tremblay, A., Tsafantakis, E., van der Most, P. J., Völker, U., Vohl, M., Vonk, J. M., Waldenberger, M., Walker, R. W., Wennauer, R., Widén, E., Willemsen, G., Wilsgaard, T., Wright, A. F., Zillikens, M. C., van Dijk, S. C., van Schoor, N. M., Asselbergs, F. W., de Bakker, P. I., Beckmann, J. S., Beilby, J., Bennett, D. A., Bergman, R. N., Bergmann, S., Böger, C. A., Boehm, B. O., Boerwinkle, E., Boomsma, D. I., Bornstein, S. R., Bottinger, E. P., Bouchard, C., Chambers, J. C., Chanock, S. J., Chasman, D. I., Cucca, F., Cusi, D., Dedoussis, G., Erdmann, J., Eriksson, J. G., Evans, D. A., de Faire, U., Farrall, M., Ferrucci, L., Ford, I., Franke, L., Franks, P. W., Froguel, P., Gansevoort, R. T., Gieger, C., Grönberg, H., Gudnason, V., Gyllensten, U., Hall, P., Hamsten, A., van der Harst, P., Hayward, C., Heliövaara, M., Hengstenberg, C., Hicks, A. A., Hingorani, A., Hofman, A., Hu, F., Huikuri, H. V., Hveem, K., James, A. L., Jordan, J. M., Jula, A., Kähönen, M., Kajantie, E., Kathiresan, S., Kiemeney, L. A., Kivimaki, M., Knekt, P. B., Koistinen, H. A., Kooner, J. S., Koskinen, S., Kuusisto, J., Maerz, W., Martin, N. G., Laakso, M., Lakka, T. A., Lehtimäki, T., Lettre, G., Levinson, D. F., Lind, L., Lokki, M., Mäntyselkä, P., Melbye, M., Metspalu, A., Mitchell, B. D., Moll, F. L., Murray, J. C., Musk, A. W., Nieminen, M. S., Njølstad, I., Ohlsson, C., Oldehinkel, A. J., Oostra, B. A., Palmer, L. J., Pankow, J. S., Pasterkamp, G., Pedersen, N. L., Pedersen, O., Penninx, B. W., Perola, M., Peters, A., Polašek, O., Pramstaller, P. P., Psaty, B. M., Qi, L., Quertermous, T., Raitakari, O. T., Rankinen, T., Rauramaa, R., Ridker, P. M., Rioux, J. D., Rivadeneira, F., Rotter, J. I., Rudan, I., Den Ruijter, H. M., Saltevo, J., Sattar, N., Schunkert, H., Schwarz, P. E., Shuldiner, A. R., Sinisalo, J., Snieder, H., Sørensen, T. I., Spector, T. D., Staessen, J. A., Stefania, B., Thorsteinsdottir, U., Stumvoll, M., Tardif, J., Tremoli, E., Tuomilehto, J., Uitterlinden, A. G., Uusitupa, M., Verbeek, A. L., Vermeulen, S. H., Viikari, J. S., Vitart, V., Völzke, H., Vollenweider, P., Waeber, G., Walker, M., Wallaschofski, H., Wareham, N. J., Watkins, H., Zeggini, E., Chakravarti, A., Clegg, D. J., Cupples, L. A., Gordon-Larsen, P., Jaquish, C. E., Rao, D. C., Abecasis, G. R., Assimes, T. L., Barroso, I., Berndt, S. I., Boehnke, M., Deloukas, P., Fox, C. S., Groop, L. C., Hunter, D. J., Ingelsson, E., Kaplan, R. C., McCarthy, M. I., Mohlke, K. L., O'Connell, J. R., Schlessinger, D., Strachan, D. P., Stefansson, K., van Duijn, C. M., Hirschhorn, J. N., Lindgren, C. M., Heid, I. M., North, K. E., Borecki, I. B., Kutalik, Z., Loos, R. J. 2015; 11 (10)

    Abstract

    Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

    View details for DOI 10.1371/journal.pgen.1005378

    View details for PubMedID 26426971

  • Autoimmune and Atopic Disorders and Risk of Classical Hodgkin Lymphoma AMERICAN JOURNAL OF EPIDEMIOLOGY Hollander, P., Rostgaard, K., Smedby, K. E., Chang, E. T., Amini, R., Brown, P. D., Glimelius, B., Adami, H., Melbye, M., Glimelius, I., Hjalgrim, H. 2015; 182 (7): 624-632

    View details for DOI 10.1093/aje/kwv081

    View details for Web of Science ID 000361811100009

    View details for PubMedID 26346543

  • The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study PLOS GENETICS Winkler, T. W., Justice, A. E., Graff, M., Barata, L., Feitosa, M. F., Chu, S., Czajkowski, J., Esko, T., Fall, T., Kilpelainen, T. O., Lu, Y., Magi, R., Mihailov, E., Pers, T. H., Rueeger, S., Teumer, A., Ehret, G. B., Ferreira, T., Heard-Costa, N. L., Karjalainen, J., Lagou, V., Mahajan, A., Neinast, M. D., Prokopenko, I., Simino, J., Teslovich, T. M., Jansen, R., Westra, H., White, C. C., Absher, D., Ahluwalia, T. S., Ahmad, S., Albrecht, E., Alves, A. C., Bragg-Gresham, J. L., de Craen, A. J., Bis, J. C., Bonnefond, A., Boucher, G., Cadby, G., Cheng, Y., Chiang, C. W., Delgado, G., Demirkan, A., Dueker, N., Eklund, N., Eiriksdottir, G., Eriksson, J., Feenstra, B., Fischer, K., Frau, F., Galesloot, T. E., Geller, F., Goel, A., Gorski, M., Grammer, T. B., Gustafsson, S., Haitjema, S., Hottenga, J., Huffman, J. E., Jackson, A. U., Jacobs, K. B., Johansson, A., Kaakinen, M., Kleber, M. E., Lahti, J., Leach, I. M., Lehne, B., Liu, Y., Lo, K. S., Lorentzon, M., Luan, J., Madden, P. A., Mangino, M., McKnight, B., Medina-Gomez, C., Monda, K. L., Montasser, M. E., Mueller, G., Mueller-Nurasyid, M., Nolte, I. M., Panoutsopoulou, K., Pascoe, L., Paternoster, L., Rayner, N. W., Renstrom, F., Rizzi, F., Rose, L. M., Ryan, K. A., Salo, P., Sanna, S., Scharnagl, H., Shi, J., Smith, A. V., Southam, L., Stancakova, A., Steinthorsdottir, V., Strawbridge, R. J., Sung, Y. J., Tachmazidou, I., Tanaka, T., Thorleifsson, G., Trompet, S., Pervjakova, N., Tyrer, J. P., Vandenput, L., van der Laan, S. W., van der Velde, N., van Setten, J., van Vliet-Ostaptchouk, J. V., Verweij, N., Vlachopoulou, E., Waite, L. L., Wang, S. R., Wang, Z., Wild, S. H., Willenborg, C., Wilson, J. F., Wong, A., Yang, J., Yengo, L., Yerges-Armstrong, L. M., Yu, L., Zhang, W., Zhao, J. H., Andersson, E. A., Bakker, S. J., Baldassarre, D., Banasik, K., Barcella, M., Barlassina, C., Bellis, C., Benaglio, P., Blangero, J., Blueher, M., Bonnet, F., Bonnycastle, L. L., Boyd, H. A., Bruinenberg, M., Buchman, A. S., Campbell, H., Chen, Y. I., Chines, P. S., Claudi-Boehm, S., Cole, J., Collins, F. S., de Geus, E. J., de Groot, L. C., Dimitriou, M., Duan, J., Enroth, S., Eury, E., Farmaki, A., Forouhi, N. G., Friedrich, N., Gejman, P. V., Gigante, B., Glorioso, N., Go, A. S., Gottesman, O., Graessler, J., Grallert, H., Grarup, N., Gu, Y., Broer, L., Ham, A. C., Hansen, T., Harris, T. B., Hartman, C. A., Hassinen, M., Hastie, N., Hattersley, A. T., Heath, A. C., Henders, A. K., Hernandez, D., Hillege, H., Holmen, O., Hovingh, K. G., Hui, J., Husemoen, L. L., Hutri-Kahonen, N., Hysi, P. G., Illig, T., De Jager, P. L., Jalilzadeh, S., Jorgensen, T., Jukema, J. W., Juonala, M., Kanoni, S., Karaleftheri, M., Khaw, K. T., Kinnunen, L., Kittner, S. J., Koenig, W., Kolcic, I., Kovacs, P., Krarup, N. T., Kratzer, W., Krueger, J., Kuh, D., Kumari, M., Kyriakou, T., Langenberg, C., Lannfelt, L., Lanzani, C., Lotay, V., Launer, L. J., Leander, K., Lindstrom, J., Linneberg, A., Liu, Y., Lobbens, S., Luben, R., Lyssenko, V., Mannisto, S., Magnusson, P. K., McArdle, W. L., Menni, C., Merger, S., Milani, L., Montgomery, G. W., Morris, A. P., Narisu, N., Nelis, M., Ong, K. K., Palotie, A., Perusse, L., Pichler, I., Pilia, M. G., Pouta, A., Rheinberger, M., Ribel-Madsen, R., Richards, M., Rice, K. M., Rice, T. K., Rivolta, C., Salomaa, V., Sanders, A. R., Sarzynski, M. A., Scholtens, S., Scott, R. A., Scott, W. R., Sebert, S., Sengupta, S., Sennblad, B., Seufferlein, T., Silveira, A., Slagboom, P. E., Smit, J. H., Sparso, T. H., Stirrups, K., Stolk, R. P., Stringham, H. M., Swertz, M. A., Swift, A. J., Syvanen, A., Tan, S., Thorand, B., Toenjes, A., Tremblay, A., Tsafantakis, E., van der Most, P. J., Voelker, U., Vohl, M., Vonk, J. M., Waldenberger, M., Walker, R. W., Wennauer, R., Widen, E., Willemsen, G., Wilsgaard, T., Wright, A. F., Zillikens, M. C., van Dijk, S. C., van Schoor, N. M., Asselbergs, F. W., de Bakker, P. I., Beckmann, J. S., Beilby, J., Bennett, D. A., Bergman, R. N., Bergmann, S., Boeger, C. A., Boehm, B. O., Boerwinkle, E., Boomsma, D. I., Bornstein, S. R., Bottinger, E. P., Bouchard, C., Chambers, J. C., Chanock, S. J., Chasman, D. I., Cucca, F., Cusi, D., Dedoussis, G., Erdmann, J., Eriksson, J. G., Evans, D. A., de Faire, U., Farrall, M., Ferrucci, L., Ford, I., Franke, L., Franks, P. W., Froguel, P., Gansevoort, R. T., Gieger, C., Gronberg, H., Gudnason, V., Gyllensten, U., Hall, P., Hamsten, A., van der Harst, P., Hayward, C., Heliovaara, M., Hengstenberg, C., Hicks, A. A., Hingorani, A., Hofman, A., Hu, F., Huikuri, H. V., Hveem, K., James, A. L., Jordan, J. M., Jula, A., Kaehoenen, M., Kajantie, E., Kathiresan, S., Kiemeney, L. A., Kivimaki, M., Knekt, P. B., Koistinen, H. A., Kooner, J. S., Koskinen, S., Kuusisto, J., Maerz, W., Martin, N. G., Laakso, M., Lakka, T. A., Lehtimaki, T., Lettre, G., Levinson, D. F., Lind, L., Lokki, M., Mantyselka, P., Melbye, M., Metspalu, A., Mitchell, B. D., Moll, F. L., Murray, J. C., Musk, A. W., Nieminen, M. S., Njolstad, I., Ohlsson, C., Oldehinkel, A. J., Oostra, B. A., Palmer, L. J., Pankow, J. S., Pasterkamp, G., Pedersen, N. L., Pedersen, O., Penninx, B. W., Perola, M., Peters, A., Polasek, O., Pramstaller, P. P., Psaty, B. M., Qi, L., Quertermous, T., Raitakari, O. T., Rankinen, T., Rauramaa, R., Ridker, P. M., Rioux, J. D., Rivadeneira, F., Rotter, J. I., Rudan, I., Den Ruijter, H. M., Saltevo, J., Sattar, N., Schunkert, H., Schwarz, P. E., Shuldiner, A. R., Sinisalo, J., Snieder, H., Sorensen, T. I., Spector, T. D., Staessen, J. A., Stefania, B., Thorsteinsdottir, U., Stumvoll, M., Tardif, J., Tremoli, E., Tuomilehto, J., Uitterlinden, A. G., Uusitupa, M., Verbeek, A. L., Vermeulen, S. H., Viikari, J. S., Vitart, V., Voelzke, H., Vollenweider, P., Waeber, G., Walker, M., Wallaschofski, H., Wareham, N. J., Watkins, H., Zeggini, E., Chakravarti, A., Clegg, D. J., Cupples, L. A., Gordon-Larsen, P., Jaquish, C. E., Rao, D. C., Abecasis, G. R., Assimes, T. L., Barroso, I., Berndt, S. I., Boehnke, M., Deloukas, P., Fox, C. S., Groop, L. C., Hunter, D. J., Ingelsson, E., Kaplan, R. C., McCarthy, M. I., Mohlke, K. L., O'Connell, J. R., Schlessinger, D., Strachan, D. P., Stefansson, K., van Duijn, C. M., Hirschhorn, J. N., Lindgren, C. M., Heid, I. M., North, K. E., Borecki, I. B., Kutalik, Z., Loos, R. J. 2015; 11 (10)

    View details for DOI 10.1371/journal.pgen.1005378

    View details for Web of Science ID 000364401600002

    View details for PubMedID 26426971

  • Long-Term Survival of Individuals Born Small and Large for Gestational Age PLOS ONE Wennerstrom, E. C., Simonsen, J., Melbye, M. 2015; 10 (9)

    Abstract

    Little is known on long-term survival and causes of death among individuals born small or large for gestational age. This study investigates birth weight in relation to survival and causes of death over time.A national cohort of 1.7 million live-born singletons in Denmark was followed during 1979-2011, using the Danish Civil Registration System, the Medical Birth Registry and the Cause of Death Registry. Cox proportional hazards were estimated for the impact of small (SGA) and large (LGA) gestation weight and mortality overall, by age group and birth cohort.Compared to normal weight children, SGA children were associated with increased risk of dying over time. Though most of the deaths occurred during the first year of life, the cumulative mortality risk was increased until 30 years of age. The hazard ratios [HR] for dying among SGA children ages <2 years were: 3.47 (95% CI, 3.30-3.64) and 1.06 (95% CI, 0.60-1.87) in 30 years and older. HR for dying among SGA adults (20-29 years) were: 1.20 (95% CI, 0.99-1.46) in years 1979-1982 and 1.61 (95% CI, 1.04-2.51) in years 1989-1994. The SGA born had increased risk of dying from infection, heart disease, respiratory disease, digestive disease, congenital malformation, perinatal conditions, and accidents, suicide, and homicide. Individuals born LGA were associated with decreased mortality risk, but with increased risk of dying from malignant neoplasm.Survival has improved independently of birth weight the past 30 years. However, children born SGA remain at significantly increased risk of dying up till they turn 30 years of age. Individuals born LGA have lower mortality risk but only in the first two years of life.

    View details for DOI 10.1371/journal.pone.0138594

    View details for Web of Science ID 000361791000041

    View details for PubMedID 26390219

    View details for PubMedCentralID PMC4577072

  • Risk of Cardiomyopathy in Younger Persons With a Family History of Death from Cardiomyopathy A Nationwide Family Study in a Cohort of 3.9 Million Persons CIRCULATION Ranthe, M. F., Carstensen, L., Oyen, N., Jensen, M. K., Axelsson, A., Wohlfahrt, J., Melbye, M., Bundgaard, H., Boyd, H. A. 2015; 132 (11): 1013-1019

    Abstract

    Recommendations for presymptomatic screening of relatives of cardiomyopathy patients are based on findings from tertiary centers. Cardiomyopathy inheritance patterns are fairly well understood, but how cardiomyopathy in younger persons (<50 years) aggregates in families at the population level is unclear. In a nationwide cohort, we examined the risk of cardiomyopathy by family history of premature death (<60 years) from cardiomyopathy.By linking Danish national register data, we constructed a cohort of 3.9 million persons born from 1950 to 2008. We ascertained family history of premature (<60 years) death from cardiomyopathy or other conditions, and cohort members were followed from 1977 to 2008 for cardiomyopathy diagnosed at <50 years. We identified 3890 cardiomyopathies in 89 million person-years of follow-up. Using Poisson regression, we estimated incidence rate ratios for cardiomyopathy by family history of premature death. Premature cardiomyopathy deaths in first- and second-degree relatives were associated with 29- and 6-fold increases in the rate of cardiomyopathy, respectively. If the first-degree relative died aged <35 years, the rate of cardiomyopathy increased 100-fold; given ≥2 premature deaths in first-degree relatives, the rate increased more than 400-fold. In contrast, a family history of premature death from other cardiac or noncardiac conditions increased the rate of cardiomyopathy 3-fold at most.A family history of premature cardiomyopathy death was associated with an increase in risk of cardiomyopathy ranging from 6- to 400-fold, depending on age, kinship, gender and number of affected family members. Our general population-based results support recommendations for presymptomatic screening of relatives of cardiomyopathy patients.

    View details for DOI 10.1161/CIRCULATIONAHA.114.013478

    View details for Web of Science ID 000361293800006

    View details for PubMedID 26276887

  • Fever during pregnancy and motor development in children: a study within the Danish National Birth Cohort DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Holst, C., Jorgensen, S. E., Wohlfahrt, J., Andersen, A. N., Melbye, M. 2015; 57 (8): 725-732

    Abstract

    The aim of this study was to examine how fever during pregnancy is associated with motor development in the child.This cohort study was based on data from females and their children, from the Danish National Birth Cohort, who took part in an 18-month and/or 7-year follow-up study. Information regarding fever (number of episodes, temperature, duration, and pregnancy week) was obtained around gestation week 12 and at the end of pregnancy. Assessments of motor development in early childhood were based on the ages at which the motor milestones 'sitting unsupported' (n=44,256) and 'walking unassisted' (n=53,959) were attained. The Developmental Coordination Disorder Questionnaire 2007 (DCDQ'07) was used to identify children with indication of developmental coordination disorder (DCD) at age 7 years (n=29,401). Any associations between the exposure to fever during pregnancy and motor development were estimated using Cox regression and logistic regression analyses.Fever during pregnancy was reported by 15,234 (28.0%) participants in the 18-month follow-up and by 7965 (26.9%) participants in the 7-year follow-up. Adjusted analyses showed no association between prenatal exposure to fever and either 'sitting unsupported' or 'walking unassisted'. The proportion of children with indication of DCD was 3.1%. The odds ratio of indication of DCD if children were exposed to fever in utero was 1.29 (95% CI 1.12-1.49). However, no dose-response association was found.We found a significant association between maternal fever during pregnancy and DCD in children at age 7 years. The lack of a dose-response association might suggest that this association is explained by the underlying causes of the fever.

    View details for DOI 10.1111/dmcn.12743

    View details for Web of Science ID 000357790000012

    View details for PubMedID 25800617

  • Directional dominance on stature and cognition in diverse human populations NATURE Joshi, P. K., Esko, T., Mattsson, H., Eklund, N., Gandin, I., Nutile, T., Jackson, A. U., Schurmann, C., Smith, A. V., Zhang, W., Okada, Y., Stancakova, A., Faul, J. D., Zhao, W., Bartz, T. M., Concas, M. P., Franceschini, N., Enroth, S., Vitart, V., Trompet, S., Guo, X., Chasman, D. I., O'Connel, J. R., Corre, T., Nongmaithem, S. S., Chen, Y., Mangino, M., Ruggiero, D., Traglia, M., Farmaki, A., Kacprowski, T., Bjonnes, A., van der Spek, A., Wu, Y., Giri, A. K., Yanek, L. R., Wang, L., Hofer, E., Rietveld, C. A., McLeod, O., Cornelis, M. C., Pattaro, C., Verweij, N., Baumbach, C., Abdellaoui, A., Warren, H. R., Vuckovic, D., Mei, H., Bouchard, C., Perry, J. R., Cappellani, S., Mirza, S. S., Benton, M. C., Broeckel, U., Medland, S. E., Lind, P., Malerba, G., Drong, A., Yengo, L., Bielak, L. F., Zhi, D., van der Most, P. J., Shriner, D., Maegi, R., Hemani, G., Karaderi, T., Wang, Z., Liu, T., Demuth, I., Zhao, J. H., Meng, W., Lataniotis, L., van der Laan, S. W., Bradfield, J. P., Wood, A. R., Bonnefond, A., Ahluwalia, T. S., Hall, L., Salvi, E., Yazar, S., Carstensen, L., de Haan, H. G., Abney, M., Afzal, U., Allison, M. A., Amin, N., Asselbergs, F. W., Bakker, S. J., Barr, R. G., Baumeister, S. E., Benjamin, D. J., Bergmann, S., Boerwinkle, E., Bottinger, E. P., Campbell, A., Chakravarti, A., Chan, Y., Chanock, S. J., Chen, C., Chen, Y. I., Collins, F. S., Connell, J., Correa, A., Cupples, L. A., Smith, G. D., Davies, G., Doerr, M., Ehret, G., Ellis, S. B., Feenstra, B., Feitosa, M. F., Ford, I., Fox, C. S., Frayling, T. M., Friedrich, N., Geller, F., Scotland, G., Gillham-Nasenya, I., Gottesman, O., Graff, M., Grodstein, F., Gu, C., Haley, C., Hammond, C. J., Harris, S. E., Harris, T. B., Hastie, N. D., Heard-Costa, N. L., Heikkila, K., Hocking, L. J., Homuth, G., Hottenga, J., Huang, J., Huffman, J. E., Hysi, P. G., Ikram, M. A., Ingelsson, E., Joensuu, A., Johansson, A., Jousilahti, P., Jukema, J. W., Kahonen, M., Kamatani, Y., Kanoni, S., Kerr, S. M., Khan, N. M., Koellinger, P., Koistinen, H. A., Kooner, M. K., Kubo, M., Kuusisto, J., Lahti, J., Launer, L. J., Lea, R. A., Lehne, B., Lehtimaki, T., Liewald, D. C., Lind, L., Loh, M., Lokki, M., London, S. J., Loomis, S. J., Loukola, A., Lu, Y., Lumley, T., Lundqvist, A., Mannisto, S., Marques-Vidal, P., Masciullo, C., Matchan, A., Mathias, R. A., Matsuda, K., Meigs, J. B., Meisinger, C., Meitinger, T., Menni, C., Mentch, F. D., Mihailov, E., Milani, L., Montasser, M. E., Montgomery, G., Morrison, A., Myers, R. H., Nadukuru, R., Navarro, P., Nelis, M., Nieminen, M. S., Nolte, I. M., O'Connor, G. T., Ogunniyi, A., Padmanabhan, S., Palmas, W. R., Pankow, J. S., Patarcic, I., Pavani, F., Peyser, P. A., Pietilainen, K., Poulter, N., Prokopenko, I., Ralhan, S., Redmond, P., Rich, S. S., Rissanen, H., Robino, A., Rose, L. M., Rose, R., Sala, C., Salako, B., Salomaa, V., Sarin, A., Saxena, R., Schmidt, H., Scott, L. J., Scott, W. R., Sennblad, B., Seshadri, S., Sever, P., Shrestha, S., Smith, B. H., Smith, J. A., Soranzo, N., Sotoodehnia, N., Southam, L., Stanton, A. V., Stathopoulou, M. G., Strauch, K., Strawbridge, R. J., Suderman, M. J., Tandon, N., Tang, S., Taylor, K. D., Tayo, B. O., Toeglhofer, A. M., Tomaszewski, M., Tsernikova, N., Tuomilehto, J., Uitterlinden, A. G., Vaidya, D., Vlieg, A. v., van Setten, J., Vasankari, T., Vedantam, S., Vlachopoulou, E., Vozzi, D., Vuoksimaa, E., Waldenberger, M., Ware, E. B., Wentworth-Shields, W., Whitfield, J. B., Wild, S., Willemsen, G., Yajnik, C. S., Yao, J., Zaza, G., Zhu, X., Salem, R. M., Melbye, M., Bisgaard, H., Samani, N. J., Cusi, D., Mackey, D. A., Cooper, R. S., Froguel, P., Pasterkamp, G., Grant, S. F., Hakonarson, H., Ferrucci, L., Scott, R. A., Morris, A. D., Palmer, C. N., Dedoussis, G., Deloukas, P., Bertram, L., Lindenberger, U., Berndt, S. I., Lindgren, C. M., Timpson, N. J., Toenjes, A., Munroe, P. B., Sorensen, T. I., Rotimi, C. N., Arnett, D. K., Oldehinkel, A. J., Kardia, S. L., Balkau, B., Gambaro, G., Morris, A. P., Eriksson, J. G., Wright, M. J., Martin, N. G., Hunt, S. C., Starr, J. M., Deary, I. J., Griffiths, L. R., Tiemeier, H., Pirastu, N., Kaprio, J., Wareham, N. J., Perusse, L., Wilson, J. G., Girotto, G., Caulfield, M. J., Raitakari, O., Boomsma, D. I., Gieger, C., van der Harst, P., Hicks, A. A., Kraft, P., Sinisalo, J., Knekt, P., Johannesson, M., Magnusson, P. K., Hamsten, A., Schmidt, R., Borecki, I. B., Vartiainen, E., Becker, D. M., Bharadwaj, D., Mohlke, K. L., Boehnke, M., van Duijn, C. M., Sanghera, D. K., Teumer, A., Zeggini, E., Metspalu, A., Gasparini, P., Ulivi, S., Ober, C., Toniolo, D., Rudan, I., Porteous, D. J., Ciullo, M., Spector, T. D., Hayward, C., Dupuis, J., Loos, R. J., Wright, A. F., Chandak, G. R., Vollenweider, P., Shuldiner, A. R., Ridker, P. M., Rotter, J. I., Sattar, N., Gyllensten, U., North, K. E., Pirastu, M., Psaty, B. M., Weir, D. R., Laakso, M., Gudnason, V., Takahashi, A., Chambers, J. C., Kooner, J. S., Strachan, D. P., Campbell, H., Hirschhorn, J. N., Perola, M., Polasek, O., Wilson, J. F. 2015; 523 (7561): 459-U176

    Abstract

    Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

    View details for DOI 10.1038/nature14618

    View details for Web of Science ID 000358378900036

    View details for PubMedCentralID PMC4516141

  • Directional dominance on stature and cognition in diverse human populations. Nature Joshi, P. K., Esko, T., Mattsson, H., Eklund, N., Gandin, I., Nutile, T., Jackson, A. U., Schurmann, C., Smith, A. V., Zhang, W., Okada, Y., Stancáková, A., Faul, J. D., Zhao, W., Bartz, T. M., Concas, M. P., Franceschini, N., Enroth, S., Vitart, V., Trompet, S., Guo, X., Chasman, D. I., O'Connel, J. R., Corre, T., Nongmaithem, S. S., Chen, Y., Mangino, M., Ruggiero, D., Traglia, M., Farmaki, A., Kacprowski, T., Bjonnes, A., van der Spek, A., Wu, Y., Giri, A. K., Yanek, L. R., Wang, L., Hofer, E., Rietveld, C. A., McLeod, O., Cornelis, M. C., Pattaro, C., Verweij, N., Baumbach, C., Abdellaoui, A., Warren, H. R., Vuckovic, D., Mei, H., Bouchard, C., Perry, J. R., Cappellani, S., Mirza, S. S., Benton, M. C., Broeckel, U., Medland, S. E., Lind, P. A., Malerba, G., Drong, A., Yengo, L., Bielak, L. F., Zhi, D., van der Most, P. J., Shriner, D., Mägi, R., Hemani, G., Karaderi, T., Wang, Z., Liu, T., Demuth, I., Zhao, J. H., Meng, W., Lataniotis, L., van der Laan, S. W., Bradfield, J. P., Wood, A. R., Bonnefond, A., Ahluwalia, T. S., Hall, L. M., Salvi, E., Yazar, S., Carstensen, L., de Haan, H. G., Abney, M., Afzal, U., Allison, M. A., Amin, N., Asselbergs, F. W., Bakker, S. J., Barr, R. G., Baumeister, S. E., Benjamin, D. J., Bergmann, S., Boerwinkle, E., Bottinger, E. P., Campbell, A., Chakravarti, A., Chan, Y., Chanock, S. J., Chen, C., Chen, Y. I., Collins, F. S., Connell, J., Correa, A., Cupples, L. A., Smith, G. D., Davies, G., Dörr, M., Ehret, G., Ellis, S. B., Feenstra, B., Feitosa, M. F., Ford, I., Fox, C. S., Frayling, T. M., Friedrich, N., Geller, F., Scotland, G., Gillham-Nasenya, I., Gottesman, O., Graff, M., Grodstein, F., Gu, C., Haley, C., Hammond, C. J., Harris, S. E., Harris, T. B., Hastie, N. D., Heard-Costa, N. L., Heikkilä, K., Hocking, L. J., Homuth, G., Hottenga, J., Huang, J., Huffman, J. E., Hysi, P. G., Ikram, M. A., Ingelsson, E., Joensuu, A., Johansson, Å., Jousilahti, P., Jukema, J. W., Kähönen, M., Kamatani, Y., Kanoni, S., Kerr, S. M., Khan, N. M., Koellinger, P., Koistinen, H. A., Kooner, M. K., Kubo, M., Kuusisto, J., Lahti, J., Launer, L. J., Lea, R. A., Lehne, B., Lehtimäki, T., Liewald, D. C., Lind, L., Loh, M., Lokki, M., London, S. J., Loomis, S. J., Loukola, A., Lu, Y., Lumley, T., Lundqvist, A., Männistö, S., Marques-Vidal, P., Masciullo, C., Matchan, A., Mathias, R. A., Matsuda, K., Meigs, J. B., Meisinger, C., Meitinger, T., Menni, C., Mentch, F. D., Mihailov, E., Milani, L., Montasser, M. E., Montgomery, G. W., Morrison, A., Myers, R. H., Nadukuru, R., Navarro, P., Nelis, M., Nieminen, M. S., Nolte, I. M., O'Connor, G. T., Ogunniyi, A., Padmanabhan, S., Palmas, W. R., Pankow, J. S., Patarcic, I., Pavani, F., Peyser, P. A., Pietilainen, K., Poulter, N., Prokopenko, I., Ralhan, S., Redmond, P., Rich, S. S., Rissanen, H., Robino, A., Rose, L. M., Rose, R., Sala, C., Salako, B., Salomaa, V., Sarin, A., Saxena, R., Schmidt, H., Scott, L. J., Scott, W. R., Sennblad, B., Seshadri, S., Sever, P., Shrestha, S., Smith, B. H., Smith, J. A., Soranzo, N., Sotoodehnia, N., Southam, L., Stanton, A. V., Stathopoulou, M. G., Strauch, K., Strawbridge, R. J., Suderman, M. J., Tandon, N., Tang, S., Taylor, K. D., Tayo, B. O., Töglhofer, A. M., Tomaszewski, M., Tšernikova, N., Tuomilehto, J., Uitterlinden, A. G., Vaidya, D., Van Hylckama Vlieg, A., van Setten, J., Vasankari, T., Vedantam, S., Vlachopoulou, E., Vozzi, D., Vuoksimaa, E., Waldenberger, M., Ware, E. B., Wentworth-Shields, W., Whitfield, J. B., Wild, S., Willemsen, G., Yajnik, C. S., Yao, J., Zaza, G., Zhu, X., Salem, R. M., Melbye, M., Bisgaard, H., Samani, N. J., Cusi, D., Mackey, D. A., Cooper, R. S., Froguel, P., Pasterkamp, G., Grant, S. F., Hakonarson, H., Ferrucci, L., Scott, R. A., Morris, A. D., Palmer, C. N., Dedoussis, G., Deloukas, P., Bertram, L., Lindenberger, U., Berndt, S. I., Lindgren, C. M., Timpson, N. J., Tönjes, A., Munroe, P. B., Sørensen, T. I., Rotimi, C. N., Arnett, D. K., Oldehinkel, A. J., Kardia, S. L., Balkau, B., Gambaro, G., Morris, A. P., Eriksson, J. G., Wright, M. J., Martin, N. G., Hunt, S. C., Starr, J. M., Deary, I. J., Griffiths, L. R., Tiemeier, H., Pirastu, N., Kaprio, J., Wareham, N. J., Pérusse, L., Wilson, J. G., Girotto, G., Caulfield, M. J., Raitakari, O., Boomsma, D. I., Gieger, C., van der Harst, P., Hicks, A. A., Kraft, P., Sinisalo, J., Knekt, P., Johannesson, M., Magnusson, P. K., Hamsten, A., Schmidt, R., Borecki, I. B., Vartiainen, E., Becker, D. M., Bharadwaj, D., Mohlke, K. L., Boehnke, M., van Duijn, C. M., Sanghera, D. K., Teumer, A., Zeggini, E., Metspalu, A., Gasparini, P., Ulivi, S., Ober, C., Toniolo, D., Rudan, I., Porteous, D. J., Ciullo, M., Spector, T. D., Hayward, C., Dupuis, J., Loos, R. J., Wright, A. F., Chandak, G. R., Vollenweider, P., Shuldiner, A. R., Ridker, P. M., Rotter, J. I., Sattar, N., Gyllensten, U., North, K. E., Pirastu, M., Psaty, B. M., Weir, D. R., Laakso, M., Gudnason, V., Takahashi, A., Chambers, J. C., Kooner, J. S., Strachan, D. P., Campbell, H., Hirschhorn, J. N., Perola, M., Polašek, O., Wilson, J. F. 2015; 523 (7561): 459-462

    Abstract

    Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

    View details for DOI 10.1038/nature14618

    View details for PubMedID 26131930

  • The new Scandinavian Donations and Transfusions database (SCANDAT2): a blood safety resource with added versatility TRANSFUSION Edgren, G., Rostgaard, K., Vasan, S. K., Wikman, A., Norda, R., Pedersen, O. B., Erikstrup, C., Nielsen, K. R., Titlestad, K., Ullum, H., Melbye, M., Nyren, O., Hjalgrim, H. 2015; 55 (7): 1600-1606

    Abstract

    Risks of transfusion-transmitted disease are currently at a record low in the developed world. Still, available methods for blood surveillance might not be sufficient to detect transmission of diseases with unknown etiologies or with very long incubation periods.We have previously created the anonymized Scandinavian Donations and Transfusions (SCANDAT) database, containing data on blood donors, blood transfusions, and transfused patients, with complete follow-up of donors and patients for a range of health outcomes. Here we describe the re-creation of SCANDAT with updated, identifiable data. We collected computerized data on blood donations and transfusions from blood banks covering all of Sweden and Denmark. After data cleaning, two structurally identical databases were created and the entire database was linked with nationwide health outcomes registers to attain complete follow-up for up to 47 years regarding hospital care, cancer, and death.After removal of erroneous records, the database contained 25,523,334 donation records, 21,318,794 transfusion records, and 3,692,653 unique persons with valid identification, presently followed over 40 million person-years, with possibility for future extension. Data quality is generally high with 96% of all transfusions being traceable to their respective donation(s) and a very high (>97%) concordance with official statistics on annual number of blood donations and transfusions.It is possible to create a binational, nationwide database with almost 50 years of follow-up of blood donors and transfused patients for a range of health outcomes. We aim to use this database for further studies of donor health, transfusion-associated risks, and transfusion-transmitted disease.

    View details for DOI 10.1111/trf.12986

    View details for Web of Science ID 000357953000004

    View details for PubMedID 25573303

  • Non-Hodgkin Lymphoma, Body Mass Index, and Cytokine Polymorphisms: A Pooled Analysis from the InterLymph Consortium CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Kane, E., Skibola, C. F., Bracci, P. M., Cerhan, J. R., Costas, L., Smedby, K. E., Holly, E. A., Maynadie, M., Novak, A. J., Lightfoot, T. J., Ansell, S. M., Smith, A. G., Liebow, M., Melbye, M., Morton, L., de Sanjose, S., Slager, S. L., Wang, S. S., Zhang, Y., Zheng, T., Roman, E. 2015; 24 (7): 1061-1070

    Abstract

    Excess adiposity has been associated with lymphomagenesis, possibly mediated by increased cytokine production causing a chronic inflammatory state. The relationship between obesity, cytokine polymorphisms, and selected mature B-cell neoplasms is reported.Data on 4,979 cases and 4,752 controls from nine American/European studies from the InterLymph consortium (1988-2008) were pooled. For diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), joint associations of body mass index (from self-reported height and weight) and 12 polymorphisms in cytokines IL1A (rs1800587), IL1B (rs16944, rs1143627), IL1RN (rs454078), IL2 (rs2069762), IL6 (rs1800795, rs1800797), IL10 (rs1800890, rs1800896), TNF (rs1800629), LTA (rs909253), and CARD15 (rs2066847) were investigated using unconditional logistic regression. BMI-polymorphism interaction effects were estimated using the relative excess risk due to interaction (RERI).Obesity (BMI ≥ 30 kg/m(2)) was associated with DLBCL risk [OR = 1.33; 95% confidence interval (CI), 1.02-1.73], as was TNF-308GA+AA (OR = 1.24; 95% CI, 1.07-1.44). Together, being obese and TNF-308GA+AA increased DLBCL risk almost 2-fold relative to those of normal weight and TNF-308GG (OR = 1.93; 95% CI, 1.27-2.94), with a RERI of 0.41 (95% CI, -0.05-0.84; Pinteraction = 0.13). For FL and CLL/SLL, no associations with obesity or TNF-308GA+AA, either singly or jointly, were observed. No evidence of interactions between obesity and the other polymorphisms were detected.Our results suggest that cytokine polymorphisms do not generally interact with BMI to increase lymphoma risk but obesity and TNF-308GA+AA may interact to increase DLBCL risk.Studies using better measures of adiposity are needed to further investigate the interactions between obesity and TNF-308G>A in the pathogenesis of lymphoma.

    View details for DOI 10.1158/1055-9965.EPI-14-1355

    View details for Web of Science ID 000357425700008

    View details for PubMedID 25962811

    View details for PubMedCentralID PMC4490950

  • ABO Blood Group and Dementia Risk - A Scandinavian Record-Linkage Study PLOS ONE Vasan, S. K., Rostgaard, K., Ullum, H., Melbye, M., Hjalgrim, H., Edgren, G. 2015; 10 (6)

    Abstract

    Dementia includes a group of neuro-degenerative disorders characterized by varying degrees of cognitive impairment. Recent data indicates that blood group AB is associated with impaired cognition in elderly patients. To date there are no large-scale studies that have examined the relationship between ABO blood group and dementia-related disorders in detail.We used data from the SCANDAT2 database that contains information on over 1.6 million blood donors from 1968 in Sweden and 1981 from Denmark. The database was linked with health outcomes data from nationwide patient and cause of death registers to investigate the relationship between blood groups and risk of different types of dementia. The incident rate ratios were estimated using log-linear Poisson regression models.Among 1,598,294 donors followed over 24 million person-years of observation we ascertained 3,615 cases of Alzheimer's disease, 1,842 cases of vascular dementia, and 9,091 cases of unspecified dementia. Overall, our study showed no association between ABO blood group and risk of Alzheimer's disease, vascular dementia or unspecified dementia. This was also true when analyses were restricted to donors aged 70 years or older except for a slight, but significantly decreased risk of all dementia combined in subjects with blood group A (IRR, 0.93; 95% confidence interval [CI], 0.88-0.98), compared to those with blood group O.Our results provide no evidence that ABO blood group influences the risk of dementia.

    View details for DOI 10.1371/journal.pone.0129115

    View details for Web of Science ID 000355701600089

    View details for PubMedID 26042891

    View details for PubMedCentralID PMC4456384

  • A Detailed Family History of Myocardial Infarction and Risk of Myocardial Infarction - A Nationwide Cohort Study PLOS ONE Ranthe, M. F., Petersen, J. A., Bundgaard, H., Wohlfahrt, J., Melbye, M., Boyd, H. A. 2015; 10 (5)

    Abstract

    Family history of myocardial infarction (MI) is an independent risk factor for MI. Several genetic variants are associated with increased risk of MI and family history of MI in a first-degree relative doubles MI risk. However, although family history of MI is not a simple dichotomous risk factor, the impact of specific, detailed family histories has not received much attention, despite its high clinical relevance. We examined risk of MI by MIs in first- and second-degree relatives and by number and age of affected relatives.Using Danish national registers, we established a nationwide cohort of persons born between 1930 and 1992 with identifiable first- or second-degree relatives. Incident MIs in both cohort members and relatives aged ≥20 years were identified. We calculated incidence rate ratios (IRRs) for MI by family history of MI, by Poisson regression. In 4.4 million persons followed for 104 million person-years, we identified 128,384 incident MIs. IRRs with 95% confidence intervals [CIs] for MI by history of MI in 1, 2 or ≥3 first-degree relatives were 1.46 (1.42-1.49), 2.38 (2.22-2.56) and 3.58 (2.66-4.81), respectively. Corresponding estimates for second-degree relatives were 1.17 (1.05-1.30), 1.87 (1.46-2.38) and 2.18 (1.09-4.36). A history of MI in combinations of first- and second-degree relatives increased risks 1.8- to 7-fold in middle-aged persons (36 to 55 years). Estimates were robust to adjustment for diabetes, hypertension, dyslipidemia and use of cardiovascular medications.A detailed family history, particularly number of affected first- and second-degree relatives, contributes meaningfully to risk assessment, especially in middle-aged persons. Future studies should test for potential improvement of risk algorithm prediction using detailed family histories.

    View details for DOI 10.1371/journal.pone.0125896

    View details for Web of Science ID 000355183900016

    View details for PubMedID 26011129

    View details for PubMedCentralID PMC4444238

  • The long-term risk of malignant astrocytic tumors after structural brain injury-a nationwide cohort study NEURO-ONCOLOGY Munch, T. N., Gortz, S., Wohlfahrt, J., Melbye, M. 2015; 17 (5): 718-724

    Abstract

    Neoplastic transformation of damaged astrocytes has been proposed as a possible pathological mechanism behind malignant astrocytic tumors. This study investigated the association between structural brain injuries causing reactive astrogliosis and long-term risk for malignant astrocytic tumors.The cohort consisted of all individuals living in Denmark between 1978 and 2011. The personal identification number assigned to all individuals allowed retrieval of diagnoses of traumatic brain injury, cerebral ischemic infarction, and intracerebral hemorrhage from the National Patient Discharge Register. Diagnoses of anaplastic astrocytoma and glioblastoma multiforme (World Health Organization grades III and IV) were retrieved from the Danish Cancer Registry. Rate ratios (RR's) were estimated using log-linear Poisson regression.In a cohort of 8.2 million individuals, 404 812 experienced a structural brain injury and 6152 developed a malignant astrocytic tumor. No significant association was observed 1-4 years after a structural brain injury (RR = 1.14; 95% CI: 0.87-1.46), whereas the long-term (5+ y) risk for malignant astrocytic tumors was significantly reduced (RR = 0.68; 95% CI: 0.49-0.90) compared with no injury. The specific long-term risks by type of injury were: traumatic brain injury RR = 0.32 (95% CI: 0.10-0.75); cerebral ischemic infarction RR = 0.69 (95% CI: 0.47-0.96); and intracerebral hemorrhage RR = 1.39 (95% CI: 0.64-2.60).We found no evidence for an association between structural brain injury and malignant astrocytic tumors within the first 5 years of follow-up. However, our study indicated a protective effect of astrogliosis-causing injuries 5 or more years after structural brain injury.

    View details for DOI 10.1093/neuonc/nou312

    View details for Web of Science ID 000356263100012

    View details for PubMedID 25416827

    View details for PubMedCentralID PMC4482857

  • Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption MOLECULAR PSYCHIATRY Cornelis, M. C., Byrne, E. M., Esko, T., Nalls, M. A., Ganna, A., Paynter, N., Monda, K. L., Amin, N., Fischer, K., Renstrom, F., Ngwa, J. S., Huikari, V., Cavadino, A., Nolte, I. M., Teumer, A., Yu, K., Marques-Vidal, P., Rawal, R., Manichaikul, A., Wojczynski, M. K., Vink, J. M., Zhao, J. H., Burlutsky, G., Lahti, J., Mikkila, V., Lemaitre, R. N., Eriksson, J., Musani, S. K., Tanaka, T., Geller, F., Luan, J., Hui, J., Maegi, R., Dimitriou, M., Garcia, M. E., Ho, W., Wright, M. J., Rose, L. M., Magnusson, P. K., Pedersen, N. L., Couper, D., Oostra, B. A., Hofman, A., Ikram, M. A., Tiemeier, H. W., Uitterlinden, A. G., Van Rooij, F. J., Barroso, I., Johansson, I., Xue, L., Kaakinen, M., Milani, L., Power, C., Snieder, H., Stolk, R. P., Baumeister, S. E., Biffar, R., Gu, F., Bastardot, F., Kutalik, Z., Jacobs, D. R., Forouhi, N. G., MIHAILOV, E., Lind, L., Lindgren, C., Michaelsson, K., Morris, A., Jensen, M., Khaw, K., Luben, R. N., Wang, J. J., Mannisto, S., Perala, M., Kahonen, M., Lehtimaki, T., Viikari, J., Mozaffarian, D., Mukamal, K., Psaty, B. M., Doering, A., Heath, A. C., Montgomery, G. W., Dahmen, N., Carithers, T., Tucker, K. L., Ferrucci, L., Boyd, H. A., Melbye, M., Treur, J. L., Mellstrom, D., Hottenga, J. J., Prokopenko, I., Toenjes, A., Deloukas, P., Kanoni, S., Lorentzon, M., Houston, D. K., Liu, Y., Danesh, J., Rasheed, A., Mason, M. A., Zonderman, A. B., Franke, L., Kristal, B. S., Karjalainen, J., Reed, D. R., Westra, H., Evans, M. K., Saleheen, D., Harris, T. B., Dedoussis, G., Curhan, G., Stumvoll, M., Beilby, J., Pasquale, L. R., Feenstra, B., Bandinelli, S., Ordovas, J. M., Chan, A. T., Peters, U., Ohlsson, C., Gieger, C., Martin, N. G., Waldenberger, M., Siscovick, D. S., Raitakari, O., Eriksson, J. G., Mitchell, P., Hunter, D. J., Kraft, P., Rimm, E. B., Boomsma, D. I., Borecki, I. B., Loos, R. J., Wareham, N. J., Vollenweider, P., Caporaso, N., Grabe, H. J., Neuhouser, M. L., Wolffenbuttel, B. H., Hu, F. B., Hyppoenen, E., Jarvelin, M., Cupples, L. A., Franks, P. W., Ridker, P. M., van Duijn, C. M., Heiss, G., Metspalu, A., North, K. E., Ingelsson, E., Nettleton, J. A., van Dam, R. M., Chasman, D. I. 2015; 20 (5): 647-656

    Abstract

    Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.

    View details for DOI 10.1038/mp.2014.107

    View details for Web of Science ID 000353706400016

    View details for PubMedID 25288136

    View details for PubMedCentralID PMC4388784

  • Mitochondrial dysfunction and risk of cancer BRITISH JOURNAL OF CANCER Lund, M., Melbye, M., Diaz, L. J., Duno, M., Wohlfahrt, J., Vissing, J. 2015; 112 (6): 1134-1140

    Abstract

    Mitochondrial mutations are commonly reported in tumours, but it is unclear whether impaired mitochondrial function per se is a cause or consequence of cancer. To elucidate this, we examined the risk of cancer in a nationwide cohort of patients with mitochondrial dysfunction.We used nationwide results on genetic testing for mitochondrial disease and the Danish Civil Registration System, to construct a cohort of 311 patients with mitochondrial dysfunction. A total of 177 cohort members were identified from genetic testing and 134 genetically untested cohort members were matrilineal relatives to a cohort member with a genetically confirmed maternally inherited mDNA mutation. Information on cancer was obtained by linkage to the Danish Cancer Register. Standardised incidence ratios (SIRs) were used to assess the relative risk of cancer.During 7334 person-years of follow-up, 19 subjects developed a primary cancer. The corresponding SIR for any primary cancer was 1.06 (95% confidence interval 0.68-1.63). Subgroup analyses according to mutational subtype yielded similar results, for example, a SIR of 0.94 (95% CI 0.53 to 1.67) for the m.3243A>G maternally inherited mDNA mutation, cases=13.Patients with mitochondrial dysfunction do not appear to be at increased risk of cancer compared with the general population.

    View details for DOI 10.1038/bjc.2015.66

    View details for Web of Science ID 000351388200023

    View details for PubMedID 25742477

    View details for PubMedCentralID PMC4366902

  • Hepatitis B Prevalence and Incidence in Greenland: A Population-Based Cohort Study AMERICAN JOURNAL OF EPIDEMIOLOGY Borresen, M. L., Andersson, M., Wohlfahrt, J., Melbye, M., Biggar, R. J., Ladefoged, K., Panum, I., Koch, A. 2015; 181 (6): 422-430

    Abstract

    Greenland remains a highly endemic area for hepatitis B virus (HBV) infection. This is in sharp contrast to other modern societies, such as Denmark. To address this discrepancy, we investigated the natural history of HBV infection in Greenland by estimating the age-specific incidence of HBV infection, the proportion of chronic carriers, and the rates of hepatitis B surface antigen seroclearance. In total, 8,879 Greenlanders (16% of the population) from population-based surveys conducted in 1987 and 1998 were followed through March 2010. Data on HBV status were supplemented by HBV test results from all available HBV registries in Greenland to determine changes in HBV status over time. Incidence rates of HBV infection and hepatitis B surface antigen seroclearance were estimated after taking into account interval censoring. The incidence of HBV infection in 5-14-year-old subjects was less than 1 per 100 person-years and peaked at 5 per 100 person-years in persons 15-24 years of age. Overall, 17.5% of persons infected in adulthood were estimated to become chronic carriers. HBV is primarily transmitted in adolescence and adulthood in Greenland. In contrast to what is observed in most other populations, HBV-infected adults in Greenland have a high risk of progressing to chronic HBV carriage. This phenomenon might explain how the high rate of infection is maintained in Greenland.

    View details for DOI 10.1093/aje/kwu287

    View details for Web of Science ID 000351508200008

    View details for PubMedID 25721415

  • Characterization of large structural genetic mosaicism in human autosomes. American journal of human genetics Machiela, M. J., Zhou, W., Sampson, J. N., Dean, M. C., Jacobs, K. B., Black, A., Brinton, L. A., Chang, I., Chen, C., Chen, C., Chen, K., Cook, L. S., Crous Bou, M., De Vivo, I., Doherty, J., Friedenreich, C. M., Gaudet, M. M., Haiman, C. A., Hankinson, S. E., Hartge, P., Henderson, B. E., Hong, Y., Hosgood, H. D., Hsiung, C. A., Hu, W., Hunter, D. J., Jessop, L., Kim, H. N., Kim, Y. H., Kim, Y. T., Klein, R., Kraft, P., Lan, Q., Lin, D., Liu, J., Le Marchand, L., Liang, X., Lissowska, J., Lu, L., Magliocco, A. M., Matsuo, K., Olson, S. H., Orlow, I., Park, J. Y., Pooler, L., Prescott, J., Rastogi, R., Risch, H. A., Schumacher, F., Seow, A., Setiawan, V. W., Shen, H., Sheng, X., Shin, M., Shu, X., Vanden Berg, D., Wang, J., Wentzensen, N., Wong, M. P., Wu, C., Wu, T., Wu, Y., Xia, L., Yang, H. P., Yang, P., Zheng, W., Zhou, B., Abnet, C. C., Albanes, D., Aldrich, M. C., Amos, C., Amundadottir, L. T., Berndt, S. I., Blot, W. J., Bock, C. H., Bracci, P. M., Burdett, L., Buring, J. E., Butler, M. A., Carreón, T., Chatterjee, N., Chung, C. C., Cook, M. B., Cullen, M., Davis, F. G., Ding, T., Duell, E. J., Epstein, C. G., Fan, J., Figueroa, J. D., Fraumeni, J. F., Freedman, N. D., Fuchs, C. S., Gao, Y., Gapstur, S. M., Patiño-Garcia, A., Garcia-Closas, M., Gaziano, J. M., Giles, G. G., Gillanders, E. M., Giovannucci, E. L., Goldin, L., Goldstein, A. M., Greene, M. H., Hallmans, G., Harris, C. C., Henriksson, R., Holly, E. A., Hoover, R. N., Hu, N., Hutchinson, A., Jenab, M., Johansen, C., Khaw, K., Koh, W., Kolonel, L. N., Kooperberg, C., Krogh, V., Kurtz, R. C., LaCroix, A., Landgren, A., Landi, M. T., Li, D., Liao, L. M., Malats, N., McGlynn, K. A., McNeill, L. H., Mcwilliams, R. R., Melin, B. S., Mirabello, L., Peplonska, B., Peters, U., Petersen, G. M., Prokunina-Olsson, L., Purdue, M., Qiao, Y., Rabe, K. G., Rajaraman, P., Real, F. X., Riboli, E., Rodríguez-Santiago, B., Rothman, N., Ruder, A. M., Savage, S. A., Schwartz, A. G., Schwartz, K. L., Sesso, H. D., Severi, G., Silverman, D. T., Spitz, M. R., Stevens, V. L., Stolzenberg-Solomon, R., Stram, D., Tang, Z., Taylor, P. R., Teras, L. R., Tobias, G. S., Viswanathan, K., Wacholder, S., Wang, Z., Weinstein, S. J., Wheeler, W., White, E., Wiencke, J. K., Wolpin, B. M., Wu, X., Wunder, J. S., Yu, K., Zanetti, K. A., Zeleniuch-Jacquotte, A., Ziegler, R. G., de Andrade, M., Barnes, K. C., Beaty, T. H., Bierut, L. J., Desch, K. C., Doheny, K. F., Feenstra, B., Ginsburg, D., Heit, J. A., Kang, J. H., Laurie, C. A., Li, J. Z., Lowe, W. L., Marazita, M. L., Melbye, M., Mirel, D. B., Murray, J. C., Nelson, S. C., Pasquale, L. R., Rice, K., Wiggs, J. L., Wise, A., Tucker, M., Pérez-Jurado, L. A., Laurie, C. C., Caporaso, N. E., Yeager, M., Chanock, S. J. 2015; 96 (3): 487-497

    Abstract

    Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

    View details for DOI 10.1016/j.ajhg.2015.01.011

    View details for PubMedID 25748358

  • Use of different types of angiotensin converting enzyme inhibitors and mortality in systolic heart failure INTERNATIONAL JOURNAL OF CARDIOLOGY Svanstrom, H., Pasternak, B., Melbye, M., Hviid, A. 2015; 182: 90-96

    Abstract

    Angiotensin converting enzyme-inhibitors (ACEIs) are the first-line treatment for patients with heart failure (HF) with reduced ejection fraction (EF). The benefit of ACEIs in HF is regarded as a class effect and different types of agents are used interchangeably. However, evidence on the comparable effectiveness of different ACEIs is scarce. We conducted a registry-based cohort study to assess all-cause mortality associated with the use of enalapril, perindopril, and trandolapril, as compared with ramipril, in patients with systolic HF.Patients with systolic HF (EF ≤40%), 2003-2012, were identified using the Danish HF Registry. New users of enalapril (n=1807), perindopril (n=1064), ramipril (n=3270), or trandolapril (n=1150), who started treatment within 60days of first-time hospital diagnosis of HF, were selected for inclusion. Subgroup analyses were conducted by sex, age, NYHA-level, EF, and ischemic heart disease. All analyses were adjusted for empirical risk scores for mortality.During follow-up, 291 deaths were observed among users of enalapril (incidence rate per 100person-years [IR], 10.1), 212 among users of perindopril (IR, 10.5), 568 among users of ramipril (IR, 10.6), and 251 among users of trandolapril (IR, 12.1). No significant differences in all-cause mortality were observed with the use of enalapril (adjusted hazard ratio [aHR] 0.95, 95% CI 0.82-1.10), perindopril (aHR 1.07, 95% CI 0.92-1.26), or trandolapril (aHR 1.08, 95% CI 0.93-1.26), as compared with ramipril. No significant differences were observed in subgroup analyses.These findings suggest equal effect of different types of ACEIs on mortality in systolic HF.

    View details for DOI 10.1016/j.ijcard.2014.12.092

    View details for Web of Science ID 000351927600035

    View details for PubMedID 25576729

  • A novel common variant in DCST2 is associated with length in early life and height in adulthood. Human molecular genetics van der Valk, R. J., Kreiner-Møller, E., Kooijman, M. N., Guxens, M., Stergiakouli, E., Sääf, A., Bradfield, J. P., Geller, F., Hayes, M. G., Cousminer, D. L., Körner, A., Thiering, E., Curtin, J. A., Myhre, R., Huikari, V., Joro, R., Kerkhof, M., Warrington, N. M., Pitkänen, N., Ntalla, I., Horikoshi, M., Veijola, R., Freathy, R. M., Teo, Y., Barton, S. J., Evans, D. M., Kemp, J. P., St Pourcain, B., Ring, S. M., Davey Smith, G., Bergström, A., Kull, I., Hakonarson, H., Mentch, F. D., Bisgaard, H., Chawes, B., Stokholm, J., Waage, J., Eriksen, P., Sevelsted, A., Melbye, M., van Duijn, C. M., Medina-Gomez, C., Hofman, A., de Jongste, J. C., Taal, H. R., Uitterlinden, A. G., Armstrong, L. L., Eriksson, J., Palotie, A., Bustamante, M., Estivill, X., Gonzalez, J. R., Llop, S., Kiess, W., Mahajan, A., Flexeder, C., Tiesler, C. M., Murray, C. S., Simpson, A., Magnus, P., Sengpiel, V., Hartikainen, A., Keinanen-Kiukaanniemi, S., Lewin, A., da Silva Couto Alves, A., Blakemore, A. I., Buxton, J. L., Kaakinen, M., Rodriguez, A., Sebert, S., Vaarasmaki, M., Lakka, T., Lindi, V., Gehring, U., Postma, D. S., Ang, W., Newnham, J. P., Lyytikäinen, L., Pahkala, K., Raitakari, O. T., Panoutsopoulou, K., Zeggini, E., Boomsma, D. I., Groen-Blokhuis, M., Ilonen, J., Franke, L., Hirschhorn, J. N., Pers, T. H., Liang, L., Huang, J., Hocher, B., Knip, M., Saw, S., Holloway, J. W., Melén, E., Grant, S. F., Feenstra, B., Lowe, W. L., Widén, E., Sergeyev, E., Grallert, H., Custovic, A., Jacobsson, B., Jarvelin, M., Atalay, M., Koppelman, G. H., Pennell, C. E., Niinikoski, H., Dedoussis, G. V., McCarthy, M. I., Frayling, T. M., Sunyer, J., Timpson, N. J., Rivadeneira, F., Bønnelykke, K., Jaddoe, V. W. 2015; 24 (4): 1155-1168

    Abstract

    Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.

    View details for DOI 10.1093/hmg/ddu510

    View details for PubMedID 25281659

    View details for PubMedCentralID PMC4447786

  • A novel common variant in DCST2 is associated with length in early life and height in adulthood HUMAN MOLECULAR GENETICS van der Valk, R. J., Kreiner-Moller, E., Kooijman, M. N., Guxens, M., Stergiakouli, E., Saaf, A., Bradfield, J. P., Geller, F., Hayes, M. G., Cousminer, D. L., Koerner, A., Thiering, E., Curtin, J. A., Myhre, R., Huikari, V., Joro, R., Kerkhof, M., Warrington, N. M., Pitkanen, N., Ntalla, I., Horikoshi, M., Veijola, R., Freathy, R. M., Teo, Y., Barton, S. J., Evans, D. M., Kemp, J. P., St Pourcain, B., Ring, S. M., Smith, G. D., Bergstrom, A., Kull, I., Hakonarson, H., Mentch, F. D., Bisgaard, H., Chawes, B., Stokholm, J., Waage, J., Eriksen, P., Sevelsted, A., Melbye, M., van Duijn, C. M., Medina-Gomez, C., Hofman, A., de Jongste, J. C., Taal, H. R., Uitterlinden, A. G., Armstrong, L. L., Eriksson, J., Palotie, A., Bustamante, M., Estivill, X., Gonzalez, J. R., Llop, S., Kiess, W., Mahajan, A., Flexeder, C., Tiesler, C. M., Murray, C. S., Simpson, A., Magnus, P., Sengpiel, V., Hartikainen, A., Keinanen-Kiukaanniemi, S., Lewin, A., Alves, A. D., Blakemore, A. I., Buxton, J. L., Kaakinen, M., Rodriguez, A., Sebert, S., Vaarasmaki, M., Lakka, T., Lindi, V., Gehring, U., Postma, D. S., Ang, W., Newnham, J. P., Lyytikainen, L., Pahkala, K., Raitakari, O. T., Panoutsopoulou, K., Zeggini, E., Boomsma, D. I., Groen-Blokhuis, M., Ilonen, J., Franke, L., Hirschhorn, J. N., Pers, T. H., Liang, L., Huang, J., Hocher, B., Knip, M., Saw, S., Holloway, J. W., Melen, E., Grant, S. F., Feenstra, B., Lowe, W. L., Widen, E., Sergeyev, E., Grallert, H., Custovic, A., Jacobsson, B., Jarvelin, M., Atalay, M., Koppelman, G. H., Pennell, C. E., Niinikoski, H., Dedoussis, G. V., McCarthy, M. I., Frayling, T. M., Sunyer, J., Timpson, N. J., Rivadeneira, F., Bonnelykke, K., Jaddoe, V. W. 2015; 24 (4): 1155-1168

    Abstract

    Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.

    View details for DOI 10.1093/hmg/ddu510

    View details for Web of Science ID 000350138300021

    View details for PubMedCentralID PMC4447786

  • Genetic studies of body mass index yield new insights for obesity biology. Nature Locke, A. E., Kahali, B., Berndt, S. I., Justice, A. E., Pers, T. H., Day, F. R., Powell, C., Vedantam, S., Buchkovich, M. L., Yang, J., Croteau-Chonka, D. C., Esko, T., Fall, T., Ferreira, T., Gustafsson, S., Kutalik, Z., Luan, J., Mägi, R., Randall, J. C., Winkler, T. W., Wood, A. R., Workalemahu, T., Faul, J. D., Smith, J. A., Hua Zhao, J., Zhao, W., Chen, J., Fehrmann, R., Hedman, Å. K., Karjalainen, J., Schmidt, E. M., Absher, D., Amin, N., Anderson, D., Beekman, M., Bolton, J. L., Bragg-Gresham, J. L., Buyske, S., Demirkan, A., Deng, G., Ehret, G. B., Feenstra, B., Feitosa, M. F., Fischer, K., Goel, A., Gong, J., Jackson, A. U., Kanoni, S., Kleber, M. E., Kristiansson, K., Lim, U., Lotay, V., Mangino, M., Mateo Leach, I., Medina-Gomez, C., Medland, S. E., Nalls, M. A., Palmer, C. D., Pasko, D., Pechlivanis, S., Peters, M. J., Prokopenko, I., Shungin, D., Stancáková, A., Strawbridge, R. J., Ju Sung, Y., Tanaka, T., Teumer, A., Trompet, S., van der Laan, S. W., van Setten, J., van Vliet-Ostaptchouk, J. V., Wang, Z., Yengo, L., Zhang, W., Isaacs, A., Albrecht, E., Ärnlöv, J., Arscott, G. M., Attwood, A. P., Bandinelli, S., Barrett, A., Bas, I. N., Bellis, C., Bennett, A. J., Berne, C., Blagieva, R., Blüher, M., Böhringer, S., Bonnycastle, L. L., Böttcher, Y., Boyd, H. A., Bruinenberg, M., Caspersen, I. H., Ida Chen, Y., Clarke, R., Warwick Daw, E., de Craen, A. J., Delgado, G., Dimitriou, M., Doney, A. S., Eklund, N., Estrada, K., Eury, E., Folkersen, L., Fraser, R. M., Garcia, M. E., Geller, F., Giedraitis, V., Gigante, B., Go, A. S., Golay, A., Goodall, A. H., Gordon, S. D., Gorski, M., Grabe, H., Grallert, H., Grammer, T. B., Gräßler, J., Grönberg, H., Groves, C. J., Gusto, G., Haessler, J., Hall, P., Haller, T., Hallmans, G., Hartman, C. A., Hassinen, M., Hayward, C., Heard-Costa, N. L., Helmer, Q., Hengstenberg, C., Holmen, O., Hottenga, J., James, A. L., Jeff, J. M., Johansson, Å., Jolley, J., Juliusdottir, T., Kinnunen, L., Koenig, W., Koskenvuo, M., Kratzer, W., Laitinen, J., Lamina, C., Leander, K., Lee, N. R., Lichtner, P., Lind, L., Lindström, J., Sin Lo, K., Lobbens, S., Lorbeer, R., Lu, Y., Mach, F., Magnusson, P. K., Mahajan, A., McArdle, W. L., McLachlan, S., Menni, C., Merger, S., Mihailov, E., Milani, L., Moayyeri, A., Monda, K. L., Morken, M. A., Mulas, A., Müller, G., Müller-Nurasyid, M., Musk, A. W., Nagaraja, R., Nöthen, M. M., Nolte, I. M., Pilz, S., Rayner, N. W., Renstrom, F., Rettig, R., Ried, J. S., Ripke, S., Robertson, N. R., Rose, L. M., Sanna, S., Scharnagl, H., Scholtens, S., Schumacher, F. R., Scott, W. R., Seufferlein, T., Shi, J., Vernon Smith, A., Smolonska, J., Stanton, A. V., Steinthorsdottir, V., Stirrups, K., Stringham, H. M., Sundström, J., Swertz, M. A., Swift, A. J., Syvänen, A., Tan, S., Tayo, B. O., Thorand, B., Thorleifsson, G., Tyrer, J. P., Uh, H., Vandenput, L., Verhulst, F. C., Vermeulen, S. H., Verweij, N., Vonk, J. M., Waite, L. L., Warren, H. R., Waterworth, D., Weedon, M. N., Wilkens, L. R., Willenborg, C., Wilsgaard, T., Wojczynski, M. K., Wong, A., Wright, A. F., Zhang, Q., Brennan, E. P., Choi, M., Dastani, Z., Drong, A. W., Eriksson, P., Franco-Cereceda, A., Gådin, J. R., Gharavi, A. G., Goddard, M. E., Handsaker, R. E., Huang, J., Karpe, F., Kathiresan, S., Keildson, S., Kiryluk, K., Kubo, M., Lee, J., Liang, L., Lifton, R. P., Ma, B., McCarroll, S. A., McKnight, A. J., Min, J. L., Moffatt, M. F., Montgomery, G. W., Murabito, J. M., Nicholson, G., Nyholt, D. R., Okada, Y., Perry, J. R., Dorajoo, R., Reinmaa, E., Salem, R. M., Sandholm, N., Scott, R. A., Stolk, L., Takahashi, A., Tanaka, T., van't Hooft, F. M., Vinkhuyzen, A. A., Westra, H., Zheng, W., Zondervan, K. T., Heath, A. C., Arveiler, D., Bakker, S. J., Beilby, J., Bergman, R. N., Blangero, J., Bovet, P., Campbell, H., Caulfield, M. J., Cesana, G., Chakravarti, A., Chasman, D. I., Chines, P. S., Collins, F. S., Crawford, D. C., Adrienne Cupples, L., Cusi, D., Danesh, J., de Faire, U., Den Ruijter, H. M., Dominiczak, A. F., Erbel, R., Erdmann, J., Eriksson, J. G., Farrall, M., Felix, S. B., Ferrannini, E., Ferrières, J., Ford, I., Forouhi, N. G., Forrester, T., Franco, O. H., Gansevoort, R. T., Gejman, P. V., Gieger, C., Gottesman, O., Gudnason, V., Gyllensten, U., Hall, A. S., Harris, T. B., Hattersley, A. T., Hicks, A. A., Hindorff, L. A., Hingorani, A. D., Hofman, A., Homuth, G., Kees Hovingh, G., Humphries, S. E., Hunt, S. C., Hyppönen, E., Illig, T., Jacobs, K. B., Jarvelin, M., Jöckel, K., Johansen, B., Jousilahti, P., Wouter Jukema, J., Jula, A. M., Kaprio, J., Kastelein, J. J., Keinanen-Kiukaanniemi, S. M., Kiemeney, L. A., Knekt, P., Kooner, J. S., Kooperberg, C., Kovacs, P., Kraja, A. T., Kumari, M., Kuusisto, J., Lakka, T. A., Langenberg, C., Le Marchand, L., Lehtimäki, T., Lyssenko, V., Männistö, S., Marette, A., Matise, T. C., McKenzie, C. A., McKnight, B., Moll, F. L., Morris, A. D., Morris, A. P., Murray, J. C., Nelis, M., Ohlsson, C., Oldehinkel, A. J., Ong, K. K., Madden, P. A., Pasterkamp, G., Peden, J. F., Peters, A., Postma, D. S., Pramstaller, P. P., Price, J. F., Qi, L., Raitakari, O. T., Rankinen, T., Rao, D. C., Rice, T. K., Ridker, P. M., Rioux, J. D., Ritchie, M. D., Rudan, I., Salomaa, V., Samani, N. J., Saramies, J., Sarzynski, M. A., Schunkert, H., Schwarz, P. E., Sever, P., Shuldiner, A. R., Sinisalo, J., Stolk, R. P., Strauch, K., Tönjes, A., Trégouët, D., Tremblay, A., Tremoli, E., Virtamo, J., Vohl, M., Völker, U., Waeber, G., Willemsen, G., Witteman, J. C., Zillikens, M. C., Adair, L. S., Amouyel, P., Asselbergs, F. W., Assimes, T. L., Bochud, M., Boehm, B. O., Boerwinkle, E., Bornstein, S. R., Bottinger, E. P., Bouchard, C., Cauchi, S., Chambers, J. C., Chanock, S. J., Cooper, R. S., de Bakker, P. I., Dedoussis, G., Ferrucci, L., Franks, P. W., Froguel, P., Groop, L. C., Haiman, C. A., Hamsten, A., Hui, J., Hunter, D. J., Hveem, K., Kaplan, R. C., Kivimaki, M., Kuh, D., Laakso, M., Liu, Y., Martin, N. G., März, W., Melbye, M., Metspalu, A., Moebus, S., Munroe, P. B., Njølstad, I., Oostra, B. A., Palmer, C. N., Pedersen, N. L., Perola, M., Pérusse, L., Peters, U., Power, C., Quertermous, T., Rauramaa, R., Rivadeneira, F., Saaristo, T. E., Saleheen, D., Sattar, N., Schadt, E. E., Schlessinger, D., Eline Slagboom, P., Snieder, H., Spector, T. D., Thorsteinsdottir, U., Stumvoll, M., Tuomilehto, J., Uitterlinden, A. G., Uusitupa, M., van der Harst, P., Walker, M., Wallaschofski, H., Wareham, N. J., Watkins, H., Weir, D. R., Wichmann, H., Wilson, J. F., Zanen, P., Borecki, I. B., Deloukas, P., Fox, C. S., Heid, I. M., O'Connell, J. R., Strachan, D. P., Stefansson, K., van Duijn, C. M., Abecasis, G. R., Franke, L., Frayling, T. M., McCarthy, M. I., Visscher, P. M., Scherag, A., Willer, C. J., Boehnke, M., Mohlke, K. L., Lindgren, C. M., Beckmann, J. S., Barroso, I., North, K. E., Ingelsson, E., Hirschhorn, J. N., Loos, R. J., Speliotes, E. K. 2015; 518 (7538): 197-206

    Abstract

    Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

    View details for DOI 10.1038/nature14177

    View details for PubMedID 25673413

    View details for PubMedCentralID PMC4382211

  • Genetic studies of body mass index yield new insights for obesity biology. Nature Locke, A. E., Kahali, B., Berndt, S. I., Justice, A. E., Pers, T. H., Day, F. R., Powell, C., Vedantam, S., Buchkovich, M. L., Yang, J., Croteau-Chonka, D. C., Esko, T., Fall, T., Ferreira, T., Gustafsson, S., Kutalik, Z., Luan, J., Mägi, R., Randall, J. C., Winkler, T. W., Wood, A. R., Workalemahu, T., Faul, J. D., Smith, J. A., Hua Zhao, J., Zhao, W., Chen, J., Fehrmann, R., Hedman, Å. K., Karjalainen, J., Schmidt, E. M., Absher, D., Amin, N., Anderson, D., Beekman, M., Bolton, J. L., Bragg-Gresham, J. L., Buyske, S., Demirkan, A., Deng, G., Ehret, G. B., Feenstra, B., Feitosa, M. F., Fischer, K., Goel, A., Gong, J., Jackson, A. U., Kanoni, S., Kleber, M. E., Kristiansson, K., Lim, U., Lotay, V., Mangino, M., Mateo Leach, I., Medina-Gomez, C., Medland, S. E., Nalls, M. A., Palmer, C. D., Pasko, D., Pechlivanis, S., Peters, M. J., Prokopenko, I., Shungin, D., Stancáková, A., Strawbridge, R. J., Ju Sung, Y., Tanaka, T., Teumer, A., Trompet, S., van der Laan, S. W., van Setten, J., van Vliet-Ostaptchouk, J. V., Wang, Z., Yengo, L., Zhang, W., Isaacs, A., Albrecht, E., Ärnlöv, J., Arscott, G. M., Attwood, A. P., Bandinelli, S., Barrett, A., Bas, I. N., Bellis, C., Bennett, A. J., Berne, C., Blagieva, R., Blüher, M., Böhringer, S., Bonnycastle, L. L., Böttcher, Y., Boyd, H. A., Bruinenberg, M., Caspersen, I. H., Ida Chen, Y., Clarke, R., Daw, E. W., de Craen, A. J., Delgado, G., Dimitriou, M., Doney, A. S., Eklund, N., Estrada, K., Eury, E., Folkersen, L., Fraser, R. M., Garcia, M. E., Geller, F., Giedraitis, V., Gigante, B., Go, A. S., Golay, A., Goodall, A. H., Gordon, S. D., Gorski, M., Grabe, H., Grallert, H., Grammer, T. B., Gräßler, J., Grönberg, H., Groves, C. J., Gusto, G., Haessler, J., Hall, P., Haller, T., Hallmans, G., Hartman, C. A., Hassinen, M., Hayward, C., Heard-Costa, N. L., Helmer, Q., Hengstenberg, C., Holmen, O., Hottenga, J., James, A. L., Jeff, J. M., Johansson, Å., Jolley, J., Juliusdottir, T., Kinnunen, L., Koenig, W., Koskenvuo, M., Kratzer, W., Laitinen, J., Lamina, C., Leander, K., Lee, N. R., Lichtner, P., Lind, L., Lindström, J., Sin Lo, K., Lobbens, S., Lorbeer, R., Lu, Y., Mach, F., Magnusson, P. K., Mahajan, A., McArdle, W. L., McLachlan, S., Menni, C., Merger, S., Mihailov, E., Milani, L., Moayyeri, A., Monda, K. L., Morken, M. A., Mulas, A., Müller, G., Müller-Nurasyid, M., Musk, A. W., Nagaraja, R., Nöthen, M. M., Nolte, I. M., Pilz, S., Rayner, N. W., Renstrom, F., Rettig, R., Ried, J. S., Ripke, S., Robertson, N. R., Rose, L. M., Sanna, S., Scharnagl, H., Scholtens, S., Schumacher, F. R., Scott, W. R., Seufferlein, T., Shi, J., Vernon Smith, A., Smolonska, J., Stanton, A. V., Steinthorsdottir, V., Stirrups, K., Stringham, H. M., Sundström, J., Swertz, M. A., Swift, A. J., Syvänen, A., Tan, S., Tayo, B. O., Thorand, B., Thorleifsson, G., Tyrer, J. P., Uh, H., Vandenput, L., Verhulst, F. C., Vermeulen, S. H., Verweij, N., Vonk, J. M., Waite, L. L., Warren, H. R., Waterworth, D., Weedon, M. N., Wilkens, L. R., Willenborg, C., Wilsgaard, T., Wojczynski, M. K., Wong, A., Wright, A. F., Zhang, Q., Brennan, E. P., Choi, M., Dastani, Z., Drong, A. W., Eriksson, P., Franco-Cereceda, A., Gådin, J. R., Gharavi, A. G., Goddard, M. E., Handsaker, R. E., Huang, J., Karpe, F., Kathiresan, S., Keildson, S., Kiryluk, K., Kubo, M., Lee, J., Liang, L., Lifton, R. P., Ma, B., McCarroll, S. A., McKnight, A. J., Min, J. L., Moffatt, M. F., Montgomery, G. W., Murabito, J. M., Nicholson, G., Nyholt, D. R., Okada, Y., Perry, J. R., Dorajoo, R., Reinmaa, E., Salem, R. M., Sandholm, N., Scott, R. A., Stolk, L., Takahashi, A., Tanaka, T., van't Hooft, F. M., Vinkhuyzen, A. A., Westra, H., Zheng, W., Zondervan, K. T., Heath, A. C., Arveiler, D., Bakker, S. J., Beilby, J., Bergman, R. N., Blangero, J., Bovet, P., Campbell, H., Caulfield, M. J., Cesana, G., Chakravarti, A., Chasman, D. I., Chines, P. S., Collins, F. S., Crawford, D. C., Cupples, L. A., Cusi, D., Danesh, J., de Faire, U., Den Ruijter, H. M., Dominiczak, A. F., Erbel, R., Erdmann, J., Eriksson, J. G., Farrall, M., Felix, S. B., Ferrannini, E., Ferrières, J., Ford, I., Forouhi, N. G., Forrester, T., Franco, O. H., Gansevoort, R. T., Gejman, P. V., Gieger, C., Gottesman, O., Gudnason, V., Gyllensten, U., Hall, A. S., Harris, T. B., Hattersley, A. T., Hicks, A. A., Hindorff, L. A., Hingorani, A. D., Hofman, A., Homuth, G., Hovingh, G. K., Humphries, S. E., Hunt, S. C., Hyppönen, E., Illig, T., Jacobs, K. B., Jarvelin, M., Jöckel, K., Johansen, B., Jousilahti, P., Jukema, J. W., Jula, A. M., Kaprio, J., Kastelein, J. J., Keinanen-Kiukaanniemi, S. M., Kiemeney, L. A., Knekt, P., Kooner, J. S., Kooperberg, C., Kovacs, P., Kraja, A. T., Kumari, M., Kuusisto, J., Lakka, T. A., Langenberg, C., Le Marchand, L., Lehtimäki, T., Lyssenko, V., Männistö, S., Marette, A., Matise, T. C., McKenzie, C. A., McKnight, B., Moll, F. L., Morris, A. D., Morris, A. P., Murray, J. C., Nelis, M., Ohlsson, C., Oldehinkel, A. J., Ong, K. K., Madden, P. A., Pasterkamp, G., Peden, J. F., Peters, A., Postma, D. S., Pramstaller, P. P., Price, J. F., Qi, L., Raitakari, O. T., Rankinen, T., Rao, D. C., Rice, T. K., Ridker, P. M., Rioux, J. D., Ritchie, M. D., Rudan, I., Salomaa, V., Samani, N. J., Saramies, J., Sarzynski, M. A., Schunkert, H., Schwarz, P. E., Sever, P., Shuldiner, A. R., Sinisalo, J., Stolk, R. P., Strauch, K., Tönjes, A., Trégouët, D., Tremblay, A., Tremoli, E., Virtamo, J., Vohl, M., Völker, U., Waeber, G., Willemsen, G., Witteman, J. C., Zillikens, M. C., Adair, L. S., Amouyel, P., Asselbergs, F. W., Assimes, T. L., Bochud, M., Boehm, B. O., Boerwinkle, E., Bornstein, S. R., Bottinger, E. P., Bouchard, C., Cauchi, S., Chambers, J. C., Chanock, S. J., Cooper, R. S., de Bakker, P. I., Dedoussis, G., Ferrucci, L., Franks, P. W., Froguel, P., Groop, L. C., Haiman, C. A., Hamsten, A., Hui, J., Hunter, D. J., Hveem, K., Kaplan, R. C., Kivimaki, M., Kuh, D., Laakso, M., Liu, Y., Martin, N. G., März, W., Melbye, M., Metspalu, A., Moebus, S., Munroe, P. B., Njølstad, I., Oostra, B. A., Palmer, C. N., Pedersen, N. L., Perola, M., Pérusse, L., Peters, U., Power, C., Quertermous, T., Rauramaa, R., Rivadeneira, F., Saaristo, T. E., Saleheen, D., Sattar, N., Schadt, E. E., Schlessinger, D., Slagboom, P. E., Snieder, H., Spector, T. D., Thorsteinsdottir, U., Stumvoll, M., Tuomilehto, J., Uitterlinden, A. G., Uusitupa, M., van der Harst, P., Walker, M., Wallaschofski, H., Wareham, N. J., Watkins, H., Weir, D. R., Wichmann, H., Wilson, J. F., Zanen, P., Borecki, I. B., Deloukas, P., Fox, C. S., Heid, I. M., O'Connell, J. R., Strachan, D. P., Stefansson, K., van Duijn, C. M., Abecasis, G. R., Franke, L., Frayling, T. M., McCarthy, M. I., Visscher, P. M., Scherag, A., Willer, C. J., Boehnke, M., Mohlke, K. L., Lindgren, C. M., Beckmann, J. S., Barroso, I., North, K. E., Ingelsson, E., Hirschhorn, J. N., Loos, R. J., Speliotes, E. K. 2015; 518 (7538): 197-206

    Abstract

    Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

    View details for DOI 10.1038/nature14177

    View details for PubMedID 25673413

  • New genetic loci link adipose and insulin biology to body fat distribution. Nature Shungin, D., Winkler, T. W., Croteau-Chonka, D. C., Ferreira, T., Locke, A. E., Mägi, R., Strawbridge, R. J., Pers, T. H., Fischer, K., Justice, A. E., Workalemahu, T., Wu, J. M., Buchkovich, M. L., Heard-Costa, N. L., Roman, T. S., Drong, A. W., Song, C., Gustafsson, S., Day, F. R., Esko, T., Fall, T., Kutalik, Z., Luan, J., Randall, J. C., Scherag, A., Vedantam, S., Wood, A. R., Chen, J., Fehrmann, R., Karjalainen, J., Kahali, B., Liu, C., Schmidt, E. M., Absher, D., Amin, N., Anderson, D., Beekman, M., Bragg-Gresham, J. L., Buyske, S., Demirkan, A., Ehret, G. B., Feitosa, M. F., Goel, A., Jackson, A. U., Johnson, T., Kleber, M. E., Kristiansson, K., Mangino, M., Mateo Leach, I., Medina-Gomez, C., Palmer, C. D., Pasko, D., Pechlivanis, S., Peters, M. J., Prokopenko, I., Stancáková, A., Ju Sung, Y., Tanaka, T., Teumer, A., van Vliet-Ostaptchouk, J. V., Yengo, L., Zhang, W., Albrecht, E., Ärnlöv, J., Arscott, G. M., Bandinelli, S., Barrett, A., Bellis, C., Bennett, A. J., Berne, C., Blüher, M., Böhringer, S., Bonnet, F., Böttcher, Y., Bruinenberg, M., Carba, D. B., Caspersen, I. H., Clarke, R., Daw, E. W., Deelen, J., Deelman, E., Delgado, G., Doney, A. S., Eklund, N., Erdos, M. R., Estrada, K., Eury, E., Friedrich, N., Garcia, M. E., Giedraitis, V., Gigante, B., Go, A. S., Golay, A., Grallert, H., Grammer, T. B., Gräßler, J., Grewal, J., Groves, C. J., Haller, T., Hallmans, G., Hartman, C. A., Hassinen, M., Hayward, C., Heikkilä, K., Herzig, K., Helmer, Q., Hillege, H. L., Holmen, O., Hunt, S. C., Isaacs, A., Ittermann, T., James, A. L., Johansson, I., Juliusdottir, T., Kalafati, I., Kinnunen, L., Koenig, W., Kooner, I. K., Kratzer, W., Lamina, C., Leander, K., Lee, N. R., Lichtner, P., Lind, L., Lindström, J., Lobbens, S., Lorentzon, M., Mach, F., Magnusson, P. K., Mahajan, A., McArdle, W. L., Menni, C., Merger, S., Mihailov, E., Milani, L., Mills, R., Moayyeri, A., Monda, K. L., Mooijaart, S. P., Mühleisen, T. W., Mulas, A., Müller, G., Müller-Nurasyid, M., Nagaraja, R., Nalls, M. A., Narisu, N., Glorioso, N., Nolte, I. M., Olden, M., Rayner, N. W., Renstrom, F., Ried, J. S., Robertson, N. R., Rose, L. M., Sanna, S., Scharnagl, H., Scholtens, S., Sennblad, B., Seufferlein, T., Sitlani, C. M., Vernon Smith, A., Stirrups, K., Stringham, H. M., Sundström, J., Swertz, M. A., Swift, A. J., Syvänen, A., Tayo, B. O., Thorand, B., Thorleifsson, G., Tomaschitz, A., Troffa, C., van Oort, F. V., Verweij, N., Vonk, J. M., Waite, L. L., Wennauer, R., Wilsgaard, T., Wojczynski, M. K., Wong, A., Zhang, Q., Hua Zhao, J., Brennan, E. P., Choi, M., Eriksson, P., Folkersen, L., Franco-Cereceda, A., Gharavi, A. G., Hedman, Å. K., Hivert, M., Huang, J., Kanoni, S., Karpe, F., Keildson, S., Kiryluk, K., Liang, L., Lifton, R. P., Ma, B., McKnight, A. J., McPherson, R., Metspalu, A., Min, J. L., Moffatt, M. F., Montgomery, G. W., Murabito, J. M., Nicholson, G., Nyholt, D. R., Olsson, C., Perry, J. R., Reinmaa, E., Salem, R. M., Sandholm, N., Schadt, E. E., Scott, R. A., Stolk, L., Vallejo, E. E., Westra, H., Zondervan, K. T., Amouyel, P., Arveiler, D., Bakker, S. J., Beilby, J., Bergman, R. N., Blangero, J., Brown, M. J., Burnier, M., Campbell, H., Chakravarti, A., Chines, P. S., Claudi-Boehm, S., Collins, F. S., Crawford, D. C., Danesh, J., de Faire, U., de Geus, E. J., Dörr, M., Erbel, R., Eriksson, J. G., Farrall, M., Ferrannini, E., Ferrières, J., Forouhi, N. G., Forrester, T., Franco, O. H., Gansevoort, R. T., Gieger, C., Gudnason, V., Haiman, C. A., Harris, T. B., Hattersley, A. T., Heliövaara, M., Hicks, A. A., Hingorani, A. D., Hoffmann, W., Hofman, A., Homuth, G., Humphries, S. E., Hyppönen, E., Illig, T., Jarvelin, M., Johansen, B., Jousilahti, P., Jula, A. M., Kaprio, J., Kee, F., Keinanen-Kiukaanniemi, S. M., Kooner, J. S., Kooperberg, C., Kovacs, P., Kraja, A. T., Kumari, M., Kuulasmaa, K., Kuusisto, J., Lakka, T. A., Langenberg, C., Le Marchand, L., Lehtimäki, T., Lyssenko, V., Männistö, S., Marette, A., Matise, T. C., McKenzie, C. A., McKnight, B., Musk, A. W., Möhlenkamp, S., Morris, A. D., Nelis, M., Ohlsson, C., Oldehinkel, A. J., Ong, K. K., Palmer, L. J., Penninx, B. W., Peters, A., Pramstaller, P. P., Raitakari, O. T., Rankinen, T., Rao, D. C., Rice, T. K., Ridker, P. M., Ritchie, M. D., Rudan, I., Salomaa, V., Samani, N. J., Saramies, J., Sarzynski, M. A., Schwarz, P. E., Shuldiner, A. R., Staessen, J. A., Steinthorsdottir, V., Stolk, R. P., Strauch, K., Tönjes, A., Tremblay, A., Tremoli, E., Vohl, M., Völker, U., Vollenweider, P., Wilson, J. F., Witteman, J. C., Adair, L. S., Bochud, M., Boehm, B. O., Bornstein, S. R., Bouchard, C., Cauchi, S., Caulfield, M. J., Chambers, J. C., Chasman, D. I., Cooper, R. S., Dedoussis, G., Ferrucci, L., Froguel, P., Grabe, H., Hamsten, A., Hui, J., Hveem, K., Jöckel, K., Kivimaki, M., Kuh, D., Laakso, M., Liu, Y., März, W., Munroe, P. B., Njølstad, I., Oostra, B. A., Palmer, C. N., Pedersen, N. L., Perola, M., Pérusse, L., Peters, U., Power, C., Quertermous, T., Rauramaa, R., Rivadeneira, F., Saaristo, T. E., Saleheen, D., Sinisalo, J., Slagboom, P. E., Snieder, H., Spector, T. D., Thorsteinsdottir, U., Stumvoll, M., Tuomilehto, J., Uitterlinden, A. G., Uusitupa, M., van der Harst, P., Veronesi, G., Walker, M., Wareham, N. J., Watkins, H., Wichmann, H., Abecasis, G. R., Assimes, T. L., Berndt, S. I., Boehnke, M., Borecki, I. B., Deloukas, P., Franke, L., Frayling, T. M., Groop, L. C., Hunter, D. J., Kaplan, R. C., O'Connell, J. R., Qi, L., Schlessinger, D., Strachan, D. P., Stefansson, K., van Duijn, C. M., Willer, C. J., Visscher, P. M., Yang, J., Hirschhorn, J. N., Zillikens, M. C., McCarthy, M. I., Speliotes, E. K., North, K. E., Fox, C. S., Barroso, I., Franks, P. W., Ingelsson, E., Heid, I. M., Loos, R. J., Cupples, L. A., Morris, A. P., Lindgren, C. M., Mohlke, K. L. 2015; 518 (7538): 187-196

    Abstract

    Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

    View details for DOI 10.1038/nature14132

    View details for PubMedID 25673412

    View details for PubMedCentralID PMC4338562

  • Common filaggrin gene mutations and risk of cervical cancer ACTA ONCOLOGICA Bager, P., Wohlfahrt, J., Sorensen, E., Ullum, H., Hogdall, C. K., Palle, C., Husemoen, L. L., Linneberg, A., Kjaer, S. K., Melbye, M., Thyssen, J. P. 2015; 54 (2): 217-223

    Abstract

    As carriers of filaggrin gene (FLG) mutations may have a compromised cervical mucosal barrier against human papillomavirus infection, our primary objective was to study their risk of cervical cancer.We genotyped 586 cervical cancer patients for the two most common FLG mutations, R501X and 2282del4, using blood from the Copenhagen Hospital Biobank, Denmark. Controls (n = 8050) were genotyped in previous population-based studies. Information on cervical cancer, mortality and emigration were obtained from national registers. Odds ratios (OR) were estimated by logistic regression with adjustment for age at blood sampling, and weighted by the genotype-specific inverse probability of death between diagnosis and sampling. Hazard ratios (HR) were estimated by Cox regression with time since diagnosis as underlying time, and with adjustment for age at diagnosis and stratification by cancer stage.The primary results showed that FLG mutations were not associated with the risk of cervical cancer (6.3% of cases and 7.7% of controls were carriers; OR adjusted 0.81, 95% CI 0.57-1.14; OR adjusted+ weighted 0.96, 95% CI 0.58-1.57). Among cases, FLG mutations increased mortality due to cervical cancer (HR 4.55, 95% CI 1.70-12.2), however, the association was reduced after stratification by cancer stage (HR 2.53, 95% CI 0.84-7.59).Carriage of FLG mutations was not associated with the risk of cervical cancer.

    View details for DOI 10.3109/0284186X.2014.973613

    View details for Web of Science ID 000348301400011

    View details for PubMedID 25383447

  • A genome-wide association study of marginal zone lymphoma shows association to the HLA region NATURE COMMUNICATIONS Vijai, J., Wang, Z., Berndt, S. I., Skibola, C. F., Slager, S. L., de Sanjose, S., Melbye, M., Glimelius, B., Bracci, P. M., Conde, L., Birmann, B. M., Wang, S. S., Brooks-Wilson, A. R., Lan, Q., de Bakker, P. I., Vermeulen, R. C., Portlock, C., Ansell, S. M., Link, B. K., Riby, J., North, K. E., Gu, J., Hjalgrim, H., Cozen, W., Becker, N., Teras, L. R., Spinelli, J. J., Turner, J., Zhang, Y., Purdue, M. P., Giles, G. G., Kelly, R. S., Zeleniuch-Jacquotte, A., Ennas, M. G., Monnereau, A., Bertrand, K. A., Albanes, D., Lightfoot, T., Yeager, M., Chung, C. C., Burdett, L., Hutchinson, A., Lawrence, C., Montalvan, R., Liang, L., Huang, J., Ma, B., Villano, D. J., Maria, A., Corines, M., Thomas, T., Novak, A. J., Dogan, A., Liebow, M., Thompson, C. A., Witzig, T. E., Habermann, T. M., Weiner, G. J., Smith, M. T., Holly, E. A., Jackson, R. D., Tinker, L. F., Ye, Y., Adami, H., Smedby, K. E., De Roos, A. J., Hartge, P., Morton, L. M., Severson, R. K., Benavente, Y., Boffetta, P., Brennan, P., Foretova, L., Maynadie, M., McKay, J., Staines, A., Diver, W. R., Vajdic, C. M., Armstrong, B. K., Kricker, A., Zheng, T., Holford, T. R., Severi, G., Vineis, P., Ferri, G. M., Ricco, R., Miligi, L., Clavel, J., Giovannucci, E., Kraft, P., Virtamo, J., Smith, A., Kane, E., Roman, E., Chiu, B. C., Fraumeni, J. F., Wu, X., Cerhan, J. R., Offit, K., Chanock, S. J., Rothman, N., Nieters, A. 2015; 6

    Abstract

    Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10(-15)) and HLA-B (rs2922994, P=2.43 × 10(-9)) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.

    View details for DOI 10.1038/ncomms6751

    View details for PubMedID 25569183

  • Supplemental folic acid in pregnancy and maternal cancer risk. Cancer epidemiology Mortensen, J. H., Øyen, N., Fomina, T., Melbye, M., Tretli, S., Vollset, S. E., Bjørge, T. 2015; 39 (6): 805–11

    Abstract

    There is evidence that increased intake of folate protects against the development of several types of cancer. Some studies have, however, raised concern about the safety of folate in relation to cancer risk. Here we examined the risk of maternal cancer after intake of supplemental folic acid in pregnancy.This is a population-based cohort study comprising 429,004 women with data from the Medical Birth Registry of Norway, the Cancer Registry of Norway, and other national registries from 1999 to 2010. Altogether 3781 cancer cases were identified during follow-up (average 7 years). Cox proportional hazards regression models were used to estimate hazard ratios of maternal cancer according to folic acid use prior to and during one or two or more pregnancies as compared to no supplement use.Folic acid supplementation use had no overall effect on cancer risk in women using folic acid supplementation in one (HR 1.08; 95% CI 1.00-1.18) or two or more pregnancies (HR 1.06; 95% CI 0.91-1.22) (ptrend=0.12). Analyses of 13 cancer types revealed no associations between folic acid and cancer.Folic acid supplementation before and during pregnancy had no overall effect on maternal cancer risk.Folic acid substitution before and/or during pregnancy does not increase the short-term overall maternal cancer risk.

    View details for PubMedID 26569032

  • Decrease in Vitamin D Status in the Greenlandic Adult Population from 1987-2010 PLOS ONE Nielsen, N. O., Jorgensen, M. E., Friis, H., Melbye, M., Soborg, B., Jeppesen, C., Lundqvist, M., Cohen, A., Hougaard, D. M., Bjerregaard, P. 2014; 9 (12)

    Abstract

    Low vitamin D status may be pronounced in Arctic populations due to limited sun exposure and decreasing intake of traditional food.To investigate serum 25(OH)D3 as a measure of vitamin D status among adult Inuit in Greenland, predictors of low serum 25(OH)D3 concentrations and the trend from 1987 to 2005-2010.A total of 2877 randomly selected Inuit (≥ 18 years) from the Inuit Health in Transition study were included. A sub-sample (n = 330) donated a blood sample in 1987 which allowed assessment of time trends in vitamin D status.The geometric mean serum 25(OH)D3 (25[OH]D2 concentrations were negligible and not reported) in 2005-2010 was lowest among the 18-29 year old individuals (30.7 nmol/L; 95% CI: 29.7; 31.7) and increased with age. In all age-groups it decreased from 1987 to 2005-2010 (32%-58%). Low 25(OH)D3 concentrations (<50 nmol/L) were present in 77% of the 18-29 year old and decreased with age. A characteristic seasonal variation in 25(OH)D3 concentrations was observed (range 33.2-57.1 nmol/L, p<0.001), with the highest concentrations in August to October. Age (2.0% per year increase; CI: 1.7, 2.2), female gender (7.1%; CI: 2.0; 12.5), alcohol intake (0.2% per increase in drinks/week; 0.0; 0.4), and traditional diet (10.0% per 100 g/d increase; CI: 7.9; 12.1) were associated with increased serum 25(OH)D3, whereas smoking (-11.6%; CI: -16.2; -6.9), BMI (-0.6%; CI: -1.1; -0.2) and latitude (-0.7% per degree increase; CI: -1.3; -0.2) were associated with decreased concentrations.We identified a remarkable decrease in vitamin D status from 1987 to 2005-2010 and a presently low vitamin D status among Inuit in Greenland. A change away from a traditional diet may well explain the observed decline. The study argues for the need of increased dietary intake of vitamin D and supplementation might be considered.

    View details for DOI 10.1371/journal.pone.0112949

    View details for Web of Science ID 000345869700024

    View details for PubMedID 25461952

    View details for PubMedCentralID PMC4252033

  • Common variants associated with general and MMR vaccine-related febrile seizures NATURE GENETICS Feenstra, B., Pasternak, B., Geller, F., Carstensen, L., Wang, T., Huang, F., Eitson, J. L., Hollegaard, M. V., Svanstrom, H., Vestergaard, M., Hougaard, D. M., Schoggins, J. W., Jan, L. Y., Melbye, M., Hviid, A. 2014; 46 (12): 1274-1282

    Abstract

    Febrile seizures represent a serious adverse event following measles, mumps and rubella (MMR) vaccination. We conducted a series of genome-wide association scans comparing children with MMR-related febrile seizures, children with febrile seizures unrelated to vaccination and controls with no history of febrile seizures. Two loci were distinctly associated with MMR-related febrile seizures, harboring the interferon-stimulated gene IFI44L (rs273259: P = 5.9 × 10(-12) versus controls, P = 1.2 × 10(-9) versus MMR-unrelated febrile seizures) and the measles virus receptor CD46 (rs1318653: P = 9.6 × 10(-11) versus controls, P = 1.6 × 10(-9) versus MMR-unrelated febrile seizures). Furthermore, four loci were associated with febrile seizures in general, implicating the sodium channel genes SCN1A (rs6432860: P = 2.2 × 10(-16)) and SCN2A (rs3769955: P = 3.1 × 10(-10)), a TMEM16 family gene (ANO3; rs114444506: P = 3.7 × 10(-20)) and a region associated with magnesium levels (12q21.33; rs11105468: P = 3.4 × 10(-11)). Finally, we show the functional relevance of ANO3 (TMEM16C) with electrophysiological experiments in wild-type and knockout rats.

    View details for DOI 10.1038/ng.3129

    View details for Web of Science ID 000345547300008

    View details for PubMedID 25344690

    View details for PubMedCentralID PMC4244308

  • Risk factors for congenital hydrocephalus: a nationwide, register-based, cohort study JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY Munch, T. N., Rasmussen, M. H., Wohlfahrt, J., Juhler, M., Melbye, M. 2014; 85 (11): 1253-1259

    Abstract

    To investigate the associations between isolated congenital hydrocephalus (CHC) and maternal characteristics, maternal medical diseases, and medicine intake during pregnancy as well as birth characteristics of the child in a retrospective, register-based, nationwide cohort study. Furthermore, to identify the risk factors unique for isolated CHC as compared to syndromic CHC.We established a cohort of all children born in Denmark between 1978 and 2008. Information on CHC and maternal medical diseases were obtained from the National Patient Discharge Register, maternal intake of medicine during pregnancy from the National Prescription Drug Register, and birth characteristics of the child from the Danish National Birth Register. Rate ratios (RR) of isolated and syndromic CHC with 95% CI were estimated using log-linear Poisson regression.In a cohort of 1928666 live-born children, we observed 1193 cases of isolated CHC (0.062/1000) born children. First-borns had an increased risk of isolated CHC compared to later-borns (1.32 95% CI 1.17 to 1.49) (0.72/1000 born children). First trimester exposure to maternal use of antidepressants was associated with a significantly increased risk of isolated CHC compared to unexposed children (RR 2.52, 95% CI 1.47 to 4.29) (1.5/1000 born children). Risk factors also found for syndromic CHC were: Male gender, multiples and maternal diabetes.The higher risk for isolated CHC in first-born children as well as behavioural aspects and comorbidities associated with maternal use of antidepressants, should be the targets for future research. Potential biological pathways by which antidepressants may cause hydrocephalus remain to be elucidated.

    View details for DOI 10.1136/jnnp-2013-306941

    View details for Web of Science ID 000344093100015

    View details for PubMedID 24667207

  • Defining the role of common variation in the genomic and biological architecture of adult human height. Nature genetics Wood, A. R., Esko, T., Yang, J., Vedantam, S., Pers, T. H., Gustafsson, S., Chu, A. Y., Estrada, K., Luan, J., Kutalik, Z., Amin, N., Buchkovich, M. L., Croteau-Chonka, D. C., Day, F. R., Duan, Y., Fall, T., Fehrmann, R., Ferreira, T., Jackson, A. U., Karjalainen, J., Lo, K. S., Locke, A. E., Mägi, R., Mihailov, E., Porcu, E., Randall, J. C., Scherag, A., Vinkhuyzen, A. A., Westra, H., Winkler, T. W., Workalemahu, T., Zhao, J. H., Absher, D., Albrecht, E., Anderson, D., Baron, J., Beekman, M., Demirkan, A., Ehret, G. B., Feenstra, B., Feitosa, M. F., Fischer, K., Fraser, R. M., Goel, A., Gong, J., Justice, A. E., Kanoni, S., Kleber, M. E., Kristiansson, K., Lim, U., Lotay, V., Lui, J. C., Mangino, M., Mateo Leach, I., Medina-Gomez, C., Nalls, M. A., Nyholt, D. R., Palmer, C. D., Pasko, D., Pechlivanis, S., Prokopenko, I., Ried, J. S., Ripke, S., Shungin, D., Stancáková, A., Strawbridge, R. J., Sung, Y. J., Tanaka, T., Teumer, A., Trompet, S., van der Laan, S. W., van Setten, J., van Vliet-Ostaptchouk, J. V., Wang, Z., Yengo, L., Zhang, W., Afzal, U., Arnlöv, J., Arscott, G. M., Bandinelli, S., Barrett, A., Bellis, C., Bennett, A. J., Berne, C., Blüher, M., Bolton, J. L., Böttcher, Y., Boyd, H. A., Bruinenberg, M., Buckley, B. M., Buyske, S., Caspersen, I. H., Chines, P. S., Clarke, R., Claudi-Boehm, S., Cooper, M., Daw, E. W., de Jong, P. A., Deelen, J., Delgado, G., Denny, J. C., Dhonukshe-Rutten, R., Dimitriou, M., Doney, A. S., Dörr, M., Eklund, N., Eury, E., Folkersen, L., Garcia, M. E., Geller, F., Giedraitis, V., Go, A. S., Grallert, H., Grammer, T. B., Gräßler, J., Grönberg, H., de Groot, L. C., Groves, C. J., Haessler, J., Hall, P., Haller, T., Hallmans, G., Hannemann, A., Hartman, C. A., Hassinen, M., Hayward, C., Heard-Costa, N. L., Helmer, Q., Hemani, G., Henders, A. K., Hillege, H. L., Hlatky, M. A., Hoffmann, W., Hoffmann, P., Holmen, O., Houwing-Duistermaat, J. J., Illig, T., Isaacs, A., James, A. L., Jeff, J., Johansen, B., Johansson, Å., Jolley, J., Juliusdottir, T., Junttila, J., Kho, A. N., Kinnunen, L., Klopp, N., Kocher, T., Kratzer, W., Lichtner, P., Lind, L., Lindström, J., Lobbens, S., Lorentzon, M., Lu, Y., Lyssenko, V., Magnusson, P. K., Mahajan, A., Maillard, M., McArdle, W. L., McKenzie, C. A., McLachlan, S., McLaren, P. J., Menni, C., Merger, S., Milani, L., Moayyeri, A., Monda, K. L., Morken, M. A., Müller, G., Müller-Nurasyid, M., Musk, A. W., Narisu, N., Nauck, M., Nolte, I. M., Nöthen, M. M., Oozageer, L., Pilz, S., Rayner, N. W., Renstrom, F., Robertson, N. R., Rose, L. M., Roussel, R., Sanna, S., Scharnagl, H., Scholtens, S., Schumacher, F. R., Schunkert, H., Scott, R. A., Sehmi, J., Seufferlein, T., Shi, J., Silventoinen, K., Smit, J. H., Smith, A. V., Smolonska, J., Stanton, A. V., Stirrups, K., Stott, D. J., Stringham, H. M., Sundström, J., Swertz, M. A., Syvänen, A., Tayo, B. O., Thorleifsson, G., Tyrer, J. P., Van Dijk, S., van Schoor, N. M., van der Velde, N., van Heemst, D., van Oort, F. V., Vermeulen, S. H., Verweij, N., Vonk, J. M., Waite, L. L., Waldenberger, M., Wennauer, R., Wilkens, L. R., Willenborg, C., Wilsgaard, T., Wojczynski, M. K., Wong, A., Wright, A. F., Zhang, Q., Arveiler, D., Bakker, S. J., Beilby, J., Bergman, R. N., Bergmann, S., Biffar, R., Blangero, J., Boomsma, D. I., Bornstein, S. R., Bovet, P., Brambilla, P., Brown, M. J., Campbell, H., Caulfield, M. J., Chakravarti, A., Collins, R., Collins, F. S., Crawford, D. C., Cupples, L. A., Danesh, J., de Faire, U., Den Ruijter, H. M., Erbel, R., Erdmann, J., Eriksson, J. G., Farrall, M., Ferrannini, E., Ferrières, J., Ford, I., Forouhi, N. G., Forrester, T., Gansevoort, R. T., Gejman, P. V., Gieger, C., Golay, A., Gottesman, O., Gudnason, V., Gyllensten, U., Haas, D. W., Hall, A. S., Harris, T. B., Hattersley, A. T., Heath, A. C., Hengstenberg, C., Hicks, A. A., Hindorff, L. A., Hingorani, A. D., Hofman, A., Hovingh, G. K., Humphries, S. E., Hunt, S. C., Hypponen, E., Jacobs, K. B., Jarvelin, M., Jousilahti, P., Jula, A. M., Kaprio, J., Kastelein, J. J., Kayser, M., Kee, F., Keinanen-Kiukaanniemi, S. M., Kiemeney, L. A., Kooner, J. S., Kooperberg, C., Koskinen, S., Kovacs, P., Kraja, A. T., Kumari, M., Kuusisto, J., Lakka, T. A., Langenberg, C., Le Marchand, L., Lehtimäki, T., Lupoli, S., Madden, P. A., Männistö, S., Manunta, P., Marette, A., Matise, T. C., McKnight, B., Meitinger, T., Moll, F. L., Montgomery, G. W., Morris, A. D., Morris, A. P., Murray, J. C., Nelis, M., Ohlsson, C., Oldehinkel, A. J., Ong, K. K., Ouwehand, W. H., Pasterkamp, G., Peters, A., Pramstaller, P. P., Price, J. F., Qi, L., Raitakari, O. T., Rankinen, T., Rao, D. C., Rice, T. K., Ritchie, M., Rudan, I., Salomaa, V., Samani, N. J., Saramies, J., Sarzynski, M. A., Schwarz, P. E., Sebert, S., Sever, P., Shuldiner, A. R., Sinisalo, J., Steinthorsdottir, V., Stolk, R. P., Tardif, J., Tönjes, A., Tremblay, A., Tremoli, E., Virtamo, J., Vohl, M., Amouyel, P., Asselbergs, F. W., Assimes, T. L., Bochud, M., Boehm, B. O., Boerwinkle, E., Bottinger, E. P., Bouchard, C., Cauchi, S., Chambers, J. C., Chanock, S. J., Cooper, R. S., de Bakker, P. I., Dedoussis, G., Ferrucci, L., Franks, P. W., Froguel, P., Groop, L. C., Haiman, C. A., Hamsten, A., Hayes, M. G., Hui, J., Hunter, D. J., Hveem, K., Jukema, J. W., Kaplan, R. C., Kivimaki, M., Kuh, D., Laakso, M., Liu, Y., Martin, N. G., März, W., Melbye, M., Moebus, S., Munroe, P. B., Njølstad, I., Oostra, B. A., Palmer, C. N., Pedersen, N. L., Perola, M., Pérusse, L., Peters, U., Powell, J. E., Power, C., Quertermous, T., Rauramaa, R., Reinmaa, E., Ridker, P. M., Rivadeneira, F., Rotter, J. I., Saaristo, T. E., Saleheen, D., Schlessinger, D., Slagboom, P. E., Snieder, H., Spector, T. D., Strauch, K., Stumvoll, M., Tuomilehto, J., Uusitupa, M., van der Harst, P., Völzke, H., Walker, M., Wareham, N. J., Watkins, H., Wichmann, H., Wilson, J. F., Zanen, P., Deloukas, P., Heid, I. M., Lindgren, C. M., Mohlke, K. L., Speliotes, E. K., Thorsteinsdottir, U., Barroso, I., Fox, C. S., North, K. E., Strachan, D. P., Beckmann, J. S., Berndt, S. I., Boehnke, M., Borecki, I. B., McCarthy, M. I., Metspalu, A., Stefansson, K., Uitterlinden, A. G., van Duijn, C. M., Franke, L., Willer, C. J., Price, A. L., Lettre, G., Loos, R. J., Weedon, M. N., Ingelsson, E., O'Connell, J. R., Abecasis, G. R., Chasman, D. I., Goddard, M. E., Visscher, P. M., Hirschhorn, J. N., Frayling, T. M. 2014; 46 (11): 1173-1186

    Abstract

    Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

    View details for DOI 10.1038/ng.3097

    View details for PubMedID 25282103

  • Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma NATURE GENETICS Cerhan, J. R., Berndt, S. I., Vijai, J., Ghesquieres, H., McKay, J., Wang, S. S., Wang, Z., Yeager, M., Conde, L., de Bakker, P. I., Nieters, A., Cox, D., Burdett, L., Monnereau, A., Flowers, C. R., De Roos, A. J., Brooks-Wilson, A. R., Lan, Q., Severi, G., Melbye, M., Gu, J., Jackson, R. D., Kane, E., Teras, L. R., Purdue, M. P., Vajdic, C. M., Spinelli, J. J., Giles, G. G., Albanes, D., Kelly, R. S., Zucca, M., Bertrand, K. A., Zeleniuch-Jacquotte, A., Lawrence, C., Hutchinson, A., Zhi, D., Habermann, T. M., Link, B. K., Novak, A. J., Dogan, A., Asmann, Y. W., Liebow, M., Thompson, C. A., Ansell, S. M., Witzig, T. E., Weiner, G. J., Veron, A. S., Zelenika, D., Tilly, H., Haioun, C., Molina, T. J., Hjalgrim, H., Glimelius, B., Adami, H., Bracci, P. M., Riby, J., Smith, M. T., Holly, E. A., Cozen, W., Hartge, P., Morton, L. M., Severson, R. K., Tinker, L. F., North, K. E., Becker, N., Benavente, Y., Boffetta, P., Brennan, P., Foretova, L., Maynadie, M., Staines, A., Lightfoot, T., Crouch, S., Smith, A., Roman, E., Diver, W. R., Offit, K., Zelenetz, A., Klein, R. J., Villano, D. J., Zheng, T., Zhang, Y., Holford, T. R., Kricker, A., Turner, J., Southey, M. C., Clavel, J., Virtamo, J., Weinstein, S., Riboli, E., Vineis, P., Kaaks, R., Trichopoulos, D., Vermeulen, R. C., Boeing, H., Tjonneland, A., Angelucci, E., di Lollo, S., Rais, M., Birmann, B. M., Laden, F., Giovannucci, E., Kraft, P., Huang, J., Ma, B., Ye, Y., Chiu, B. C., Sampson, J., Liang, L., Park, J., Chung, C. C., Weisenburger, D. D., Chatterjee, N., Fraumeni, J. F., Slager, S. L., Wu, X., de Sanjose, S., Smedby, K. E., Salles, G., Skibola, C. F., Rothman, N., Chanock, S. J. 2014; 46 (11): 1233-1238

    Abstract

    Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10(-13) and 3.63 × 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.

    View details for DOI 10.1038/ng.3105

    View details for Web of Science ID 000344131900015

    View details for PubMedCentralID PMC4213349

  • Defining the role of common variation in the genomic and biological architecture of adult human height NATURE GENETICS Wood, A. R., Esko, T., Yang, J., Vedantam, S., Pers, T. H., Gustafsson, S., Chun, A. Y., Estrada, K., Luan, J., Kutalik, Z., Amin, N., Buchkovich, M. L., Croteau-Chonka, D. C., Day, F. R., Duan, Y., Fall, T., Fehrmann, R., Ferreira, T., Jackson, A. U., Karjalainen, J., Lo, K. S., Locke, A. E., Maegi, R., Mihailov, E., Porcu, E., Randall, J. C., Scherag, A., Vinkhuyzen, A. A., Westra, H., Winkler, T. W., Workalemahu, T., Zhao, J. H., Absher, D., Albrecht, E., Anderson, D., Baron, J., Beekman, M., Demirkan, A., Ehret, G. B., Feenstra, B., Feitosa, M. F., Fischer, K., Fraser, R. M., Goel, A., Gong, J., Justice, A. E., Kanoni, S., Kleber, M. E., Kristiansson, K., Lim, U., Lotay, V., Lui, J. C., Mangino, M., Leach, I. M., Medina-Gomez, C., Nalls, M. A., Nyholt, D. R., Palmer, C. D., Pasko, D., Pechlivanis, S., Prokopenko, I., Ried, J. S., Ripke, S., Shungin, D., Stancakova, A., Strawbridge, R. J., Sung, Y. J., Tanaka, T., Teumer, A., Trompet, S., van der Laan, S. W., van Setten, J., van Vliet-Ostaptchouk, J. V., Wang, Z., Yengo, L., Zhang, W., Afzal, U., Arnloev, J., Arscott, G. M., Bandinelli, S., Barrett, A., Bellis, C., Bennett, A. J., Berne, C., Blueher, M., Bolton, J. L., Boettcher, Y., Boyd, H. A., Bruinenberg, M., Buckley, B. M., Buyske, S., Caspersen, I. H., Chines, P. S., Clarke, R., Claudi-Boehm, S., Cooper, M., Daw, E. W., de Jong, P. A., Deelen, J., Delgado, G., Denny, J. C., Dhonukshe-Rutten, R., Dimitriou, M., Doney, A. S., Doerr, M., Eklund, N., Eury, E., Folkersen, L., Garcia, M. E., Geller, F., Giedraitis, V., Go, A. S., Grallert, H., Grammer, T. B., Graessler, J., Groenberg, H., de Groot, L. C., Groves, C. J., Haessler, J., Hall, P., Haller, T., Hallmans, G., Hannemann, A., Hartman, C. A., Hassinen, M., Hayward, C., Heard-Costa, N. L., Helmer, Q., Hemani, G., Henders, A. K., Hillege, H. L., Hlatky, M. A., Hoffmann, W., Hoffmann, P., Holmen, O., Houwing-Duistermaat, J. J., Illig, T., Isaacs, A., James, A. L., Jeff, J., Johansen, B., Johansson, A., Jolley, J., Juliusdottir, T., Junttila, J., Kho, A. N., Kinnunen, L., Klopp, N., Kocher, T., Kratzer, W., Lichtner, P., Lind, L., Lindstroem, J., Lobbens, S., Lorentzon, M., Lu, Y., Lyssenko, V., Magnusson, P. K., Mahajan, A., Maillard, M., McArdle, W. L., McKenzie, C. A., McLachlan, S., McLaren, P. J., Menni, C., Merger, S., Milani, L., Moayyeri, A., Monda, K. L., Morken, M. A., Mueller, G., Mueller-Nurasyid, M., Musk, A. W., Narisu, N., Nauck, M., Nolte, I. M., Noethen, M. M., Oozageer, L., Pilz, S., Rayner, N. W., Renstrom, F., Robertson, N. R., Rose, L. M., Roussel, R., Sanna, S., Scharnagl, H., Scholtens, S., Schumacher, F. R., Schunkert, H., Scott, R. A., Sehmi, J., Seufferlein, T., Shin, J., Silventoinen, K., Smit, J. H., Smith, A. V., Smolonska, J., Stanton, A. V., Stirrups, K., Stott, D. J., Stringham, H. M., Sundstrom, J., Swertz, M. A., Syvanen, A., Tayo, B. O., Thorleifsson, G., Tyrer, J. P., Van Dijk, S., van Schoor, N. M., van der Velde, N., van Heemst, D., van Oort, F. V., Vermeulen, S. H., Verweij, N., Vonk, J. M., Waite, L. L., Waldenberger, M., Wennauer, R., Wilkens, L. R., Willenborg, C., Wilsgaard, T., Wojczynski, M. K., Wong, A., Wright, A. F., Zhang, Q., Arveiler, D., Bakker, S. J., Beilby, J., Bergman, R. N., Bergmann, S., Biffar, R., Blangero, J., Boomsma, D. I., Bornstein, S. R., Bovet, P., Brambilla, P., Brown, M. J., Campbell, H., Caulfield, M. J., Chakravarti, A., Collins, R., Collins, F. S., Crawford, D. C., Cupples, L. A., Danesh, J., de Faire, U., Den Ruijter, H. M., Erbel, R., Erdmann, J., Eriksson, J. G., Farrall, M., Ferrannini, E., Ferrieres, J., Ford, I., Forouhi, N. G., Forrester, T., Gansevoort, R. T., Gejman, P. V., Gieger, C., Golay, A., Gottesman, O., Gudnason, V., Gyllensten, U., Haas, D. W., Hall, A. S., Harris, T. B., Hattersley, A. T., Heath, A. C., Hengstenberg, C., Hicks, A. A., Hindorff, L. A., Hingorani, A. D., Hofman, A., Hovingh, G. K., Humphries, S. E., Hunt, S. C., Hypponen, E., Jacobs, K. B., Jarvelin, M., Jousilahti, P., Jula, A. M., Kaprio, J., Kastelein, J. J., Kayser, M., Kee, F., Keinanen-Kiukaanniemi, S. M., Kiemeney, L. A., Kooner, J. S., Kooperberg, C., Koskinen, S., Kovacs, P., Kraja, A. T., Kumari, M., Kuusisto, J., Lakka, T. A., Langenberg, C., Le Marchand, L., Lehtimaki, T., Lupoli, S., Madden, P. A., Mannisto, S., Manunta, P., Marette, A., Matise, T. C., McKnight, B., Meitinger, T., Moll, F. L., Montgomery, G. W., Morris, A. D., Morris, A. P., Murray, J. C., Nelis, M., Ohlsson, C., Oldehinkel, A. J., Ong, K. K., Ouwehand, W. H., Pasterkamp, G., Peters, A., Pramstaller, P. P., Price, J. F., Qi, L., Raitakari, O. T., Rankinen, T., Rao, D. C., Rice, T. K., Ritchie, M., Rudan, I., Salomaa, V., Samani, N. J., Saramies, J., Sarzynski, M. A., Schwarz, P. E., Sebert, S., Sever, P., Shuldiner, A. R., Sinisalo, J., Steinthorsdottir, V., Stolk, R. P., Tardif, J., Toenjes, A., Tremblay, A., Tremoli, E., Virtamo, J., Vohl, M., Amouyel, P., Asselbergs, F. W., Assimes, T. L., Bochud, M., Boehm, B. O., Boerwinkle, E., Bottinger, E. P., Bouchard, C., Cauchi, S., Chambers, J. C., Chanock, S. J., Cooper, R. S., de Bakker, P. I., Dedoussis, G., Ferrucci, L., Franks, P. W., Froguel, P., Groop, L. C., Haiman, C. A., Hamsten, A., Hayes, M. G., Hui, J., Hunter, D. J., Hveem, K., Jukema, J. W., Kaplan, R. C., Kivimaki, M., Kuh, D., Laakso, M., Liu, Y., Martin, N. G., Maerz, W., Melbye, M., Moebus, S., Munroe, P. B., Njolstad, I., Oostra, B. A., Palmer, C. N., Pedersen, N. L., Perola, M., Perusse, L., Peters, U., Powell, J. E., Power, C., Quertermous, T., Rauramaa, R., Reinmaa, E., Ridker, P. M., Rivadeneira, F., Rotter, J. I., Saaristo, T. E., Saleheen, D., Schlessinger, D., Slagboom, P. E., Snieder, H., Spector, T. D., Strauch, K., Stumvoll, M., Tuomilehto, J., Uusitupa, M., van der Harst, P., Voelzke, H., Walker, M., Wareham, N. J., Watkins, H., Wichmann, H., Wilson, J. F., Zanen, P., Deloukas, P., Heid, I. M., Lindgren, C. M., Mohlke, K. L., Speliotes, E. K., Thorsteinsdottir, U., Barroso, I., Fox, C. S., North, K. E., Strachan, D. P., Beckmann, J. S., Berndt, S. I., Boehnke, M., Borecki, I. B., McCarthy, M. I., Metspalu, A., Stefansson, K., Uitterlinden, A. G., van Duijn, C. M., Franke, L., Willer, C. J., Price, A. L., Lettre, G., Loos, R. J., Weedon, M. N., Ingelsson, E., O'Connell, J. R., Abecasis, G. R., Chasman, D. I., Goddard, M. E., Visscher, P. M., Hirschhorn, J. N., Frayling, T. M. 2014; 46 (11): 1173-1186

    Abstract

    Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

    View details for DOI 10.1038/ng.3097

    View details for Web of Science ID 000344131900008

  • A comprehensive evaluation of the role of genetic variation in follicular lymphoma survival BMC MEDICAL GENETICS Baecklund, F., Foo, J., Bracci, P., Darabi, H., Karlsson, R., Hjalgrim, H., Rosenquist, R., Adami, H., Glimelius, B., Melbye, M., Conde, L., Liu, J., Humphreys, K., Skibola, C. F., Smedby, K. E. 2014; 15

    Abstract

    Survival in follicular lymphoma (FL) is highly variable, even within prognostic groups defined by tumor grade and the Follicular Lymphoma International Prognostic Index. Studies suggest that germline single nucleotide polymorphisms (SNPs) may hold prognostic information but further investigation is needed.We explored the association between SNPs and FL outcome using two approaches: 1) Two independent genome-wide association studies (GWAS) of ~300.000 SNPs followed by a meta-analysis encompassing 586 FL patients diagnosed in Denmark/Sweden 1999-2002 and in the United States 2001-2006; and 2) Investigation of 22 candidate-gene variants previously associated with FL outcome in the Danish/Swedish cohort (N = 373). We estimated time to lymphoma-specific death (approach 1 and 2) and lymphoma progression (approach 2) with hazard ratios (HR) and 95% confidence intervals (CI) in a multivariable Cox regression model.In the GWAS meta-analysis, using a random effects model, no variants were associated with lymphoma-specific death at a genome-wide significant level (p < 5.0 ×10(-8)). The strongest association was observed for tightly linked SNPs on 17q24 near the ABCA10 and ABCA6 genes (rs10491178 HRrandom = 3.17, 95% CI 2.09-4.79, prandom = 5.24 ×10(-8)). The ABCA10 and ABCA6 genes belong to a family of genes encoding for ABC transporter proteins, implicated in multidrug resistance. In line with a previous study, rs2466571 in CD46 (HR = 0.73, 95% CI 0.58-0.91, p = 0.006) showed nominal association with lymphoma progression, as did two highly linked SNPs in IL8 (rs4073 HR = 0.78, 95% CI 0.62-0.97, p = 0.02; rs2227307 HR = 0.75, 95% CI 0.60-0.94, p = 0.01) previously associated with overall survival.The results suggest a possible role for multidrug resistance in FL survival and add to the evidence that genetic variation in CD46 and IL8 may have prognostic implications in FL. Our findings need further confirmation in other independent populations or in a larger multicenter GWAS.

    View details for DOI 10.1186/s12881-014-0113-6

    View details for Web of Science ID 000344103200001

    View details for PubMedID 25294155

    View details for PubMedCentralID PMC4411784

  • Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche NATURE Perry, J. R., Day, F., Elks, C. E., Sulem, P., Thompson, D. J., Ferreira, T., He, C., Chasman, D. I., Esko, T., Thorleifsson, G., Albrecht, E., Ang, W. Q., Corre, T., Cousminer, D. L., Feenstra, B., Franceschini, N., Ganna, A., Johnson, A. D., Kjellqvist, S., Lunetta, K. L., McMahon, G., Nolte, I. M., Paternoster, L., Porcu, E., Smith, A. V., Stolk, L., Teumer, A., Tsernikova, N., Tikkanen, E., Ulivi, S., Wagner, E. K., Amin, N., Bierut, L. J., Byrne, E. M., Hottenga, J., Koller, D. L., Mangino, M., Pers, T. H., Yerges-Armstrong, L. M., Zhao, J. H., Andrulis, I. L., Anton-Culver, H., Atsma, F., Bandinelli, S., Beckmann, M. W., Benitez, J., Blomqvist, C., Bojesen, S. E., Bolla, M. K., Bonanni, B., Brauch, H., Brenner, H., Buring, J. E., Chang-Claude, J., Chanock, S., Chen, J., Chenevix-Trench, G., Collee, J. M., Couch, F. J., Couper, D., Coviello, A. D., Cox, A., Czene, K., D'Adamo, A. P., Smith, G. D., De Vivo, I., Demerath, E. W., Dennis, J., Devilee, P., Dieffenbach, A. K., Dunning, A. M., Eiriksdottir, G., Eriksson, J. G., Fasching, P. A., Ferrucci, L., Flesch-Janys, D., Flyger, H., Foroud, T., Franke, L., Garcia, M. E., Garcia-Closas, M., Geller, F., de Geus, E. E., Giles, G. G., Gudbjartsson, D. F., Gudnason, V., Guenel, P., Guo, S., Hall, P., Hamann, U., Haring, R., Hartman, C. A., Heath, A., Hofman, A., Hooning, M. J., Hopper, J. L., Hu, F. B., Hunter, D. J., Karasik, D., Kiel, D. P., Knight, J. A., Kosma, V., Kutalik, Z., Lai, S., Lambrechts, D., Lindblom, A., Maegi, R., Magnusson, P. K., Mannermaa, A., Martin, N. G., Masson, G., McArdle, P. F., McArdle, W. L., Melbye, M., Michailidou, K., Mihailov, E., Milani, L., Milne, R. L., Nevanlinna, H., Neven, P., Nohr, E. A., Oldehinkel, A. J., Oostra, B. A., Palotie, A., Peacock, M., Pedersen, N. L., Peterlongo, P., Peto, J., Pharoah, P. D., Postma, D. S., Pouta, A., Pylkaes, K., Radice, P., Ring, S., Rivadeneira, F., Robino, A., Rose, L. M., Rudolph, A., Salomaa, V., Sanna, S., Schlessinger, D., Schmidt, M. K., Southey, M. C., Sovio, U., Stampfer, M. J., Stoeckl, D., Storniolo, A. M., Timpson, N. J., Tyrer, J., Visser, J. A., Vollenweider, P., Voelzke, H., Waeber, G., Waldenberger, M., Wallaschofski, H., Wang, Q., Willemsen, G., Winqvist, R., Wolffenbuttel, B. H., Wright, M. J., Boomsma, D. I., Econs, M. J., Khaw, K., Loos, R. J., McCarthy, M. I., Montgomery, G. W., Rice, J. P., Streeten, E. A., Thorsteinsdottir, U., van Duijn, C. M., Alizadeh, B. Z., Bergmann, S., Boerwinkle, E., Boyd, H. A., Crisponi, L., Gasparini, P., Gieger, C., Harris, T. B., Ingelsson, E., Jaervelin, M., Kraft, P., Lawlor, D., Metspalu, A., Pennell, C. E., Ridker, P. M., Snieder, H., Sorensen, T. I., Spector, T. D., Strachan, D. P., Uitterlinden, A. G., Wareham, N. J., Widen, E., Zygmunt, M., Murray, A., Easton, D. F., Stefansson, K., Murabito, J. M., Ong, K. K. 2014; 514 (7520): 92-?

    Abstract

    Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

    View details for DOI 10.1038/nature13545

    View details for Web of Science ID 000342420800042

  • Genome-wide Association Study Identifies Five Susceptibility Loci for Follicular Lymphoma outside the HLA Region AMERICAN JOURNAL OF HUMAN GENETICS Skibola, C. F., Berndt, S. I., Vijai, J., Conde, L., Wang, Z., Yeager, M., de Bakker, P. I., Birmann, B. M., Vajdic, C. M., Foo, J., Bracci, P. M., Vermeulen, R. C., Slager, S. L., de Sanjose, S., Wang, S. S., Linet, M. S., Salles, G., Lan, Q., Severi, G., Hjalgrim, H., Lightfoot, T., Melbye, M., Gu, J., Ghesquieres, H., Link, B. K., Morton, L. M., Holly, E. A., Smith, A., Tinker, L. F., Teras, L. R., Kricker, A., Becker, N., Purdue, M. P., Spinelli, J. J., Zhang, Y., Giles, G. G., Vineis, P., Monnereau, A., Bertrand, K. A., Albanes, D., Zeleniuch-Jacquotte, A., Gabbas, A., Chung, C. C., Burdett, L., Hutchinson, A., Lawrence, C., Montalvan, R., Liang, L., Huang, J., Ma, B., Liu, J., Adami, H., Glimelius, B., Ye, Y., Nowakowski, G. S., Dogan, A., Thompson, C. A., Habermann, T. M., Novak, A. J., Liebow, M., Witzig, T. E., Weiner, G. J., Schenk, M., Hartge, P., De Roos, A. J., Cozen, W., Zhi, D., Akers, N. K., Riby, J., Smith, M. T., Lacher, M., Villano, D. J., Maria, A., Roman, E., Kane, E., Jackson, R. D., North, K. E., Diver, W. R., Turner, J., Armstrong, B. K., Benavente, Y., Boffetta, P., Brennan, P., Foretova, L., Maynadie, M., Staines, A., McKay, J., Brooks-Wilson, A. R., Zheng, T., Holford, T. R., Chamosa, S., Kaaks, R., Kelly, R. S., Ohlsson, B., Travis, R. C., Weiderpass, E., Clave, J., Giovannucci, E., Kraft, P., Virtamo, J., Mazza, P., Cocco, P., Ennas, M. G., Chiu, B. C., Fraumeni, J. R., Nieters, A., Offit, K., Wu, X., Cerhan, J. R., Smedby, K. E., Chanock, S. J., Rothman, N. 2014; 95 (4): 462-471

    Abstract

    Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 × 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10(-67) to 2.67 × 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [OR(per-allele)] = 1.44; p = 4.59 × 10(-16)) and rs3130437 in HLA class I (OR(per-allele) = 1.23; p = 8.23 × 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.

    View details for DOI 10.1016/j.ajhg.2014.09.004

    View details for PubMedID 25279986

  • Association of Treatment With Carvedilol vs Metoprolol Succinate and Mortality in Patients With Heart Failure JAMA INTERNAL MEDICINE Pasternak, B., Svanstrom, H., Melbye, M., Hviid, A. 2014; 174 (10): 1597-1604

    Abstract

    The β-blockers carvedilol and metoprolol succinate both reduce mortality in patients with heart failure (HF), but the comparative clinical effectiveness of these drugs is unknown.To investigate whether carvedilol is associated with improved survival compared with metoprolol succinate.Cohort study of patients with incident HF with reduced left ventricular ejection fraction (LVEF) (≤40%) who received carvedilol (n = 6026) or metoprolol succinate (n = 5638) using data from a Danish national HF registry linked with health care and administrative databases.All-cause mortality (primary outcome) and cardiovascular mortality (secondary outcome) were analyzed using Cox regression with adjustment for a propensity score, derived from a range of clinical, socioeconomic, and demographic characteristics.The mean (SD) age of the patients was 69.3 (9.1) years, 71% were men, and 51% were hospitalized at index HF diagnosis. During a median (interquartile range) 2.4 (1.0-3.0) years of follow-up, 875 carvedilol users and 754 metoprolol users died; the cumulative incidence of mortality was 18.3% and 18.8%, respectively. The adjusted hazard ratio for carvedilol users vs metoprolol users was 0.99 (95% CI, 0.88 to 1.11), corresponding to an absolute risk difference of -0.07 (95% CI, -0.84 to 0.77) deaths per 100 person-years. Estimates were consistent across subgroup analyses by sex, age, levels of LVEF, New York Heart Association classification, and history of ischemic heart disease. A higher proportion of carvedilol users achieved the recommended daily target dose (50 mg; 3124 [52%]) than did metoprolol users (200 mg; 689 [12%]); among patients who reached the target dose, the adjusted hazard ratio was 0.97 (95% CI, 0.72-1.30). A robustness analysis with 1:1 propensity score matching confirmed the primary findings (hazard ratio, 0.97 [95% CI, 0.84-1.13]). The adjusted hazard ratio for cardiovascular mortality was 1.05 (95% CI, 0.88-1.26).These findings from real-world clinical practice indicate that the effectiveness of carvedilol and metoprolol succinate in patients with HF is similar.

    View details for DOI 10.1001/jamainternmed.2014.3258

    View details for Web of Science ID 000345909100018

    View details for PubMedID 25173681

  • Atypical Antipsychotics Olanzapine, Quetiapine, and Risperidone and Risk of Acute Major Cardiovascular Events in Young and Middle-Aged Adults: A Nationwide Register-Based Cohort Study in Denmark CNS DRUGS Pasternak, B., Svanstrom, H., Ranthe, M. F., Melbye, M., Hviid, A. 2014; 28 (10): 963-973

    Abstract

    A number of serious cardiovascular safety concerns related to the use of atypical antipsychotics, compared with no use, have emerged, but nearly all reports are from studies of older patients. We aimed to compare the risk of cardiovascular events between the three most commonly used atypical antipsychotics in young and middle-aged adults.We conducted a nationwide register-based cohort study in Denmark, 1997-2011, including adults aged 18-64 years, who started treatment with oral or intramuscular olanzapine (n = 15,774), oral quetiapine (n = 18,717), and oral or intramuscular risperidone (n = 14,134). The primary outcome was any major cardiovascular event (composite of cardiovascular mortality, acute coronary syndrome, or ischemic stroke) within 1 year following treatment initiation. Cox regression was used to estimate hazard ratios (HRs) while on current antipsychotic monotherapy in the outpatient setting, adjusting for an outcome-specific disease risk score.The crude rate of any major cardiovascular event was 5.3 per 1,000 person-years among olanzapine users, 3.4 in quetiapine users, and 5.2 in risperidone users. Compared with risperidone, the risk of any major cardiovascular event was not significantly different in olanzapine users (HR 0.90, 95 % confidence interval [CI] 0.53-1.52) and quetiapine users (HR 0.79, 95 % CI 0.45-1.39). The absolute risk difference per 1,000 person-years on treatment was -0.5 (95 % CI -2.4 to 2.7) events for olanzapine and -1.1 (95 % CI -2.9 to 2.0) events for quetiapine.Among young and middle-aged outpatients, the risk of acute major cardiovascular events was similar with use of olanzapine, quetiapine, and risperidone. Although moderate relative differences cannot be ruled out, any differences are small in absolute terms.

    View details for DOI 10.1007/s40263-014-0176-0

    View details for Web of Science ID 000344614100007

    View details for PubMedID 24895158

  • Genome-wide association analyses identify variants in developmental genes associated with hypospadias NATURE GENETICS Geller, F., Feenstra, B., Carstensen, L., Pers, T. H., van Rooij, I. A., Korberg, I. B., Choudhry, S., Karjalainen, J. M., Schnack, T. H., Hollegaard, M. V., Feitz, W. F., Roeleveld, N., Hougaard, D. M., Hirschhorn, J. N., Franke, L., Baskin, L. S., Nordenskjold, A., van der Zanden, L. F., Melbye, M. 2014; 46 (9): 957-?

    Abstract

    Hypospadias is a common congenital condition in boys in which the urethra opens on the underside of the penis. We performed a genome-wide association study on 1,006 surgery-confirmed hypospadias cases and 5,486 controls from Denmark. After replication genotyping of an additional 1,972 cases and 1,812 controls from Denmark, the Netherlands and Sweden, 18 genomic regions showed independent association with P < 5 × 10(-8). Together, these loci explain 9% of the liability to developing this condition. Several of the identified regions harbor genes with key roles in embryonic development (including HOXA4, IRX5, IRX6 and EYA1). Subsequent pathway analysis with GRAIL and DEPICT provided additional insight into possible genetic mechanisms causing hypospadias.

    View details for DOI 10.1038/ng.3063

    View details for Web of Science ID 000341579400009

    View details for PubMedID 25108383

  • Risk of cancer in relatives of patients with myotonic dystrophy: a population-based cohort study EUROPEAN JOURNAL OF NEUROLOGY Lund, M., Diaz, L. J., Gortz, S., Feenstra, B., Duno, M., Juncker, I., Eiberg, H., Vissing, J., Wohlfahrt, J., Melbye, M. 2014; 21 (9): 1192-1197

    Abstract

    Myotonic dystrophies (DM) are autosomal dominantly inherited neuromuscular disorders caused by unstable nucleotide repeat expansions. DM and cancer have been associated, but the pathogenesis behind the association remains unclear. It could relate to derived effects of the DM genotype in which case non-DM relatives of DM patients would not be expected to be at increased risk of cancer. To elucidate this, a population-based cohort study investigating risk of cancer in relatives of DM patients was conducted.DM was identified using the National Danish Patient Registry and results of genetic testing. Information on cancer was obtained from the Danish Cancer Registry. A population-based cohort of 5 757 565 individuals with at least one relative was established using the Danish Family Relations Database based on kinship links in the Danish Civil Registration System. Familial aggregation of cancer was evaluated by (incidence) rate ratios (RRs) comparing the rate of cancer amongst relatives of patients with DM from 1977 to 2010 (exposed) with the rate of cancer amongst persons with a relative of the same type but without DM (non-exposed).In first-degree relatives of individuals with DM the adjusted RR of cancer was 0.89 (95% confidence interval 0.71-1.12) overall, and in stratified analyses 0.68 (0.37-1.12) before age 50 and 0.96 (0.74-1.23) at age 50 or older.The present study does not support an increased risk of cancer in non-DM relatives of DM patients suggesting that cancer and DM are associated through derived effects of the DM genotype.

    View details for DOI 10.1111/ene.12466

    View details for Web of Science ID 000340240000009

    View details for PubMedID 24838088

  • The effectiveness of BCG vaccination in preventing Mycobacterium tuberculosis infection and disease in Greenland THORAX Michelsen, S. W., Soborg, B., Koch, A., Carstensen, L., Hoff, S. T., Agger, E. M., Lillebaek, T., SORENSEN, H. C., Wohlfahrt, J., Melbye, M. 2014; 69 (9): 851-856

    Abstract

    The BCG vaccine's ability to prevent Mycobacterium tuberculosis infection (MTI) remains highly debated. In Greenland, BCG vaccination was introduced in 1955, but was temporarily discontinued (1991-1996) due to nationwide policy changes. The study aimed to use the transient stop in BCG vaccination to evaluate the effect of vaccination on MTI prevalence and TB incidence.MTI study: A cross-sectional study (2012), comprising East Greenlanders born during 1982-2006, evaluated the effect of BCG vaccination on MTI prevalence; a positive interferon γ release assay defined an MTI case. Associations were estimated using logistic regression. TB study: a cohort study covering the same birth cohorts with follow-up until 2012 evaluated the vaccine's effect on TB incidence. A personal identifier allowed for follow-up in the TB notification system. Associations were estimated using Cox regression.MTI study: Included 953 participants; 81% were BCG-vaccinated; 29% had MTI, 23% among vaccinated and 57% among non-vaccinated. BCG vaccination reduced the odds of MTI, OR 0.52 (95% CI 0.32 to 0.85), p=0.01. Vaccine effectiveness against MTI was 20%. TB study: Included 1697 participants followed for 21,148 person-years. 6% were notified with TB, 4% among vaccinated and 11% among non-vaccinated. BCG vaccination reduced the risk of TB, HR 0.50 (95% CI 0.26 to 0.95), p=0.03, yielding a vaccine effectiveness of 50%.BCG vaccination was effective in reducing both MTI and TB disease among children and young adults in a TB high-endemic setting in Greenland.

    View details for DOI 10.1136/thoraxjnl-2014-205688

    View details for Web of Science ID 000340239900014

    View details for PubMedID 24969643

  • Cardiac involvement in myotonic dystrophy: a nationwide cohort study EUROPEAN HEART JOURNAL Lund, M., Diaz, L. J., Ranthe, M. F., Petri, H., Duno, M., Juncker, I., Eiberg, H., Vissing, J., Bundgaard, H., Wohlfahrt, J., Melbye, M. 2014; 35 (32): 2158-2164

    Abstract

    To quantify the association between myotonic dystrophy (DM) and cardiac disease in a nationwide cohort.We identified a nationwide cohort of 1146 DM patients (period 1977-2011) using the National Patient Registry (NPR) and a subcohort of 485 patients who had undergone genetic testing for DM1. Information on incident cardiac diseases was obtained from the NPR. We estimated standardized incidence ratios (SIRs) of cardiac disease compared with the background population, overall and according to selected diagnostic subgroups (cardiomyopathy, heart failure, conduction disorders, arrhythmias, and device implantation). In the DM cohort, SIR for any cardiac disease was 3.42 [95% confidence interval (CI) 3.01-3.86]; for a cardiac disease belonging to the selected subgroups 6.91 (95% CI: 5.93-8.01) and for other cardiac disease 2.59 (95% CI: 2.03-3.25). For a cardiac disease belonging to the selected subgroups, the risk was particularly high in the first year after DM diagnosis [SIR 15.4 (95% CI: 10.9-21.3)] but remained significantly elevated in subsequent years [SIR 6.07 (95% CI: 5.11-7.16]). The risk was higher in young cohort members [e.g. 20-39 years: SIR 18.1 (95% CI: 12.3-25.8)] compared with older [e.g. 60-79 years: SIR 3.99 (95% CI: 2.98-5.23)] but remained significantly increased in all age categories. Results were similar in separate analyses of the genetically confirmed DM1 patients.Myotonic dystrophy is strongly associated with cardiac disease. The risk is pronounced in the young and remains elevated throughout life, stressing the importance of lifelong cardiac follow-up from time of DM diagnosis.

    View details for DOI 10.1093/eurheartj/ehu157

    View details for Web of Science ID 000342233000011

    View details for PubMedID 24742887

  • Etiologic Heterogeneity Among Non-Hodgkin Lymphoma Subtypes: The InterLymph Non-Hodgkin Lymphoma Subtypes Project. Journal of the National Cancer Institute. Monographs Morton, L. M., Slager, S. L., Cerhan, J. R., Wang, S. S., Vajdic, C. M., Skibola, C. F., Bracci, P. M., de Sanjosé, S., Smedby, K. E., Chiu, B. C., Zhang, Y., Mbulaiteye, S. M., Monnereau, A., Turner, J. J., Clavel, J., Adami, H., Chang, E. T., Glimelius, B., Hjalgrim, H., Melbye, M., Crosignani, P., di Lollo, S., Miligi, L., Nanni, O., Ramazzotti, V., Rodella, S., Costantini, A. S., Stagnaro, E., Tumino, R., Vindigni, C., Vineis, P., Becker, N., Benavente, Y., Boffetta, P., Brennan, P., Cocco, P., Foretova, L., Maynadié, M., Nieters, A., Staines, A., Colt, J. S., Cozen, W., Davis, S., De Roos, A. J., Hartge, P., Rothman, N., Severson, R. K., Holly, E. A., Call, T. G., Feldman, A. L., Habermann, T. M., Liebow, M., Blair, A., Cantor, K. P., Kane, E. V., Lightfoot, T., Roman, E., Smith, A., Brooks-Wilson, A., Connors, J. M., Gascoyne, R. D., Spinelli, J. J., Armstrong, B. K., Kricker, A., Holford, T. R., Lan, Q., Zheng, T., Orsi, L., Dal Maso, L., Franceschi, S., La Vecchia, C., Negri, E., Serraino, D., Bernstein, L., Levine, A., Friedberg, J. W., Kelly, J. L., Berndt, S. I., Birmann, B. M., Clarke, C. A., Flowers, C. R., Foran, J. M., Kadin, M. E., Paltiel, O., Weisenburger, D. D., Linet, M. S., Sampson, J. N. 2014; 2014 (48): 130-144

    Abstract

    Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes.We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case-control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE).Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10(-4)), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10(-4)). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.

    View details for DOI 10.1093/jncimonographs/lgu013

    View details for PubMedID 25174034

  • Medical History, Lifestyle, Family History, and Occupational Risk Factors for Peripheral T-Cell Lymphomas: The InterLymph Non-Hodgkin Lymphoma Subtypes Project. Journal of the National Cancer Institute. Monographs Wang, S. S., Flowers, C. R., Kadin, M. E., Chang, E. T., Hughes, A. M., Ansell, S. M., Feldman, A. L., Lightfoot, T., Boffetta, P., Melbye, M., Lan, Q., Sampson, J. N., Morton, L. M., Zhang, Y., Weisenburger, D. D. 2014; 2014 (48): 66-75

    Abstract

    Accounting for 10%-15% of all non-Hodgkin lymphomas in Western populations, peripheral T-cell lymphomas (PTCL) are the most common T-cell lymphoma but little is known about their etiology. Our aim was to identify etiologic risk factors for PTCL overall, and for specific PTCL subtypes, by analyzing data from 15 epidemiologic studies participating in the InterLymph Consortium.A pooled analysis of individual-level data for 584 histologically confirmed PTCL cases and 15912 controls from 15 case-control studies conducted in Europe, North America, and Australia was undertaken. Data collected from questionnaires were harmonized to permit evaluation of a broad range of potential risk factors. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression.Risk factors associated with increased overall PTCL risk with a P value less than .05 included: a family history of hematologic malignancies (OR = 1.92, 95% CI = 1.30 to 2.84); celiac disease (OR = 17.8, 95% CI = 8.61 to 36.79); eczema (OR = 1.41, 95% CI = 1.07 to 1.85); psoriasis (OR = 1.97, 95% CI = 1.17 to 3.32); smoking 40 or more years (OR = 1.92, 95% CI = 1.41 to 2.62); and employment as a textile worker (ever) (OR = 1.58, 95% CI = 1.05 to 2.38) and electrical fitter (ever) (OR = 2.89, 95% CI = 1.41 to 5.95). Exposures associated with reduced overall PTCL risk included a personal history of allergies (OR = 0.69, 95% CI = 0.54 to 0.87), alcohol consumption (ever) (OR = 0.64, 95% CI = 0.49 to 0.82), and having ever lived or worked on a farm (OR = 0.72, 95% CI = 0.55% to 0.95%). We also observed the well-established risk elevation for enteropathy-type PTCL among those with celiac disease in our data. Conclusions Our pooled analyses identified a number of new potential risk factors for PTCL and require further validation in independent series.

    View details for DOI 10.1093/jncimonographs/lgu012

    View details for PubMedID 25174027

  • Rationale and Design of the International Lymphoma Epidemiology Consortium (InterLymph) Non-Hodgkin Lymphoma Subtypes Project. Journal of the National Cancer Institute. Monographs Morton, L. M., Sampson, J. N., Cerhan, J. R., Turner, J. J., Vajdic, C. M., Wang, S. S., Smedby, K. E., de Sanjosé, S., Monnereau, A., Benavente, Y., Bracci, P. M., Chiu, B. C., Skibola, C. F., Zhang, Y., Mbulaiteye, S. M., Spriggs, M., Robinson, D., Norman, A. D., Kane, E. V., Spinelli, J. J., Kelly, J. L., La Vecchia, C., Dal Maso, L., Maynadié, M., Kadin, M. E., Cocco, P., Costantini, A. S., Clarke, C. A., Roman, E., Miligi, L., Colt, J. S., Berndt, S. I., Mannetje, A., De Roos, A. J., Kricker, A., Nieters, A., Franceschi, S., Melbye, M., Boffetta, P., Clavel, J., Linet, M. S., Weisenburger, D. D., Slager, S. L. 2014; 2014 (48): 1-14

    Abstract

    Non-Hodgkin lymphoma (NHL), the most common hematologic malignancy, consists of numerous subtypes. The etiology of NHL is incompletely understood, and increasing evidence suggests that risk factors may vary by NHL subtype. However, small numbers of cases have made investigation of subtype-specific risks challenging. The International Lymphoma Epidemiology Consortium therefore undertook the NHL Subtypes Project, an international collaborative effort to investigate the etiologies of NHL subtypes. This article describes in detail the project rationale and design.We pooled individual-level data from 20 case-control studies (17471 NHL cases, 23096 controls) from North America, Europe, and Australia. Centralized data harmonization and analysis ensured standardized definitions and approaches, with rigorous quality control.The pooled study population included 11 specified NHL subtypes with more than 100 cases: diffuse large B-cell lymphoma (N = 4667), follicular lymphoma (N = 3530), chronic lymphocytic leukemia/small lymphocytic lymphoma (N = 2440), marginal zone lymphoma (N = 1052), peripheral T-cell lymphoma (N = 584), mantle cell lymphoma (N = 557), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (N = 374), mycosis fungoides/Sézary syndrome (N = 324), Burkitt/Burkitt-like lymphoma/leukemia (N = 295), hairy cell leukemia (N = 154), and acute lymphoblastic leukemia/lymphoma (N = 152). Associations with medical history, family history, lifestyle factors, and occupation for each of these 11 subtypes are presented in separate articles in this issue, with a final article quantitatively comparing risk factor patterns among subtypes.The International Lymphoma Epidemiology Consortium NHL Subtypes Project provides the largest and most comprehensive investigation of potential risk factors for a broad range of common and rare NHL subtypes to date. The analyses contribute to our understanding of the multifactorial nature of NHL subtype etiologies, motivate hypothesis-driven prospective investigations, provide clues for prevention, and exemplify the benefits of international consortial collaboration in cancer epidemiology.

    View details for DOI 10.1093/jncimonographs/lgu005

    View details for PubMedID 25174022

  • A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus NATURE COMMUNICATIONS Cozen, W., Timofeeva, M. N., Li, D., Diepstra, A., Hazelett, D., Delahaye-Sourdeix, M., Edlund, C. K., Franke, L., Rostgaard, K., Van den Berg, D. J., Cortessis, V. K., Smedby, K. E., Glaser, S. L., Westra, H., Robison, L. L., Mack, T. M., Ghesquieres, H., HWANG, A. E., Nieters, A., De Sanjose, S., Lightfoot, T., Becker, N., Maynadie, M., Foretova, L., ROMAN, E., Benavente, Y., RAND, K. A., NATHWANI, B. N., Glimelius, B., Staines, A., Boffetta, P., Link, B. K., Kiemeney, L., Ansell, S. M., Bhatia, S., Strong, L. C., Galan, P., Vatten, L., Habermann, T. M., Duell, E. J., Lake, A., Veenstra, R. N., Visser, L., Liu, Y., Urayama, K. Y., Montgomery, D., Gaborieau, V., Weiss, L. M., Byrnes, G., Lathrop, M., Cocco, P., Best, T., Skol, A. D., Adami, H., Melbye, M., Cerhan, J. R., Gallagher, A., Taylor, G. M., Slager, S. L., Brennan, P., Coetzee, G. A., Conti, D. V., Onel, K., Jarrett, R. F., Hjalgrim, H., van den Berg, A., Mckay, J. D. 2014; 5

    Abstract

    Recent genome-wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified associations with genetic variation at both HLA and non-HLA loci; however, much of heritable HL susceptibility remains unexplained. Here we perform a meta-analysis of three HL GWAS totaling 1,816 cases and 7,877 controls followed by replication in an independent set of 1,281 cases and 3,218 controls to find novel risk loci. We identify a novel variant at 19p13.3 associated with HL (rs1860661; odds ratio (OR)=0.81, 95% confidence interval (95% CI)=0.76-0.86, Pcombined=3.5 × 10(-10)), located in intron 2 of TCF3 (also known as E2A), a regulator of B- and T-cell lineage commitment known to be involved in HL pathogenesis. This meta-analysis also notes associations between previously published loci at 2p16, 5q31, 6p31, 8q24 and 10p14 and HL subtypes. We conclude that our data suggest a link between the 19p13.3 locus, including TCF3, and HL risk.

    View details for DOI 10.1038/ncomms4856

    View details for Web of Science ID 000338830700001

    View details for PubMedID 24920014

    View details for PubMedCentralID PMC4055950

  • Risk of Retinal Detachment After Pediatric Cataract Surgery INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Haargaard, B., Andersen, E. W., Oudin, A., Poulsen, G., Wohlfahrt, J., la Cour, M., Melbye, M. 2014; 55 (5): 2947-2951

    Abstract

    To determine the long-term risk of retinal detachment following pediatric cataract surgery and to identify risk factors for retinal detachment.We included all children (aged 0 to 17 years) who during the time period of 1977 to 2005 underwent pediatric cataract surgery in Denmark, excluding cataract cases caused by trauma, or acquired systemic or acquired ocular pathology, and cases with ocular anomalies associated with the development of retinal detachment. Cases of cataract were ascertained from the mandatory Danish National Patient Register, and information on retinal detachment was based on medical chart review.Among 1043 eyes of 656 children undergoing surgery for pediatric cataract, 25 eyes (23 children) developed retinal detachment at a median time of 9.1 years after surgery. The overall 20-year risk of retinal detachment was 7% (95% confidence interval [CI]: 3%-11%) among cataract patients. In otherwise normal children having isolated cataract, the risk was 3% (95% CI: 0%-7%). A significantly higher risk of developing retinal detachment was found in children with mental retardation (23% [95% CI: 9%-35%]) or in cataract cases with other ocular or systemic anomalies (16% [95% CI: 6%-24%]).The estimated overall risk of retinal detachment 20 years after pediatric cataract surgery was 7%, but only 3% for isolated cataract. Particularly high risks of retinal detachment after cataract surgery were associated with mental retardation and having other ocular or systemic diseases.

    View details for DOI 10.1167/iovs.14-13996

    View details for Web of Science ID 000339484800019

    View details for PubMedID 24713483

  • The origin and emergence of an HIV-1 epidemic: from introduction to endemicity AIDS Bruhn, C. A., Audelin, A. M., Helleberg, M., Bjorn-Mortensen, K., Obel, N., Gerstoft, J., Nielsen, C., Melbye, M., Medstrand, P., Gilbert, M. T., Esbjornsson, J. 2014; 28 (7): 1031-1040

    Abstract

    To describe, at patient-level detail, the determining events and factors involved in the development of a country's HIV-1 epidemic.Clinical information for all recorded Greenlandic HIV-1 patients was analysed and correlated with both novel and previously analysed pol sequences, representing more than half of the entire Greenlandic HIV-1 epidemic. Archival blood samples were sequenced to link early infection chain descriptions to the subsequent epidemic.In-depth phylogenetic analyses were used in synergy with clinical information to assess number of introductions of HIV-1 into Greenland, the source of geographic origin, time of epidemic introduction and its epidemiological characteristics such as initial transmission chain, geographic dispersal within Greenland, method of infection, cluster size, sociological and behavioural factors.Despite its small population size and isolated geographic location, data support at least 25 introductions of HIV-1 into Greenland. Only a single of these led to an epidemic. This introduction occurred between 1985 and 1986, and the epidemic cluster is still active. Facilitating factors for the emergence and spread of the epidemic cluster include a rapid transition from MSM to heterosexual spread, high prevalence of other sexually transmitted diseases, rapid dispersal to larger cities and early emergence in a distinct subpopulation with high-risk behaviour including disregard for condomizing.The synergistic use of disparate data categories yields such unique detail, that the Greenland epidemic now serves as a model example for the epidemic emergence of HIV-1 in a society. This renders it suitable for testing of present and future sequence-based epidemiological methodologies.

    View details for DOI 10.1097/QAD.0000000000000198

    View details for Web of Science ID 000335350900012

    View details for PubMedID 24451158

  • Use of macrolides in mother and child and risk of infantile hypertrophic pyloric stenosis: nationwide cohort study BMJ-BRITISH MEDICAL JOURNAL Lund, M., Pasternak, B., Davidsen, R. B., Feenstra, B., Krogh, C., Diaz, L. J., Wohlfahrt, J., Melbye, M. 2014; 348

    Abstract

    To assess the association between use of macrolide antibiotics in mothers and infants from pregnancy onset until 120 days after birth and infantile hypertrophic pyloric stenosis (IHPS).Nationwide register based cohort study.Denmark, 1996-2011.999,378 liveborn singletons and linked individual level information on macrolide prescriptions (maternal use during pregnancy, n=30,091; maternal use after birth, n=21,557; use in infants, n=6591), surgery for IHPS, and potential confounders.Surgery for IHPS by three categories of macrolide use: in mothers during pregnancy, in mothers after birth, and in infants after birth.880 infants developed IHPS (0.9 cases per 1000 births). Compared with infants with no use of macrolides, the adjusted rate ratio for IHPS in infants with use of macrolides during days 0 to 13 after birth was 29.8 (95% confidence interval 16.4 to 54.1) and during days 14 to 120 was 3.24 (1.20 to 8.74); the corresponding absolute risk differences were 24.4 (95% confidence interval 13.0 to 44.1) and 0.65 (0.06 to 2.21) cases per 1000 infants exposed to macrolides, respectively. The rate ratio for maternal use of macrolides for days 0 to 13 after birth was 3.49 (1.92 to 6.34) and for days 14 to 120 was 0.70 (0.26 to 1.90); the corresponding absolute risk differences were 2.15 (0.82 to 4.64) and -0.11 (-0.26 to 0.31). The rate ratios for maternal use of macrolides during pregnancy were 1.02 (0.65 to 1.59) for weeks 0 to 27 and 1.77 (0.95 to 3.31) for weeks 28 to birth; the corresponding absolute risk differences were 0.01 (-0.31 to 0.50) and 0.67 (-0.06 to 2.02).Treatment of young infants with macrolide antibiotics was strongly associated with IHPS and should therefore only be administered if potential treatment benefits outweigh the risk. Maternal use of macrolides during the first two weeks after birth was also associated with an increased risk of IHPS. A possible association was also found with use during late pregnancy.

    View details for DOI 10.1136/bmj.g1908

    View details for Web of Science ID 000333032100007

    View details for PubMedID 24618148

    View details for PubMedCentralID PMC3949411

  • Epilepsy, anti-epileptic medication use and risk of cancer INTERNATIONAL JOURNAL OF CANCER Kaae, J., Carstensen, L., Wohlfahrt, J., Melbye, M., Boyd, H. A. 2014; 134 (4): 932-938

    Abstract

    Whether the powerful medications used to treat epilepsy increase the risk of cancer has been debated for decades, but until now no study could disentangle the contributions of anti-epileptic medications and epilepsy itself to cancer risk. Using a cohort comprising all Danish residents ≥ 16 years old at some point during the period 1996-2010 (>56 million person-years of follow-up) and information from national health registers, we examined associations between anti-epileptic medication use and cancer rates in persons with and without epilepsy, and between epilepsy and cancer rates in treated and untreated individuals. Associations were expressed as incidence rate ratios (IRRs) estimated using Poisson regression. Among persons without epilepsy, use of anti-epileptic medication increased the rates of most cancers little or not at all, although we observed moderately increased rates of liver, mouth and throat, and respiratory tract cancers (IRRs 1.40-1.59). In contrast, we observed strong associations between epilepsy and the rates of central nervous system and mouth and throat cancers (IRRs 2.00-3.91), and a modest association between epilepsy and the rate of respiratory tract cancers (IRRs 1.30-1.35), independent of anti-epileptic medication use. Our finding of only modest increases in cancer risk directly attributable to anti-epileptic medication use suggests that these medications may not be as strongly carcinogenic as has been feared, and that it is not primarily anti-epileptic medications that are responsible for the increased cancer risk among epileptics but another aspect of epilepsy diagnosis or treatment or an etiologic factor common to the two conditions.

    View details for DOI 10.1002/ijc.28396

    View details for Web of Science ID 000327889700021

    View details for PubMedID 23901034

  • Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature Perry, J. R., Day, F., Elks, C. E., Sulem, P., Thompson, D. J., Ferreira, T., He, C., Chasman, D. I., Esko, T., Thorleifsson, G., Albrecht, E., Ang, W. Q., Corre, T., Cousminer, D. L., Feenstra, B., Franceschini, N., Ganna, A., Johnson, A. D., Kjellqvist, S., Lunetta, K. L., McMahon, G., Nolte, I. M., Paternoster, L., Porcu, E., Smith, A. V., Stolk, L., Teumer, A., Tšernikova, N., Tikkanen, E., Ulivi, S., Wagner, E. K., Amin, N., Bierut, L. J., Byrne, E. M., Hottenga, J. J., Koller, D. L., Mangino, M., Pers, T. H., Yerges-Armstrong, L. M., Hua Zhao, J., Andrulis, I. L., Anton-Culver, H., Atsma, F., Bandinelli, S., Beckmann, M. W., Benitez, J., Blomqvist, C., Bojesen, S. E., Bolla, M. K., Bonanni, B., Brauch, H., Brenner, H., Buring, J. E., Chang-Claude, J., Chanock, S., Chen, J., Chenevix-Trench, G., Collée, J. M., Couch, F. J., Couper, D., Coviello, A. D., Cox, A., Czene, K., D'adamo, A. P., Davey Smith, G., De Vivo, I., Demerath, E. W., Dennis, J., Devilee, P., Dieffenbach, A. K., Dunning, A. M., Eiriksdottir, G., Eriksson, J. G., Fasching, P. A., Ferrucci, L., Flesch-Janys, D., Flyger, H., Foroud, T., Franke, L., Garcia, M. E., García-Closas, M., Geller, F., de Geus, E. E., Giles, G. G., Gudbjartsson, D. F., Gudnason, V., Guénel, P., Guo, S., Hall, P., Hamann, U., Haring, R., Hartman, C. A., Heath, A. C., Hofman, A., Hooning, M. J., Hopper, J. L., Hu, F. B., Hunter, D. J., Karasik, D., Kiel, D. P., Knight, J. A., Kosma, V. M., Kutalik, Z., Lai, S., Lambrechts, D., Lindblom, A., Mägi, R., Magnusson, P. K., Mannermaa, A., Martin, N. G., Masson, G., McArdle, P. F., McArdle, W. L., Melbye, M., Michailidou, K., Mihailov, E., Milani, L., Milne, R. L., Nevanlinna, H., Neven, P., Nohr, E. A., Oldehinkel, A. J., Oostra, B. A., Palotie, A., Peacock, M., Pedersen, N. L., Peterlongo, P. 2014; 514 (7520): 92–97

    Abstract

    Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

    View details for PubMedID 25231870

  • Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma. Nature genetics Cerhan, J. R., Berndt, S. I., Vijai, J., Ghesquières, H., McKay, J., Wang, S. S., Wang, Z., Yeager, M., Conde, L., de Bakker, P. I., Nieters, A., Cox, D., Burdett, L., Monnereau, A., Flowers, C. R., De Roos, A. J., Brooks-Wilson, A. R., Lan, Q., Severi, G., Melbye, M., Gu, J., Jackson, R. D., Kane, E., Teras, L. R., Purdue, M. P., Vajdic, C. M., Spinelli, J. J., Giles, G. G., Albanes, D., Kelly, R. S., Zucca, M., Bertrand, K. A., Zeleniuch-Jacquotte, A., Lawrence, C., Hutchinson, A., Zhi, D., Habermann, T. M., Link, B. K., Novak, A. J., Dogan, A., Asmann, Y. W., Liebow, M., Thompson, C. A., Ansell, S. M., Witzig, T. E., Weiner, G. J., Veron, A. S., Zelenika, D., Tilly, H., Haioun, C., Molina, T. J., Hjalgrim, H., Glimelius, B., Adami, H. O., Bracci, P. M., Riby, J., Smith, M. T., Holly, E. A., Cozen, W., Hartge, P., Morton, L. M., Severson, R. K., Tinker, L. F., North, K. E., Becker, N., Benavente, Y., Boffetta, P., Brennan, P., Foretova, L., Maynadie, M., Staines, A., Lightfoot, T., Crouch, S., Smith, A., Roman, E., Diver, W. R., Offit, K., Zelenetz, A., Klein, R. J., Villano, D. J., Zheng, T., Zhang, Y., Holford, T. R., Kricker, A., Turner, J., Southey, M. C., Clavel, J., Virtamo, J., Weinstein, S., Riboli, E., Vineis, P., Kaaks, R., Trichopoulos, D., Vermeulen, R. C., Boeing, H., Tjonneland, A., Angelucci, E., Di Lollo, S., Rais, M., Birmann, B. M., Laden, F., Giovannucci, E., Kraft, P., Huang, J., Ma, B., Ye, Y., Chiu, B. C., Sampson, J., Liang, L., Park, J. H., Chung, C. C., Weisenburger, D. D., Chatterjee, N., Fraumeni, J. F., Slager, S. L., Wu, X., de Sanjose, S., Smedby, K. E., Salles, G., Skibola, C. F., Rothman, N., Chanock, S. J. 2014; 46 (11): 1233–38

    Abstract

    Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10(-13) and 3.63 × 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.

    View details for PubMedID 25261932

  • Authors' reply to de Vries. BMJ (Clinical research ed.) Lund, M., Pasternak, B., Wohlfahrt, J., Melbye, M. 2014; 349: g5206

    View details for PubMedID 25139721

  • Use of Selective Serotonin Reuptake Inhibitors during Pregnancy and Risk of Autism NEW ENGLAND JOURNAL OF MEDICINE Hviid, A., Melbye, M., Pasternak, B. 2013; 369 (25): 2406-2415

    Abstract

    Studies have raised concern about an association between the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy and an increased risk of autism spectrum disorders in the offspring.We conducted a cohort study of all singleton live births in Denmark from 1996 through 2005 (626,875 births), with follow-up through 2009. Using Danish population registries, we linked information on maternal use of SSRIs before and during pregnancy, autism spectrum disorders diagnosed in the offspring, and a range of potential confounders. We used a survival analysis of the time to diagnosis in the offspring with Poisson regression to estimate rate ratios of autism spectrum disorders according to maternal use of SSRIs.During 5,057,282 person-years of follow-up, we identified 3892 cases of autism spectrum disorder (incidence rate, 77.0 per 100,000 person-years). A total of 52 cases during 42,400 person-years of follow-up involved offspring of women who were exposed to SSRIs during their pregnancy (incidence rate, 122.6 per 100,000 person-years). As compared with no use of SSRIs both before and during pregnancy, use during pregnancy was not associated with a significantly increased risk of autism spectrum disorders (fully adjusted rate ratio, 1.20; 95% confidence interval [CI], 0.90 to 1.61). Among women who received SSRIs before pregnancy but not during pregnancy, the corresponding fully adjusted rate ratio was 1.46 (95% CI, 1.17 to 1.81).We did not detect a significant association between maternal use of SSRIs during pregnancy and autism spectrum disorder in the offspring. On the basis of the upper boundary of the confidence interval, our study could not rule out a relative risk up to 1.61, and therefore the association warrants further study. (Funded by the Danish Health and Medicines Authority.).

    View details for DOI 10.1056/NEJMoa1301449

    View details for Web of Science ID 000328586000008

    View details for PubMedID 24350950

  • Spironolactone use and the risk of breast and gynecologic cancers CANCER EPIDEMIOLOGY Biggar, R. J., Andersen, E. W., Wohlfahrt, J., Melbye, M. 2013; 37 (6): 870-875

    Abstract

    Spironolactone, an aldosterone-antagonist, is associated with gynecomastia. Digoxin, which can also cause gynecomastia, has been associated with increased incidence of breast and uterus cancers. We therefore postulated that spironolactone use might also increase these cancer risks. Using a nationwide prescription drug registry between 1995 and 2010, we identified use of spironolactone in a cohort of Danish women (≥20 years old). In users and non-users, incidence rate ratios adjusted by age group and calendar-year examined risk of breast and uterus cancers, both estrogen-sensitive, and ovary and cervix cancers, both relatively estrogen-insensitive. As an added control exposure, risk ratios in women who used another diuretic, furosemide, were examined by the same approach. Among 2.3 million women (28.5 million person-years), risks of breast, uterus, ovary, and cervix cancers were generally increased about 10-30% in both spironolactone and furosemide users. In the first year of drug exposure, incidences were increased, especially for ovary cancers. However, incidence increases in the first year of use were not specific for estrogen-sensitive cancers, occurred with both spironolactone and furosemide, and were driven by exposures immediately prior to diagnosis. For drug exposure ≥1 years before cancer diagnosis, incidences of these cancers were not significantly increased. We conclude that associations observed with first use in the year immediately before cancer diagnosis were driven by reverse causality, i.e., because of treatment for symptoms related to the incipient cancer. With respect to breast, uterus, ovarian and cervical cancer, there is no evidence of increased risk with spironolactone or furosemide use.

    View details for DOI 10.1016/j.canep.2013.10.004

    View details for Web of Science ID 000328251000015

    View details for PubMedID 24189467

  • Associations of Personal and Family Preeclampsia History With the Risk of Early-, Intermediate- and Late-Onset Preeclampsia AMERICAN JOURNAL OF EPIDEMIOLOGY Boyd, H. A., Tahir, H., Wohlfahrt, J., Melbye, M. 2013; 178 (11): 1611-1619

    Abstract

    Preeclampsia encompasses multiple conditions of varying severity. We examined the recurrence and familial aggregation of preeclampsia by timing of onset, which is a marker for severity. We ascertained personal and family histories of preeclampsia for women who delivered live singletons in Denmark in 1978-2008 (almost 1.4 million pregnancies). Using log-linear binomial regression, we estimated risk ratios for the associations between personal and family histories of preeclampsia and the risk of early-onset (before 34 weeks of gestation, which is typically the most severe), intermediate-onset (at 34-36 weeks of gestation), and late-onset (after 36 weeks of gestation) preeclampsia. Previous early-, intermediate-, or late-onset preeclampsia increased the risk of recurrent preeclampsia with the same timing of onset 25.2 times (95% confidence interval (CI): 21.8, 29.1), 19.7 times (95% CI: 17.0, 22.8), and 10.3 times (95% CI: 9.85, 10.9), respectively, compared with having no such history. Preeclampsia in a woman's family was associated with a 24%-163% increase in preeclampsia risk, with the strongest associations for early- and intermediate-onset preeclampsia in female relatives. Preeclampsia in the man's family did not affect a woman's risk of early-onset preeclampsia and was only weakly associated with her risks of intermediate- and late-onset preeclampsia. Early-onset preeclampsia appears to have the largest genetic component, whereas environmental factors likely contribute most to late-onset preeclampsia. The role of paternal genes in the etiology of preeclampsia appears to be limited.

    View details for DOI 10.1093/aje/kwt189

    View details for Web of Science ID 000327717600003

    View details for PubMedID 24049162

  • Association Between Oral Fluoroquinolone Use and Retinal Detachment JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Pasternak, B., Svanstrom, H., Melbye, M., Hviid, A. 2013; 310 (20): 2184-2190

    Abstract

    A recent study of ophthalmologic patients found a strong association between fluoroquinolone use and retinal detachment. Given the prevalent use of fluoroquinolones, this could, if confirmed in the general population, translate to many excess cases of retinal detachment that are potentially preventable.To investigate if oral fluoroquinolone use is associated with an increased risk of retinal detachment.A nationwide, register-based cohort study in Denmark from 1997 through 2011, using linked data on participant characteristics, filled prescriptions, and cases of retinal detachment with surgical treatment (scleral buckling, vitrectomy, or pneumatic retinopexy). The cohort included 748,792 episodes of fluoroquinolone use (660,572 [88%] ciprofloxacin) and 5,520,446 control episodes of nonuse.Poisson regression was used to estimate rate ratios (RRs) for incident retinal detachment, adjusting for a propensity score that included a total of 21 variables. The risk windows were classified as current use (days 1-10 from start of treatment), recent use (days 11-30), past use (days 31-60), and distant use (days 61-180).A total of 566 cases of retinal detachment occurred, of which 465 (82%) were rhegmatogenous detachments; 72 in fluoroquinolone users and 494 in control nonusers. The crude incidence rate was 25.3 cases per 100,000 person-years in current users, 18.9 in recent users, 26.8 in past users, and 24.8 in distant users compared with 19.0 in nonusers. Compared with nonuse, fluoroquinolone use was not associated with a significantly increased risk of retinal detachment: the adjusted RRs were 1.29 (95% CI, 0.53 to 3.13) for current use; 0.97 (95% CI, 0.46 to 2.05) for recent use; 1.37 (95% CI, 0.80 to 2.35) for past use; and 1.27 (95% CI, 0.93 to 1.75) for distant use. The absolute risk difference, estimated as the adjusted number of retinal detachment cases per 1,000,000 treatment episodes, was 1.5 (95% CI, -2.4 to 11.1) for current use.In this cohort study based on the general Danish population, oral fluoroquinolone use was not associated with increased risk of retinal detachment. Given its limited power, this study can only rule out more than a 3-fold increase in the relative risk associated with current fluoroquinolone use; however, any differences in absolute risk are likely to be of minor, if any, clinical significance.

    View details for DOI 10.1001/jama.2013.280500

    View details for Web of Science ID 000327404400027

    View details for PubMedID 24281462

  • Vitamin D Status during Pregnancy and the Risk of Subsequent Postpartum Depression: A Case-Control Study PLOS ONE Nielsen, N. O., Strom, M., Boyd, H. A., Andersen, E. W., Wohlfahrt, J., Lundqvist, M., Cohen, A., Hougaard, D. M., Melbye, M. 2013; 8 (11)

    Abstract

    Epidemiological studies have provided evidence of an association between vitamin D insufficiency and depression and other mood disorders, and a role for vitamin D in various brain functions has been suggested. We hypothesized that low vitamin D status during pregnancy might increase the risk of postpartum depression (PPD). The objective of the study was thus to determine whether low vitamin D status during pregnancy was associated with postpartum depression. In a case-control study nested in the Danish National Birth Cohort, we measured late pregnancy serum concentrations of 25[OH]D3 in 605 women with PPD and 875 controls. Odds ratios [OR) for PPD were calculated for six levels of 25[OH]D3. Overall, we found no association between vitamin D concentrations and risk of PPD (p = 0.08). Compared with women with vitamin D concentrations between 50 and 79 nmol/L, the adjusted odds ratios for PPD were 1.35 (95% CI: 0.64; 2.85), 0.83 (CI: 0.50; 1.39) and 1.13 (CI: 0.84; 1.51) among women with vitamin D concentrations < 15 nmol/L, 15-24 nmol/L and 25-49 nmol/L, respectively, and 1.53 (CI: 1.04; 2.26) and 1.89 (CI: 1.06; 3.37) among women with vitamin D concentrations of 80-99 nmol/L and ≥ 100 nmol/L, respectively. In an additional analysis among women with sufficient vitamin D (≥ 50 nmol/L), we observed a significant positive association between vitamin D concentrations and PPD. Our results did not support an association between low maternal vitamin D concentrations during pregnancy and risk of PPD. Instead, an increased risk of PPD was found among women with the highest vitamin D concentrations.

    View details for DOI 10.1371/journal.pone.0080686

    View details for Web of Science ID 000327652100050

    View details for PubMedID 24312237

    View details for PubMedCentralID PMC3842313

  • Exposure to UV radiation and risk of Hodgkin lymphoma: a pooled analysis. Blood Monnereau, A., Glaser, S. L., Schupp, C. W., Ekström Smedby, K., de Sanjosé, S., Kane, E., Melbye, M., Forétova, L., Maynadié, M., Staines, A., Becker, N., Nieters, A., Brennan, P., Boffetta, P., Cocco, P., Glimelius, I., Clavel, J., Hjalgrim, H., Chang, E. T. 2013; 122 (20): 3492-3499

    Abstract

    Ultraviolet radiation (UVR) exposure has been inversely associated with Hodgkin lymphoma (HL) risk, but only inconsistently, only in a few studies, and without attention to HL heterogeneity. We conducted a pooled analysis of HL risk focusing on type and timing of UVR exposure and on disease subtypes by age, histology, and tumor-cell Epstein-Barr virus (EBV) status. Four case-control studies contributed 1320 HL cases and 6381 controls. We estimated lifetime, adulthood, and childhood UVR exposure and history of sunburn and sunlamp use. We used 2-stage estimation with mixed-effects models and weighted pooled effect estimates by inverse marginal variances. We observed statistically significant inverse associations with HL risk for UVR exposures during childhood and adulthood, sunburn history, and sunlamp use, but we found no significant dose-response relationships. Risks were significant only for EBV-positive HL (pooled odds ratio, 0.56; 95% confidence interval, 0.35 to 0.91 for the highest overall UVR exposure category), with a significant linear trend for overall exposure (P = .03). Pooled relative risk estimates were not heterogeneous across studies. Increased UVR exposure may protect against HL, particularly EBV-positive HL. Plausible mechanisms involving UVR induction of regulatory T cells or the cellular DNA damage response suggest opportunities for new prevention targets.

    View details for DOI 10.1182/blood-2013-04-497586

    View details for PubMedID 24016459

    View details for PubMedCentralID PMC3829118

  • Metoclopramide in Pregnancy and Risk of Major Congenital Malformations and Fetal Death JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Pasternak, B., Svanstrom, H., Molgaard-Nielsen, D., Melbye, M., Hviid, A. 2013; 310 (15): 1601-1611

    Abstract

    Metoclopramide, a drug frequently used for nausea and vomiting in pregnancy, is thought to be safe, but information on the risk of specific malformations and fetal death is lacking.To investigate the safety of metoclopramide use in pregnancy.Register-based cohort study in Denmark, 1997-2011. From a cohort of 1,222,503 pregnancies, metoclopramide-exposed and unexposed women were matched (1:4 ratio) on the basis of age, calendar year, and propensity scores.Primary outcomes were major congenital malformations overall, 20 individual malformation categories (selected according to power criteria), spontaneous abortion, and stillbirth. In matched analyses, logistic regression was used to estimate prevalence odds ratios of malformations and Cox regression to estimate hazard ratios (HRs) of spontaneous abortion.Among 28,486 women exposed to metoclopramide in the first trimester, 721 had an infant with a major congenital malformation (25.3 [95% CI, 23.5-27.1] cases per 1000 births), compared with 3024 among 113,698 unexposed women (26.6 [95% CI, 25.7-27.5] per 1000 births). There were no significant associations between metoclopramide use and malformations overall (prevalence odds ratio, 0.93 [95% CI, 0.86-1.02]) or any of the 20 individual malformation categories, eg, neural tube defects, transposition of great vessels, ventricular septal defect, atrial septal defect, tetralogy of Fallot, coarctation of the aorta, cleft lip, cleft palate, anorectal atresia/stenosis, and limb reduction (upper limit of 95% CI below 2.0 for 17 of 20 categories). Metoclopramide was not associated with increased risk of spontaneous abortion (757 cases [20.0 {95% CI, 18.5-21.4} per 1000] among 37,946 metoclopramide-exposed women and 9414 cases [62.1 {95% CI, 60.9-63.3} per 1000] among 151,661 unexposed women; HR, 0.35 [95% CI, 0.33-0.38]) and stillbirth (142 cases [3.5 {95% CI, 2.9-4.1} per 1000] among 40,306 metoclopramide-exposed women and 634 cases [3.9 {95% CI, 3.6-4.2} per 1000] among 161,098 unexposed women; HR, 0.90 [95% CI, 0.74-1.08]).Metoclopramide use in pregnancy was not associated with increased risk of major congenital malformations overall, any of the 20 individual malformation categories assessed, spontaneous abortion, or stillbirth. These safety data may help inform decision making when treatment with metoclopramide is considered in pregnancy.

    View details for DOI 10.1001/jama.2013.278343

    View details for Web of Science ID 000325624800023

    View details for PubMedID 24129464

  • Genome-wide association study of primary tooth eruption identifies pleiotropic loci associated with height and craniofacial distances. Human molecular genetics Fatemifar, G., Hoggart, C. J., Paternoster, L., Kemp, J. P., Prokopenko, I., Horikoshi, M., Wright, V. J., Tobias, J. H., Richmond, S., Zhurov, A. I., Toma, A. M., Pouta, A., Taanila, A., Sipila, K., Lähdesmäki, R., Pillas, D., Geller, F., Feenstra, B., Melbye, M., Nohr, E. A., Ring, S. M., St Pourcain, B., Timpson, N. J., Davey Smith, G., Jarvelin, M., Evans, D. M. 2013; 22 (18): 3807-3817

    Abstract

    Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption, we performed a population-based genome-wide association study of 'age at first tooth' and 'number of teeth' using 5998 and 6609 individuals, respectively, from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2 446 724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studies were combined using fixed effects inverse variance meta-analysis. We identified a total of 15 independent loci, with 10 loci reaching genome-wide significance (P < 5 × 10(-8)) for 'age at first tooth' and 11 loci for 'number of teeth'. Together, these associations explain 6.06% of the variation in 'age of first tooth' and 4.76% of the variation in 'number of teeth'. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including an SNP in the protein-coding region of BMP4 (rs17563, P = 9.080 × 10(-17)). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development.

    View details for DOI 10.1093/hmg/ddt231

    View details for PubMedID 23704328

    View details for PubMedCentralID PMC3749866

  • Genome-wide association study of primary tooth eruption identifies pleiotropic loci associated with height and craniofacial distances HUMAN MOLECULAR GENETICS Fatemifar, G., Hoggart, C. J., Paternoster, L., Kemp, J. P., Prokopenko, I., Horikoshi, M., Wright, V. J., Tobias, J. H., Richmond, S., Zhurov, A. I., Toma, A. M., Pouta, A., Taanila, A., Sipila, K., Lahdesmaki, R., Pillas, D., Geller, F., Feenstra, B., Melbye, M., Nohr, E. A., Ring, S. M., St Pourcain, B., Timpson, N. J., Smith, G. D., Jarvelin, M., Evans, D. M. 2013; 22 (18): 3807-3817

    Abstract

    Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption, we performed a population-based genome-wide association study of 'age at first tooth' and 'number of teeth' using 5998 and 6609 individuals, respectively, from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2 446 724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studies were combined using fixed effects inverse variance meta-analysis. We identified a total of 15 independent loci, with 10 loci reaching genome-wide significance (P < 5 × 10(-8)) for 'age at first tooth' and 11 loci for 'number of teeth'. Together, these associations explain 6.06% of the variation in 'age of first tooth' and 4.76% of the variation in 'number of teeth'. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including an SNP in the protein-coding region of BMP4 (rs17563, P = 9.080 × 10(-17)). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development.

    View details for DOI 10.1093/hmg/ddt231

    View details for Web of Science ID 000323582000016

    View details for PubMedCentralID PMC3749866

  • Plasma Lipids, Genetic Variants Near APOA1, and the Risk of Infantile Hypertrophic Pyloric Stenosis JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Feenstra, B., Geller, F., Carstensen, L., Romitti, P. A., Korberg, I. B., Bedell, B., Krogh, C., Fan, R., Svenningsson, A., Caggana, M., Nordenskjold, A., Mills, J. L., Murray, J. C., Melbye, M. 2013; 310 (7): 714-721

    Abstract

    Infantile hypertrophic pyloric stenosis (IHPS) is a serious condition in which hypertrophy of the pyloric sphincter muscle layer leads to gastric outlet obstruction. Infantile hypertrophic pyloric stenosis shows strong familial aggregation and heritability, but knowledge about specific genetic risk variants is limited.To search the genome comprehensively for genetic associations with IHPS and validate findings in 3 independent sample sets.During stage 1, we used reference data from the 1000 Genomes Project for imputation into a genome-wide data set of 1001 Danish surgery-confirmed samples (cases diagnosed 1987-2008) and 2371 disease-free controls. In stage 2, the 5 most significantly associated loci were tested in independent case-control sample sets from Denmark (cases diagnosed 1983-2010), Sweden (cases diagnosed 1958-2011), and the United States (cases diagnosed 1998-2005), with a total of 1663 cases and 2315 controls.Association of genetic variation with the presence of infantile hypertrophic pyloric stenosis.We found a new genome-wide significant locus for IHPS at chromosome 11q23.3. The single-nucleotide polymorphism (SNP) with the lowest P value at the locus, rs12721025 (odds ratio [OR], 1.59; 95% CI, 1.38-1.83; P = 1.9 × 10(-10)), is located 301 bases downstream of the apolipoprotein A-I (APOA1) gene and is correlated (r2 between 0.46 and 0.80) with SNPs previously found to be associated with levels of circulating cholesterol. For these SNPs, the cholesterol-lowering allele consistently was associated with increased risk of IHPS.This study identified a new genome-wide significant locus for IHPS. Characteristics of this locus suggest the possibility of an inverse relationship between levels of circulating cholesterol in neonates and IHPS risk, which warrants further investigation.

    View details for DOI 10.1001/jama.2013.242978

    View details for Web of Science ID 000323254500021

    View details for PubMedID 23989729

    View details for PubMedCentralID PMC4031654

  • Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia NATURE GENETICS Berndt, S. I., Skibola, C. F., Joseph, V., Camp, N. J., Nieters, A., Wang, Z., Cozen, W., Monnereau, A., Wang, S. S., Kelly, R. S., Lan, Q., Teras, L. R., Chatterjee, N., Chung, C. C., Yeager, M., Brooks-Wilson, A. R., Hartge, P., Purdue, M. P., Birmann, B. M., Armstrong, B. K., Cocco, P., Zhang, Y., Severi, G., Zeleniuch-Jacquotte, A., Lawrence, C., Burdette, L., Yuenger, J., Hutchinson, A., Jacobs, K. B., Call, T. G., Shanafelt, T. D., Novak, A. J., Kay, N. E., Liebow, M., Wang, A. H., Smedby, K. E., Adami, H., Melbye, M., Glimelius, B., Chang, E. T., Glenn, M., Curtin, K., Cannon-Albright, L. A., Jones, B., Diver, W. R., Link, B. K., Weiner, G. J., Conde, L., Bracci, P. M., Riby, J., Holly, E. A., Smith, M. T., Jackson, R. D., Tinker, L. F., Benavente, Y., Becker, N., Boffetta, P., Brennan, P., Foretova, L., Maynadie, M., McKay, J., Staines, A., Rabe, K. G., Achenbach, S. J., Vachon, C. M., Goldin, L. R., Strom, S. S., Lanasa, M. C., Spector, L. G., Leis, J. F., Cunningham, J. M., Weinberg, J. B., Morrison, V. A., Caporaso, N. E., Norman, A. D., Linet, M. S., De Roos, A. J., Morton, L. M., Severson, R. K., Riboli, E., Vineis, P., Kaaks, R., Trichopoulos, D., Masala, G., Weiderpass, E., Chirlaque, M., Vermeulen, R. C., Travis, R. C., Giles, G. G., Albanes, D., Virtamo, J., Weinstein, S., Clavel, J., Zheng, T., Holford, T. R., Offit, K., Zelenetz, A., Klein, R. J., Spinelli, J. J., Bertrand, K. A., Laden, F., Giovannucci, E., Kraft, P., Kricker, A., Turner, J., Vajdic, C. M., Ennas, M. G., Ferri, G. M., Miligi, L., Liang, L., Sampson, J., Crouch, S., Park, J., North, K. E., Cox, A., Snowden, J. A., Wright, J., Carracedo, A., Lopez-Otin, C., Bea, S., Salaverria, I., Martin-Garcia, D., Campo, E., Fraumeni, J. F., de Sanjose, S., Hjalgrim, H., Cerhan, J. R., Chanock, S. J., Rothman, N., Slager, S. L. 2013; 45 (8): 868-U202

    View details for DOI 10.1038/ng.2652

    View details for Web of Science ID 000322374900008

    View details for PubMedID 23770605

  • Parvovirus B19 infection in pregnancy and subsequent morbidity and mortality in offspring INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Lassen, J., Bager, P., Wohlfahrt, J., Bottiger, B., Melbye, M. 2013; 42 (4): 1070-1076

    Abstract

    Because parvovirus B19 infection in pregnancy has been associated with infant morbidity and mortality in case reports and after intrauterine transfusion, we tested the population-based association using serum and hospital data of high quality.We established a cohort of 113 228 children born to women tested for parvovirus B19 infection during pregnancy in a major diagnostic laboratory in Denmark, from 1994 to 2009. Information on 20 selected morbidity diagnoses and on mortality was obtained from the Danish National Patient Register, the Danish Cancer Register and the Danish Civil Registration System. Incidence rate ratios (IRR) were estimated by log-linear Poisson regression with adjustment for age and sex of the child, maternal age and year of maternal parvovirus B19 test.A total of 1095 (1.0%) children were born to mothers who were infected with parvovirus B19 during pregnancy. During 1 million person-years of follow-up, 10 856 children experienced morbidity and 590 children died. Overall, maternal infection status was neither associated with morbidity during infancy (IRR 0.64; 95% CI: 0.40 to 1.02) or childhood (IRR 0.93; 95% CI: 0.77 to 1.14), nor with infant mortality (IRR 0.98; 95% CI: 0.44 to 2.20). Specifically, there was no association with 19 of 20 morbidities. An excess risk of cancer in the central nervous system was observed (IRR 5.88; 95% CI: 1.41 to 24.6); however, the number of exposed cases was very small (n = 2).Parvovirus B19 infection during pregnancy was not associated with overall morbidity or mortality in infancy and childhood.

    View details for DOI 10.1093/ije/dyt117

    View details for Web of Science ID 000325167800023

    View details for PubMedID 24062296

  • Sequence variants in oxytocin pathway genes and preterm birth: a candidate gene association study BMC MEDICAL GENETICS Kim, J., Stirling, K. J., Cooper, M. E., Ascoli, M., Momany, A. M., McDonald, E. L., Ryckman, K. K., Rhea, L., Schaa, K. L., Cosentino, V., Gadow, E., Saleme, C., Shi, M., Hallman, M., Plunkett, J., Teramo, K. A., Muglia, L. J., Feenstra, B., Geller, F., Boyd, H. A., Melbye, M., Marazita, M. L., Dagle, J. M., Murray, J. C. 2013; 14

    Abstract

    Preterm birth (PTB) is a complex disorder associated with significant neonatal mortality and morbidity and long-term adverse health consequences. Multiple lines of evidence suggest that genetic factors play an important role in its etiology. This study was designed to identify genetic variation associated with PTB in oxytocin pathway genes whose role in parturition is well known.To identify common genetic variants predisposing to PTB, we genotyped 16 single nucleotide polymorphisms (SNPs) in the oxytocin (OXT), oxytocin receptor (OXTR), and leucyl/cystinyl aminopeptidase (LNPEP) genes in 651 case infants from the U.S. and one or both of their parents. In addition, we examined the role of rare genetic variation in susceptibility to PTB by conducting direct sequence analysis of OXTR in 1394 cases and 1112 controls from the U.S., Argentina, Denmark, and Finland. This study was further extended to maternal triads (maternal grandparents-mother of a case infant, N=309). We also performed in vitro analysis of selected rare OXTR missense variants to evaluate their functional importance.Maternal genetic effect analysis of the SNP genotype data revealed four SNPs in LNPEP that show significant association with prematurity. In our case-control sequence analysis, we detected fourteen coding variants in exon 3 of OXTR, all but four of which were found in cases only. Of the fourteen variants, three were previously unreported novel rare variants. When the sequence data from the maternal triads were analyzed using the transmission disequilibrium test, two common missense SNPs (rs4686302 and rs237902) in OXTR showed suggestive association for three gestational age subgroups. In vitro functional assays showed a significant difference in ligand binding between wild-type and two mutant receptors.Our study suggests an association between maternal common polymorphisms in LNPEP and susceptibility to PTB. Maternal OXTR missense SNPs rs4686302 and rs237902 may have gestational age-dependent effects on prematurity. Most of the OXTR rare variants identified do not appear to significantly contribute to the risk of PTB, but those shown to affect receptor function in our in vitro study warrant further investigation. Future studies with larger sample sizes are needed to confirm the findings of this study.

    View details for DOI 10.1186/1471-2350-14-77

    View details for Web of Science ID 000322794400001

    View details for PubMedID 23889750

    View details for PubMedCentralID PMC3737028

  • The Short- and Long-Term Risk of Stroke after Herpes Zoster - A Nationwide Population-Based Cohort Study PLOS ONE Sreenivasan, N., Basit, S., Wohlfahrt, J., Pasternak, B., Munch, T. N., Nielsen, L. P., Melbye, M. 2013; 8 (7)

    Abstract

    Varicella zoster virus (VZV) is known to cause VZV vasculopathy, which may be associated with stroke. A recent study found an increased risk of stroke within one year of herpes zoster. We aimed to investigate the short and long-term effects of herpes zoster on the risk of stroke.Using Danish national registers, we constructed a cohort consisting of all Danish adults ≥18 years old between 1995 and 2008 (n = 4.6 million; person-years of follow-up = 52.9 million). Individual-level information on prescriptions for herpes zoster antiviral treatment and diagnoses of stroke was obtained from national registers. We compared the risk of stroke in persons who had received the specific dosage of acyclovir for herpes zoster with persons who had never received antiviral treatment by Poisson regression.During follow-up, 2.5% received treatment for herpes zoster and 5.0% were diagnosed with stroke. Individuals who had received medication had a 127% (95% CI 83-182%) increased risk the first two weeks, 17% (CI 9-24%) between two weeks and one year, and 5% (2-9%) after the first year. The increased risk was greatest in the youngest age group (<40). To control for healthcare-seeking behaviour, we conducted parallel analyses investigating the risk of selected fractures after herpes zoster and found no similar increased risks.This large nationwide cohort study found an increased risk of stroke after treatment for herpes zoster. Although the short-term risk was particularly high, we cannot rule out the possibility of a small but important long-term risk.

    View details for DOI 10.1371/journal.pone.0069156

    View details for Web of Science ID 000322000600042

    View details for PubMedID 23874897

    View details for PubMedCentralID PMC3714240

  • Coding Variants at Hexa-allelic Amino Acid 13 of HLA-DRB1 Explain Independent SNP Associations with Follicular Lymphoma Risk AMERICAN JOURNAL OF HUMAN GENETICS Foo, J. N., Smedby, K. E., Akers, N. K., Berglund, M., Irwan, I. D., Jia, X., Li, Y., Conde, L., Darabi, H., Bracci, P. M., Melbye, M., Adami, H., Glimelius, B., Khor, C. C., Hjalgrim, H., Padyukov, L., Humphreys, K., Enblad, G., Skibola, C. F., de Bakker, P. I., Liu, J. 2013; 93 (1): 167-172

    Abstract

    Non-Hodgkin lymphoma represents a diverse group of blood malignancies, of which follicular lymphoma (FL) is a common subtype. Previous genome-wide association studies (GWASs) have identified in the human leukocyte antigen (HLA) class II region multiple independent SNPs that are significantly associated with FL risk. To dissect these signals and determine whether coding variants in HLA genes are responsible for the associations, we conducted imputation, HLA typing, and sequencing in three independent populations for a total of 689 cases and 2,446 controls. We identified a hexa-allelic amino acid polymorphism at position 13 of the HLA-DR beta chain that showed the strongest association with FL within the major histocompatibility complex (MHC) region (multiallelic p = 2.3 × 10⁻¹⁵). Out of six possible amino acids that occurred at that position within the population, we classified two as high risk (Tyr and Phe), two as low risk (Ser and Arg), and two as moderate risk (His and Gly). There was a 4.2-fold difference in risk (95% confidence interval = 2.9-6.1) between subjects carrying two alleles encoding high-risk amino acids and those carrying two alleles encoding low-risk amino acids (p = 1.01 × 10⁻¹⁴). This coding variant might explain the complex SNP associations identified by GWASs and suggests a common HLA-DR antigen-driven mechanism for the pathogenesis of FL and rheumatoid arthritis.

    View details for DOI 10.1016/j.ajhg.2013.05.020

    View details for Web of Science ID 000321804500017

    View details for PubMedID 23791106

    View details for PubMedCentralID PMC3710749

  • Pregnancy Loss and Later Risk of Atherosclerotic Disease CIRCULATION Ranthe, M. F., Andersen, E. A., Wohlfahrt, J., Bundgaard, H., Melbye, M., Boyd, H. A. 2013; 127 (17): 1775-?

    Abstract

    Pregnancy losses and atherosclerotic disease may be etiologically linked through underlying pathology. We examined whether miscarriage and stillbirth increase later risk of myocardial infarction, cerebral infarction, and renovascular hypertension.Among women pregnant at least once between 1977 and 2008, we identified a cohort of women with miscarriages, stillbirths, or live singleton births. These women were followed from the end of pregnancy for incident myocardial infarction, cerebral infarction, and renovascular hypertension. Using Poisson regression, we estimated incidence rate ratios for each of the outcomes by history of miscarriage and stillbirth. Among 1,031,279 women followed for >15,928,900 person-years, we identified 27 98 myocardial infarctions, 40 53 cerebral infarctions, and 1269 instances of renovascular hypertension. Women with stillbirths had 2.69 (95% confidence interval, 2.06-3.50), 1.74 (1.32-2.28), and 2.42 (1.59-3.69) times the rates of myocardial infarction, cerebral infarction, and renovascular hypertension, respectively, as women with no stillbirths. Compared with women with no miscarriages, women with miscarriages had 1.13 (1.03-1.24), 1.16 (1.07-1.25), and 1.20 (1.05-1.38) times the rates of these same outcomes, respectively; these associations were dose dependent, with each additional miscarriage increasing the rates of myocardial and cerebral infarction and renovascular hypertension by 9% (3% to 16%), 13% (7% to 19%), and 19% (9% to 30%), respectively. Associations were strongest in younger women (<35 years).Pregnancy losses were associated with subsequent risks of myocardial infarction, cerebral infarction, and renovascular hypertension, consistent with either shared etiology or the initiation of pathological processes by a pregnancy loss leading to atherosclerosis.

    View details for DOI 10.1161/CIRCULATIONAHA.112.000285

    View details for Web of Science ID 000318215000011

    View details for PubMedID 23536362

  • X-Chromosomal Maternal and Fetal SNPs and the Risk of Spontaneous Preterm Delivery in a Danish/Norwegian Genome-Wide Association Study PLOS ONE Myking, S., Boyd, H. A., Myhre, R., Feenstra, B., Jugessur, A., Pay, A. S., Ostensen, I. H., Morken, N., Busch, T., Ryckman, K. K., Geller, F., Magnus, P., Gjessing, H. K., Melbye, M., Jacobsson, B., Murray, J. C. 2013; 8 (4)

    Abstract

    Recent epidemiological studies suggest that the maternal genome is an important contributor to spontaneous preterm delivery (PTD). There is also a significant excess of males among preterm born infants, which may imply an X-linked mode of inheritance for a subset of cases. To explore this, we examined the effect of maternal and fetal X-chromosomal single nucleotide polymorphisms (SNPs) on the risk of PTD in two independent genome-wide association studies and one replication study.Participants were recruited from the Danish National Birth Cohort and the Norwegian Mother and Child cohort studies. Data from these two populations were first analyzed independently, and then combined in a meta-analysis. Overall, we evaluated 12,211 SNPs in 1,535 case-mother dyads and 1,487 control-mother dyads. Analyses were done using a hybrid design that combines case-mother dyads and control-mother dyads, as implemented in the Haplin statistical software package. A sex-stratified analysis was performed for the fetal SNPs. In the replication study, 10 maternal and 16 fetal SNPs were analyzed using case-parent triads from independent studies of PTD in the United States, Argentina and Denmark.In the meta-analysis, the G allele at the maternal SNP rs2747022 in the FERM domain containing 7 gene (FRMD7) increased the risk of spontaneous PTD by 1.2 (95% confidence interval (CI): 1.1, 1.4). Although an association with this SNP was confirmed in the replication study, it was no longer statistically significant after a Bonferroni correction for multiple testing.We did not find strong evidence in our data to implicate X-chromosomal SNPs in the etiology of spontaneous PTD. Although non-significant after correction for multiple testing, the mother's G allele at rs2747022 in FRMD7 increased the risk of spontaneous PTD across all populations in this study, thus warranting further investigation in other populations.

    View details for DOI 10.1371/journal.pone.0061781

    View details for Web of Science ID 000317893400107

    View details for PubMedID 23613933

    View details for PubMedCentralID PMC3628886

  • Risk of cardiovascular disease in family members of young sudden cardiac death victims EUROPEAN HEART JOURNAL Ranthe, M. F., Winkel, B. G., Andersen, E. W., Risgaard, B., Wohlfahrt, J., Bundgaard, H., Haunso, S., Melbye, M., Tfelt-Hansen, J., Boyd, H. A. 2013; 34 (7): 503-511

    Abstract

    Descriptive and genetic studies suggest that relatives of sudden cardiac death (SCD) victims have an increased risk of several cardiovascular diseases (CVDs). Given the severe consequences of undiagnosed CVD and the availability of effective treatment, the potential for prevention in this group is enormous if they do have an increased CVD risk. This nationwide prospective population-based cohort study described the risk of CVDs in relatives of young SCD victims, compared with the general population.All SCD victims aged 1-35 years in Denmark, 2000-2006, were identified (n = 470), along with their first- and second-degree relatives (n = 3073). We compared the incidence of CVD in those relatives with that in the background population using standardized incidence ratios (SIRs). The observed number of CVDs over 11 years of follow-up was 292, compared with 219 expected based on national rates [SIR 1.33, 95% confidence interval (CI) 1.19-1.50]. Risks varied significantly with age; the SIR for those <35 years was 3.53 (95% CI 2.65-4.69), compared with SIRs of 1.59 (95% CI 1.35-1.89) and 0.91 (95% CI 0.75-1.10) for those aged 35-60 years or >60 years, respectively (P(homogeneity) < 0.0001). For first-degree relatives <35 years, SIRs for ischaemic heart disease, cardiomyopathy, and ventricular arrhythmia were 5.99 (95% CI 1.95-0.13.98), 17.91 (95% CI 4.88-45.87), and 19.15 (95% CI 7.70-39.45), respectively.CVDs co-aggregated significantly with SCD in families, with young first-degree relatives at greatest risk. Results clearly indicate that family members of young SCD victims should be offered comprehensive and systematic screening, with focus on the youngest relatives.

    View details for DOI 10.1093/eurheartj/ehs350

    View details for Web of Science ID 000315673600007

    View details for PubMedID 23150455

  • New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism NATURE GENETICS Horikoshi, M., Yaghootkar, H., Mook-Kanamori, D. O., Sovio, U., Taal, H. R., Hennig, B. J., Bradfield, J. P., St Pourcain, B., Evans, D. M., Charoen, P., Kaakinen, M., Cousminer, D. L., Lehtimaki, T., Kreiner-Moller, E., Warrington, N. M., Bustamante, M., Feenstra, B., Berry, D. J., Thiering, E., Pfab, T., Barton, S. J., Shields, B. M., Kerkhof, M., van Leeuwen, E. M., Fulford, A. J., Kutalik, Z., Zhao, J. H., Den Hoed, M., Mahajan, A., Lindi, V., Goh, L., Hottenga, J., Wu, Y., Raitakari, O. T., Harder, M. N., Meirhaeghe, A., Ntalla, I., Salem, R. M., Jameson, K. A., Zhou, K., Monies, D. M., Lagou, V., Kirin, M., Heikkinen, J., Adair, L. S., Alkuraya, F. S., Al-Odaib, A., Amouyel, P., Andersson, E. A., Bennett, A. J., Blakemore, A. I., Buxton, J. L., Dallongeville, J., Das, S., de Geus, E. J., Estivill, X., Flexeder, C., Froguel, P., Geller, F., Godfrey, K. M., Gottrand, F., Groves, C. J., Hansen, T., Hirschhorn, J. N., Hofman, A., Hollegaard, M. V., Hougaard, D. M., Hyppoenen, E., Inskip, H. M., Isaacs, A., Jorgensen, T., Kanaka-Gantenbein, C., Kemp, J. P., Kiess, W., Kilpelainen, T. O., Klopp, N., Knight, B. A., Kuzawa, C. W., McMahon, G., Newnham, J. P., Niinikoski, H., Oostra, B. A., Pedersen, L., Postma, D. S., Ring, S. M., Rivadeneira, F., Robertson, N. R., Sebert, S., Simell, O., Slowinski, T., Tiesler, C. M., Toenjes, A., Vaag, A., Viikari, J. S., Vink, J. M., Vissing, N. H., Wareham, N. J., Willemsen, G., Witte, D. R., Zhang, H., Zhao, J., Wilson, J. F., Stumvoll, M., Prentice, A. M., Meyer, B. F., Pearson, E. R., Boreham, C. A., Cooper, C., Gillman, M. W., Dedoussis, G. V., Moreno, L. A., Pedersen, O., Saarinen, M., Mohlke, K. L., Boomsma, D. I., Saw, S., Lakka, T. A., Koerner, A., Loos, R. J., Ong, K. K., Vollenweider, P., van Duijn, C. M., Koppelman, G. H., Hattersley, A. T., Holloway, J. W., Hocher, B., Heinrich, J., Power, C., Melbye, M., Guxens, M., Pennell, C. E., Bonnelykke, K., Bisgaard, H., Eriksson, J. G., Widen, E., Hakonarson, H., Uitterlinden, A. G., Pouta, A., Lawlor, D. A., Smith, G. D., Frayling, T. M., McCarthy, M. I., Grant, S. F., Jaddoe, V. W., Jarvelin, M., Timpson, N. J., Prokopenko, I., Freathy, R. M. 2013; 45 (1): 76-U115

    Abstract

    Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.

    View details for DOI 10.1038/ng.2477

    View details for Web of Science ID 000312838800016

    View details for PubMedID 23202124

    View details for PubMedCentralID PMC3605762

  • Breast cancer in women using digoxin: tumor characteristics and relapse risk BREAST CANCER RESEARCH Biggar, R. J., Andersen, E. W., Kroman, N., Wohlfahrt, J., Melbye, M. 2013; 15 (1)

    Abstract

    Digoxin use is associated with increased incidence of breast and uterus cancers. We postulated that digoxin use might affect tumor characteristics and increase relapse risk in women with breast cancer.Incident breast cancer cases in Danish women (n = 49,312; 1995 to 2008) were identified. Analyses were conducted in women 20 to 74 years old. Relapse hazard ratios (HR) were compared in women using and not using digoxin, adjusting for age, calendar period, protocol, tumor size, nodal involvement, histology grade, estrogen-receptor (ER) status, and anti-estrogen therapy in Cox regression models.At diagnosis, tumors in digoxin users were more likely ER+ (85.4% vs. 78.6%: P = 0.002) and have grade 1 ductal histology (37.2% vs. 25.7%; P = 0.004), compared to non-users. 45 relapses occurred in women already using digoxin at breast cancer diagnosis (1,487 person-years); 24 relapses occurred in women later starting digoxin (384 person-years). Overall relapse risk HR in digoxin users was 1.13 (95% confidence interval: 0.88, 1.46) compared to non-users. Relapse risk in digoxin users was significantly increased in the first year (2.19; 1.26, 3.78) but not thereafter (0.99; 0.74, 1.32) (P = 0.02 for difference in HRs). First-year relapse hazard was high in digoxin-using women with ER+ tumors (2.51; 1.39, 4.55) but not ER- tumors (0.72; 0.10, 5.27). Recurrence hazard was not significantly changed among digoxin-using women also using tamoxifen.Breast cancers arising in digoxin-using women had better prognostic features. After adjustment for markers, overall breast cancer relapse risk in digoxin users was not increased significantly, although recurrence hazards for ER+ tumors were higher in the first year following diagnosis.

    View details for DOI 10.1186/bcr3386

    View details for Web of Science ID 000320158100022

    View details for PubMedID 23421975

    View details for PubMedCentralID PMC3672748

  • Association of maternal CNVs in GSTT1/GSTT2 with smoking, preterm delivery, and low birth weight. Frontiers in genetics Zheng, X., Feingold, E., Ryckman, K. K., Shaffer, J. R., Boyd, H. A., Feenstra, B., Melbye, M., Marazita, M. L., Murray, J. C., Cuenco, K. T. 2013; 4: 196-?

    Abstract

    Preterm delivery (PTD) is an adverse birth outcome associated with increased infant mortality and negative lifelong health consequences. PTD may be the result of interactions between genetics and maternal/fetal environmental factors including smoking exposure (SMK). A common deletion in the GSTT1 gene was previously reported to affect birth outcomes in smokers. In this study, we dissect the associations among SMK, birth outcomes, and copy number variations (CNVs) in the GSTT1/GSTT2 region. A preterm birth case-control dataset of 1937 mothers was part of the GENEVA preterm birth study, which included genome-wide genotyping used to identify CNVs. We examined the association of SMK with birth outcomes, detected CNVs within the GSTT1/GSTT2 region using PennCNV, and examined associations of the identified CNVs with preterm birth and with birth weight (BW) in full term birth controls, including interactions with SMK. Finally, we tested the association of CNVs in GSTT1/GSTT2 with SMK. We confirmed the association of smoking with low BW and PTD. We identified 2 CNVs in GSTT2 (GSTT2 (a) and GSTT2 (b) ), 1 CNV in GSTTP1 and 2 CNVs in GSTT1 (GSTT1 (a) and GSTT1 (b) ). The GSTT2 (a) deletion was associated with reduced BW (-284 g, p = 2.50E-7) in smokers, and was more common in smokers [odds ratio(OR) = 1.30, p = 0.04]. We found that the size of the reported common deletion CNV in GSTT1 was larger than previously shown. The GSTTP1 and GSTT1 (b) null genotypes were in high linkage disequilibrium (LD) (D' = 0.89) and less common in smokers (OR = 0.68, p = 0.019 and OR = 0.73, p = 0.055, respectively). These two deletions were in partial LD with GSTT2 (a) and GSTT2 (b) duplications. All 5 CNVs seem to be associated with increased risk of preterm birth before 35 completed weeks. CNVs in the GSTTT1/GSTT2 region appear associated with low BW and PTD outcomes, but LD complicated these CNVs in GSTT1/GSTT2. In genetic association studies of BW, multiple CNVs in this region need to be investigated instead of a single polymorphism.

    View details for DOI 10.3389/fgene.2013.00196

    View details for PubMedID 24194744

    View details for PubMedCentralID PMC3809558

  • Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5CHRNA3CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight HUMAN MOLECULAR GENETICS Tyrrell, J., Huikari, V., Christie, J. T., Cavadino, A., Bakker, R., Brion, M. A., Geller, F., Paternoster, L., Myhre, R., Potter, C., Johnson, P. C., Ebrahim, S., Feenstra, B., Hartikainen, A., Hattersley, A. T., Hofman, A., Kaakinen, M., Lowe, L. P., Magnus, P., McConnachie, A., Melbye, M., Ng, J. W., Nohr, E. A., Power, C., Ring, S. M., Sebert, S. P., Sengpiel, V., Taal, H. R., Watt, G. C., Sattar, N., Relton, C. L., Jacobsson, B., Frayling, T. M., Srensen, T. I., Murray, J. C., Lawlor, D. A., Pennell, C. E., Jaddoe, V. W., Hypponen, E., Lowe, W. L., Jarvelin, M., Smith, G. D., Freathy, R. M. 2012; 21 (24): 5344-5358

    View details for DOI 10.1093/hmg/dds372

    View details for Web of Science ID 000311965600010

  • Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight. Human molecular genetics Tyrrell, J., Huikari, V., Christie, J. T., Cavadino, A., Bakker, R., Brion, M. A., Geller, F., Paternoster, L., Myhre, R., Potter, C., Johnson, P. C., Ebrahim, S., Feenstra, B., Hartikainen, A., Hattersley, A. T., Hofman, A., Kaakinen, M., Lowe, L. P., Magnus, P., McConnachie, A., Melbye, M., Ng, J. W., Nohr, E. A., Power, C., Ring, S. M., Sebert, S. P., Sengpiel, V., Taal, H. R., Watt, G. C., Sattar, N., Relton, C. L., Jacobsson, B., Frayling, T. M., Sørensen, T. I., Murray, J. C., Lawlor, D. A., Pennell, C. E., Jaddoe, V. W., Hypponen, E., Lowe, W. L., Jarvelin, M., Davey Smith, G., Freathy, R. M. 2012; 21 (24): 5344-5358

    Abstract

    Maternal smoking during pregnancy is associated with low birth weight. Common variation at rs1051730 is robustly associated with smoking quantity and was recently shown to influence smoking cessation during pregnancy, but its influence on birth weight is not clear. We aimed to investigate the association between this variant and birth weight of term, singleton offspring in a well-powered meta-analysis. We stratified 26 241 European origin study participants by smoking status (women who smoked during pregnancy versus women who did not smoke during pregnancy) and, in each stratum, analysed the association between maternal rs1051730 genotype and offspring birth weight. There was evidence of interaction between genotype and smoking (P = 0.007). In women who smoked during pregnancy, each additional smoking-related T-allele was associated with a 20 g [95% confidence interval (95% CI): 4-36 g] lower birth weight (P = 0.014). However, in women who did not smoke during pregnancy, the effect size estimate was 5 g per T-allele (95% CI: -4 to 14 g; P = 0.268). To conclude, smoking status during pregnancy modifies the association between maternal rs1051730 genotype and offspring birth weight. This strengthens the evidence that smoking during pregnancy is causally related to lower offspring birth weight and suggests that population interventions that effectively reduce smoking in pregnant women would result in a reduced prevalence of low birth weight.

    View details for DOI 10.1093/hmg/dds372

    View details for PubMedID 22956269

    View details for PubMedCentralID PMC3516066

  • Self-reported history of infections and the risk of non-Hodgkin lymphoma: An InterLymph pooled analysis INTERNATIONAL JOURNAL OF CANCER Becker, N., Falster, M. O., Vajdic, C. M., de Sanjose, S., Martinez-Maza, O., Bracci, P. M., Melbye, M., Smedby, K. E., Engels, E. A., Turner, J., Vineis, P., Costantini, A. S., Holly, E. A., Spinelli, J. J., La Vecchia, C., Zheng, T., Chiu, B. C., Montella, M., Cocco, P., Maynadie, M., Foretova, L., Staines, A., Brennan, P., Davis, S., Severson, R., Cerhan, J. R., Breen, E. C., Birmann, B., Cozen, W., Grulich, A. E., Newton, R. 2012; 131 (10): 2342-2348

    Abstract

    We performed a pooled analysis of data on self-reported history of infections in relation to the risk of non-Hodgkin lymphoma (NHL) from 17 case-control studies that included 12,585 cases and 15,416 controls aged 16-96 years at recruitment. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were estimated in two-stage random-effect or joint fixed-effect models, adjusting for age, sex and study centre. Data from the 2 years before diagnosis (or date of interview for controls) were excluded. A self-reported history of infectious mononucleosis was associated with an excess risk of NHL (OR = 1.26, 95% CI = 1.01-1.57 based on data from 16 studies); study-specific results indicate significant (I(2) = 51%, p = 0.01) heterogeneity. A self-reported history of measles or whooping cough was associated with an approximate 15% reduction in risk. History of other infection was not associated with NHL. We find little clear evidence of an association between NHL risk and infection although the limitations of data based on self-reported medical history (particularly of childhood illness reported by older people) are well recognized.

    View details for DOI 10.1002/ijc.27438

    View details for Web of Science ID 000309185300015

    View details for PubMedID 22266776

    View details for PubMedCentralID PMC3406230

  • Parvovirus B19 Infection in the First Trimester of Pregnancy and Risk of Fetal Loss: A Population-based Case-Control Study AMERICAN JOURNAL OF EPIDEMIOLOGY Lassen, J., Jensen, A. K., Bager, P., Pedersen, C. B., Panum, I., Norgaard-Pedersen, B., Aaby, P., Wohlfahrt, J., Melbye, M. 2012; 176 (9): 803-807

    Abstract

    Because parvovirus B19 infection during pregnancy has been associated with increased risk of fetal loss in small or selected study populations, the authors evaluated the risk in a population-based study. A nested case-control study was conducted by using a population-based screening for syphilis in 3 regions in Denmark from 1992 to 1994. Cases of women with fetal loss were identified in the National Patient Register (n = 2,918), and control women with live-born children were identified in the Medical Birth Register (n = 8,429) by matching on age and sampling week. First-trimester serum samples were tested for parvovirus B19 immunoglobulin M positivity. Parvovirus B19 immunoglobulin M positivity was associated with a 71% increased risk of fetal loss (odds ratio = 1.71, 95% confidence interval: 1.02, 2.86). Adjustment for number of children or stratifying for gestational age at loss did not change the risk estimate. Assuming causality, only 0.1% of fetal losses were attributable to parvovirus B19 positivity, a proportion which could increase to approximately 1% during epidemic periods. In conclusion, acute parvovirus B19 infection during the first trimester of pregnancy was associated with an increased risk of fetal loss. However, the impact on the overall burden of fetal losses appeared small even during epidemics.

    View details for DOI 10.1093/aje/kws177

    View details for Web of Science ID 000310371200008

    View details for PubMedID 23051601

  • No observed association for mitochondrial SNPs with preterm delivery and related outcomes PEDIATRIC RESEARCH Alleman, B. W., Myking, S., Ryckman, K. K., Myhre, R., Feingold, E., Feenstra, B., Geller, F., Boyd, H. A., Shaffer, J. R., Zhang, Q., Begum, F., Crosslin, D., Doheny, K., Pugh, E., Pay, A. S., Ostensen, I. H., Morken, N., Magnus, P., Marazita, M. L., Jacobsson, B., Melbye, M., Murray, J. C. 2012; 72 (5): 539-544

    Abstract

    Preterm delivery (PTD) is the leading cause of neonatal morbidity and mortality. Epidemiologic studies indicate recurrence of PTD is maternally inherited, creating a strong possibility that mitochondrial variants contribute to its etiology. This study examines the association between mitochondrial genotypes and PTD and related outcomes.This study combined, through meta-analysis, two case-control, genome-wide association studies: one from the Danish National Birth Cohort Study and one from the Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health. The outcomes of PTD (≤36 wk), very PTD (≤32 wk), and preterm prelabor rupture of membranes (PPROM) were examined. A total of 135 individual single-nucleotide polymorphism (SNP) associations were tested using the combined genome from mothers and neonates (case vs. control) in each population and then pooled via meta-analysis.After meta-analysis, there were four SNPs for the outcome of PTD below P ≤ 0.10 and two below P ≤ 0.05. For the additional outcomes of very PTD and PPROM, there were three and four SNPs, respectively, below P ≤ 0.10.Given the number of tests, no single SNP reached study-wide significance (P = 0.0006). Our study does not support the hypothesis that mitochondrial genetics contributes to the maternal transmission of PTD and related outcomes.

    View details for DOI 10.1038/pr.2012.112

    View details for Web of Science ID 000311771000014

    View details for PubMedID 22902432

    View details for PubMedCentralID PMC3694399

  • Trichuris suis ova therapy for allergic rhinitis does not affect allergen-specific cytokine responses despite a parasite-specific cytokine response CLINICAL AND EXPERIMENTAL ALLERGY Bourke, C. D., Mutapi, F., Nausch, N., Photiou, D. M., Poulsen, L. K., Kristensen, B., Arnved, J., Ronborg, S., Roepstorff, A., Thamsborg, S., Kapel, C., Melbye, M., Bager, P. 2012; 42 (11): 1582-1595

    Abstract

    Parasitic helminths have been shown to reduce inflammation in most experimental models of allergic disease, and this effect is mediated via cytokine responses. However, in humans, the effects of controlled helminth infection on cytokine responses during allergy have not been studied.The aim was to investigate whether infection with the nematode parasite Trichuris suis alters systemic cytokine levels, cellular cytokine responses to parasite antigens and pollen allergens and/or the cytokine profile of allergic individuals.In a randomized double-blinded placebo-controlled clinical trial (UMIN trial registry, Registration no. R000001298, Trial ID UMIN000001070, URL: http://www.umin.ac.jp/map/english), adults with grass pollen-induced allergic rhinitis received three weekly doses of 2500 Trichuris suis ova (n = 45) or placebo (n = 44) over 6 months. IFN-γ, TNF-α, IL-4, IL-5, IL-10 and IL-13 were quantified via cytometric bead array in plasma. Cytokines, including active TGF-β, were also quantified in supernatants from peripheral blood mononuclear cells cultured with parasite antigens or pollen allergens before, during and after the grass pollen season for a sub-cohort of randomized participants (T. suis ova-treated, n = 12, Placebo-treated, n = 10).Helminth infection induced a Th2-polarized cytokine response comprising elevated plasma IL-5 and parasite-specific IL-4, IL-5 and IL-13, and a global shift in the profile of systemic cytokine responses. Infection also elicited high levels of the regulatory cytokine IL-10 in response to T. suis antigens. Despite increased production of T. suis-specific cytokines in T. suis ova-treated participants, allergen-specific cytokine responses during the grass pollen season and the global profile of PBMC cytokine responses were not affected by T. suis ova treatment.This study suggests that cytokines induced by Trichuris suis ova treatment do not alter allergic reactivity to pollen during the peak of allergic rhinitis symptoms.

    View details for DOI 10.1111/j.1365-2222.2012.04063.x

    View details for Web of Science ID 000310482700007

    View details for PubMedID 23106658

  • Antibiotic use and risk of non-hodgkin lymphomas INTERNATIONAL JOURNAL OF CANCER Rasmussen, M. H., Hjalgrim, H., Molgaard-Nielsen, D., Wohlfahrt, J., Melbye, M. 2012; 131 (7): E1158-E1165

    Abstract

    Clinical case reports have suggested that specific bacterial infections are associated with certain non-Hodgkin lymphoma (NHL) subtypes. Epidemiological case-control studies have been conducted using antibiotics as a proxy for bacterial infections, but with inconclusive results. The aim of this study was, in a cohort design, based on the unique nationwide Danish registers, to investigate the association between use of antibiotics and the risk of NHL subtypes. On the basis of the Civil Registration System, we established a cohort of the entire adult (≥ 15 years) Danish population. Information on use of antibiotics came from the Danish Drug Prescription Registry and lymphoma diagnosis from the Danish Cancer Registry. Associations were assessed by adjusted rate ratios (RRs). In total, 13,602 patients were diagnosed with one of the NHL subtypes during 51.6 million person-years of follow-up (1995-2008). We observed positive associations between use of antibiotics and plasma cell myeloma [RR = 1.11, 95% confidence intervals (CIs) = 1.00-1.24], chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (RR = 1.32, 95% CI = 1.20-1.45), mantle cell lymphoma (MCL) (RR = 1.40, 95% CI = 1.04-1.88) and anaplastic large T-cell lymphoma (ALCL) (RR = 1.83, 95% CI = 1.00-3.36). Among these, the increased risk of CLL/SLL, MCL and ALCL, respectively, did not vary by years since use, and only the risk of CLL/SLL risk differed by number of prescriptions. While causality could not be established in our study, an intriguing positive long-term association between antibiotic use and CLL/SLL risk was observed. To what extent these findings indicate a role for bacteria in lymphoma pathogenesis requires further investigation.

    View details for DOI 10.1002/ijc.27626

    View details for Web of Science ID 000306915700011

    View details for PubMedID 22552810

  • Bottle-feeding and the Risk of Pyloric Stenosis PEDIATRICS Krogh, C., Biggar, R. J., Fischer, T. K., Lindholm, M., Wohlfahrt, J., Melbye, M. 2012; 130 (4): E943-E949

    Abstract

    Bottle-feeding has been suggested to increase the risk of pyloric stenosis (PS). However, large population-based studies are needed. We examined the effect of bottle-feeding during the first 4 months after birth, by using detailed data about the timing of first exposure to bottle-feeding and extensive confounder information.We performed a large population-based cohort study based on the Danish National Birth Cohort, which provided information on infants and feeding practice. Information about surgery for PS was obtained from the Danish National Patient Register. The association between bottle-feeding and the risk of PS was evaluated by hazard ratios (HRs) estimated in a Cox regression model, adjusting for possible confounders.Among 70148 singleton infants, 65 infants had surgery for PS, of which 29 were bottle-fed before PS diagnosis. The overall HR of PS for bottle-fed infants compared with not bottle-fed infants was 4.62 (95% confidence interval [CI]: 2.78-7.65). Among bottle-fed infants, risk increases were similar for infants both breast and bottle-fed (HR: 3.36 [95% CI: 1.60-7.03]), formerly breastfed (HR: 5.38 [95% CI: 2.88-10.06]), and never breastfed (HR: 6.32 [95% CI: 2.45-16.26]) (P = .76). The increased risk of PS among bottle-fed infants was observed even after 30 days since first exposure to bottle-feeding and did not vary with age at first exposure to bottle-feeding.Bottle-fed infants experienced a 4.6-fold higher risk of PS compared with infants who were not bottle-fed. The result adds to the evidence supporting the advantage of exclusive breastfeeding in the first months after birth.

    View details for DOI 10.1542/peds.2011-2785

    View details for Web of Science ID 000309412100021

    View details for PubMedID 22945411

    View details for PubMedCentralID PMC3457615

  • Familial Aggregation of Lone Atrial Fibrillation in Young Persons JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Oyen, N., Ranthe, M. F., Carstensen, L., Boyd, H. A., Olesen, M. S., Olesen, S., Wohlfahrt, J., Melbye, M. 2012; 60 (10): 917-921

    Abstract

    This study investigated whether an individual's risk of developing lone atrial fibrillation (AF) before age 60 years is associated with lone AF in relatives.Genetic factors may play a role in the development of lone AF.Using Danish national registers, a cohort was established of ~4 million persons born between 1950 and 2008, and those with a family history of lone AF (AF without preceding cardiovascular/endocrine diagnoses) were identified. Individuals were followed up until the first diagnosis of lone AF. Poisson regression was used to estimate incidence rate ratios (IRRs).In ~92 million person-years of follow-up, 9,507 persons were identified as having lone AF. The IRRs for lone AF given an affected first- or second-degree relative were 3.48 (95% confidence interval [CI]: 3.08 to 3.93) and 1.64 (95% CI: 1.04 to 2.59), respectively. IRRs were higher for men than for women but were not associated with the affected relative's sex. IRR for lone AF was 6.24 (95% CI: 2.59 to 15.0), given at least 2 first-degree relatives affected with lone AF. The IRR for lone AF in persons aged <40 years given a first-degree relative affected at age <40 years was 5.42 (95% CI: 3.80 to 7.72), and 8.53 (95% CI: 3.82 to 19.0) in persons age <30 years given a first-degree relative affected at age <30 years.A family history of lone AF is associated with substantial risk of lone AF, with the strongest risks associated with young age at onset, multiple affected relatives, and in first-degree relatives. These results suggest routine evaluation of the families of at least certain types of patients with lone AF.

    View details for DOI 10.1016/j.jacc.2012.03.046

    View details for Web of Science ID 000308425000009

    View details for PubMedID 22726627

  • Family History of Premature Death and Risk of Early Onset Cardiovascular Disease JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Ranthe, M. F., Carstensen, L., Oyen, N., Tfelt-Hansen, J., Christiansen, M., Mckenna, W. J., Wohlfahrt, J., Melbye, M., Boyd, H. A. 2012; 60 (9): 814-821

    Abstract

    The purpose of this study was to examine the effect of a family history of premature death, cardiovascular death in particular, on the risk of early cardiovascular disease.Studies suggest that fatal cardiovascular events and less severe cardiovascular diseases may co-occur in families. Consequently, a family history of premature death may indicate a familial cardiac frailty that predisposes to early cardiovascular disease.We ascertained family history of premature death (age <60 years) in all individuals born in Denmark from 1950 to 2008 and followed this cohort for early cardiovascular disease (age <50 years). Using Poisson regression, we estimated incidence rate ratios (IRRs) reflecting the effect of premature death in the family on early cardiovascular disease risk.Among 3,985,301 persons followed up for 89,294,258 person-years, 129,825, 31,172, and 5,214 were diagnosed with any early cardiovascular disease, ischemic heart disease, and ventricular arrhythmia, respectively. IRRs for these conditions given a history of premature cardiovascular death in first-degree relatives were 1.72 (95% confidence interval [CI]: 1.68 to 1.77), 2.21 (95% CI: 2.11 to 2.31), and 1.94 (95% CI: 1.70 to 2.20), respectively. With ≥2 cardiovascular deaths in a family, corresponding IRRs were 3.30 (95% CI: 2.77 to 3.94), 5.00 (95% CI: 3.87 to 6.45), and 6.18 (95% CI: 3.32 to 11.50). The IRR for any early cardiovascular disease given a family history of premature noncardiovascular death was significantly lower, 1.12 (95% CI: 1.10 to 1.14) (p(cardiac vs. noncardiac) < 0.0001).Family history of premature cardiovascular death was consistently and significantly associated with a risk of early cardiovascular disease, suggesting an inherited cardiac vulnerability. These results should be kept in mind when assessing cardiovascular disease risk in persons with a family history of premature cardiovascular death.

    View details for DOI 10.1016/j.jacc.2012.06.018

    View details for Web of Science ID 000308137600006

    View details for PubMedID 22917005

  • Increased Genetic Vulnerability to Smoking at CHRNA5 in Early-Onset Smokers ARCHIVES OF GENERAL PSYCHIATRY Hartz, S. M., Short, S. E., Saccone, N. L., Culverhouse, R., Chen, L., Schwantes-An, T., Coon, H., Han, Y., Stephens, S. H., Sun, J., Chen, X., Ducci, F., Dueker, N., Franceschini, N., Frank, J., Geller, F., Guobjartsson, D., Hansel, N. N., Jiang, C., Keskitalo-Vuokko, K., Liu, Z., Lyytikainen, L., Michel, M., Rawal, R., Hum, S., Rosenberger, A., Scheet, P., Shaffer, J. R., Teumer, A., Thompson, J. R., Vink, J. M., Vogelzangs, N., Wenzlaff, A. S., Wheeler, W., Xiao, X., Yang, B., Aggen, S. H., Balmforth, A. J., Baumeister, S. E., Beaty, T., Bennett, S., Bergen, A. W., Boyd, H. A., Broms, U., Campbell, H., Chatterjee, N., Chen, J., Cheng, Y., Cichon, S., Couper, D., Cucca, F., Dick, D. M., Foroud, T., Furberg, H., Giegling, I., Gu, F., Hall, A. S., Hallfors, J., Han, S., Hartmann, A. M., Hayward, C., Heikkila, K., Hewitt, J. K., Hottenga, J. J., Jensen, M. K., Jousilahti, P., Kaakinen, M., Kittner, S. J., Konte, B., Korhonen, T., Landi, M., Laatikainen, T., Leppert, M., Levy, S. M., Mathias, R. A., McNeil, D. W., Medland, S. E., Montgomery, G. W., Muley, T., Murray, T., Nauck, M., North, K., Pergadia, M., Polasek, O., Ramos, E. M., Ripatti, S., Risch, A., Ruczinski, I., Rudan, I., Salomaa, V., Schlessinger, D., Styrkarsdottir, U., Terracciano, A., Uda, M., Willemsen, G., Wu, X., Abecasis, G., Barnes, K., Bickeboeller, H., Boerwinkle, E., Boomsma, D. I., Caporaso, N., Duan, J., Edenberg, H. J., Francks, C., Gejman, P. V., Gelernter, J., Grabe, H. J., Hops, H., Jarvelin, M., Viikari, J., Kahonen, M., Kendler, K. S., Lehtimaki, T., Levinson, D. F., Marazita, M. L., Marchini, J., Melbye, M., Mitchell, B. D., Murray, J. C., Nothen, M. M., Penninx, B. W., Raitakari, O., Rietschel, M., Rujescu, D., Samani, N. J., Sanders, A. R., Schwartz, A. G., Shete, S., Shi, J., Spitz, M., Stefansson, K., Swan, G. E., Thorgeirsson, T., Volzke, H., Wei, Q., Wichmann, H., Amos, C. I., Breslau, N., Cannon, D. S., Ehringer, M., Grucza, R., Hatsukami, D., Heath, A., Johnson, E. O., Kaprio, J., Madden, P., Martin, N. G., Stevens, V. L., Stitzel, J. A., Weiss, R. B., Kraft, P., Bierut, L. J. 2012; 69 (8): 854-861

    Abstract

    Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968.To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking.Primary data.Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy.Uniform statistical analysis scripts were run locally. Starting with 94,050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33,348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum.Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13,843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19,505) (P = .01).These results highlight an increased genetic vulnerability to smoking in early-onset smokers.

    View details for DOI 10.1001/archgenpsychiatry.2012.124

    View details for Web of Science ID 000307185000011

    View details for PubMedID 22868939

    View details for PubMedCentralID PMC3482121

  • Digoxin use and the risk of cancers of the corpus uteri, ovary and cervix INTERNATIONAL JOURNAL OF CANCER Biggar, R. J., Wohlfahrt, J., Melbye, M. 2012; 131 (3): 716-721

    Abstract

    Digoxin is a phyto-estrogen capable of inducing hormonal effects. Use has been associated with increased risk of breast cancer, an estrogen-sensitive malignancy. The incidence of corpus uteri (uterus) cancer is also strongly increased with exposure to estrogens. Therefore, we evaluated whether digoxin use might also increase its incidence. In all women in Denmark, we identified digoxin users from 1995 through 2008 using a nationwide pharmacy registry system. Cancer occurrence was obtained from Danish Cancer Registry. Relative risk was determined using incidence risk ratios (RR) and 95% confidence intervals (CIs) relative to non-users after adjustment for age- and calendar-time. For ovarian and cervical cancers, RRs in users and non-users were similarly evaluated, these cancers representing gynecological cancers with weak or no associations to estrogen exposure. Of 2.1 million women, 104,648 (4.9%) had digoxin exposure and 137,493 6.5% had exposure to angina drugs but not digoxin during the study period. For uterus cancer, the RR was increased in current digoxin users (1.48, 95% CI: 1.32-1.65; N = 350). Incidence was marginally increased in former users. For ovary and cervix cancers, RRs in current digoxin users were 1.06 (95% CI: 0.92-1.22; N = 207) and 1.00 (95% CI: 0.79-1.25; N = 81), respectively. We examined risks in women using angina drugs but not digoxin to determine whether being under cardiac care affected risk. Among women using angina drugs only, RRs for uterus, ovary or cervix cancers were not statistically significant. We conclude that women currently using digoxin, a phyto-estrogen, have an increased risk of developing uterus cancers.

    View details for DOI 10.1002/ijc.26424

    View details for Web of Science ID 000304440100038

    View details for PubMedID 21913187

  • Use of amiloride and multiple sclerosis: registry-based cohort studies PHARMACOEPIDEMIOLOGY AND DRUG SAFETY Pasternak, B., Svanstrom, H., Nielsen, N. M., Melbye, M., Hviid, A. 2012; 21 (8): 890-895

    Abstract

    Amiloride reduces functional neurological deficits and neuronal damage in animal models of multiple sclerosis (MS). We investigated whether amiloride use was associated with reduced risk of incident MS and of MS hospitalization and death in humans.We conducted two propensity score-matched cohort studies, linking nationwide registry data on filled drug prescriptions, diagnostic information, and covariates. First, we compared rates of incident MS in new users of amiloride and new users of an active control treatment, thiazide diuretics. Second, rates of hospitalizations for MS and of death were compared between users of amiloride and thiazides in a cohort of MS patients. Treatment groups were matched 1 : 4 on propensity scores that included a wide range of covariates, and Cox regression was used to estimate hazard ratios (HRs).Comparing 36 659 users of amiloride and 177 031 users of thiazides, there were 19 cases of incident MS during 92 548 person-years of follow-up among amiloride users and 81 cases during 567 599 person-years of follow-up among thiazide users. There was no significantly decreased risk of MS associated with amiloride use (HR 1.34, 95%CI 0.81-2.20). In the cohort of MS patients, amiloride use was not associated with significantly decreased risk of MS hospitalization (HR 1.11, 95%CI 0.79-1.59) or death (HR 1.38, 95%CI 0.83-2.28).Amiloride use was not associated with significantly decreased risk of incident MS or hospitalizations and death among patients with MS. Because amiloride users were represented by older patients, risks could not be evaluated in younger individuals.

    View details for DOI 10.1002/pds.3269

    View details for Web of Science ID 000306895200013

    View details for PubMedID 22555991

  • Familial aggregation of congenital hydrocephalus in a nationwide cohort BRAIN Munch, T. N., Rostgaard, K., Rasmussen, M. H., Wohlfahrt, J., Juhler, M., Melbye, M. 2012; 135: 2409-2415

    Abstract

    The objective of the study was to investigate familial aggregation of primary congenital hydrocephalus in an unselected, nationwide population. Based on the Danish Central Person Register, we identified all children born in Denmark between 1978 and 2008 and their family members (up to third-degree relatives). Information on primary congenital hydrocephalus was obtained from the National Patient Discharge Register. Using binomial log-linear regression, we estimated recurrence risk ratios of congenital hydrocephalus. An alternative log-linear regression model was applied to quantify the genetic effect and the maternal effect. Of 1 928 683 live-born children, 2194 had a diagnosis of idiopathic congenital hydrocephalus (1.1/1000). Of those, 75 (3.4%) had at least one other family member with primary congenital hydrocephalus. Significantly increased recurrence risk ratios of primary congenital hydrocephalus were observed for same-sex twins, first- and second-degree relatives as follows: 34.8 (95% confidence interval: 16.4-74.0), 6.2 (95% confidence interval 4.3-8.9) and 2.2 (95% confidence interval 1.6-3.1), respectively. Recurrence risk ratio for third-degree relatives was 1.5 (95% confidence interval 0.8-2.7). A maternal component was supported by the facts that recurrence risk ratios for opposite-sex twins (37.3, 95% confidence interval 11.9-116.7) were significantly higher than other first-degree relatives and that recurrence risk ratios for maternal half-siblings (8.4, 95% confidence interval 3.7-18.7) were significantly higher than for paternal half-siblings (3.0, 95% confidence interval 0.8-12.2). This population-based study found strong evidence of familial aggregation of primary congenital hydrocephalus, which supports the existence of a genetic component to the aetiology. In addition, the pattern of association suggests that a strong maternal component contributes to the familial aggregation.

    View details for DOI 10.1093/brain/aws158

    View details for Web of Science ID 000307170300020

    View details for PubMedID 22763745

  • Risk of Adverse Fetal Outcomes Following Administration of a Pandemic Influenza A(H1N1) Vaccine During Pregnancy JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Pasternak, B., Svanstrom, H., Molgaard-Nielsen, D., Krause, T. G., Emborg, H., Melbye, M., Hviid, A. 2012; 308 (2): 165-174

    Abstract

    Assessment of the fetal safety of vaccination against influenza A(H1N1)pdm09 in pregnancy has been limited.To investigate whether exposure to an adjuvanted influenza A(H1N1)pdm09 vaccine during pregnancy was associated with increased risk of adverse fetal outcomes.Registry-based cohort study based on all liveborn singleton infants in Denmark, delivered between November 2, 2009, and September 30, 2010. In propensity score-matched analyses, we estimated prevalence odds ratios (PORs) of adverse fetal outcomes, comparing infants exposed and unexposed to an AS03-adjuvanted influenza A(H1N1)pdm09 vaccine during pregnancy.Major birth defects, preterm birth, and small size for gestational age.From a cohort of 53,432 infants (6989 [13.1%] exposed to the influenza A[H1N1]pdm09 vaccine during pregnancy [345 in the first trimester and 6644 in the second or third trimester]), 660 (330 exposed) were included in propensity score-matched analyses of adverse fetal outcomes associated with first-trimester exposure. For analysis of small size for gestational age after second- or third-trimester exposure, 13,284 (6642 exposed) were included; for analyses of preterm birth, 12,909 (6543 exposed) were included. A major birth defect was diagnosed in 18 of 330 infants (5.5%) exposed to the vaccine in the first trimester, compared with 15 of 330 unexposed infants (4.5%) (POR, 1.21; 95% CI, 0.60-2.45). Preterm birth occurred in 31 of 330 infants (9.4%) exposed in the first trimester, compared with 24 of 330 unexposed infants (7.3%) (POR, 1.32; 95% CI, 0.76-2.31), and in 302 of 6543 infants (4.6%) with second- or third-trimester exposure, compared with 295 of 6366 unexposed infants (4.6%) (POR, 1.00; 95% CI, 0.84-1.17). Small size for gestational age was observed in 25 of 330 infants (7.6%) with first-trimester exposure compared with 31 of 330 unexposed infants (9.4%) (POR, 0.79; 95% CI, 0.46-1.37), and in 641 of 6642 infants (9.7%) with second- or third-trimester exposure, compared with 657 of 6642 unexposed infants (9.9%) (POR, 0.97; 95% CI, 0.87-1.09).In this Danish cohort, exposure to an adjuvanted influenza A(H1N1)pdm09 vaccine during pregnancy was not associated with a significantly increased risk of major birth defects, preterm birth, or fetal growth restriction.

    View details for DOI 10.1001/jama.2012.6131

    View details for Web of Science ID 000306219500030

    View details for PubMedID 22782418

  • Pre- and Perinatal Risk Factors for Pyloric Stenosis and Their Influence on the Male Predominance AMERICAN JOURNAL OF EPIDEMIOLOGY Krogh, C., Gortz, S., Wohlfahrt, J., Biggar, R. J., Melbye, M., Fischer, T. K. 2012; 176 (1): 24-31

    Abstract

    Pyloric stenosis occurs with a nearly 5-fold male predominance. To what extent this is due to environmental factors is unknown. In a cohort of all children born in Denmark, 1977-2008, the authors examined the association between pre- and perinatal exposures and pyloric stenosis and investigated whether these factors modified the male predominance. Information on pre- and perinatal factors and pyloric stenosis was obtained from national registers. Poisson regression models were used to estimate rate ratios. Among 1,925,313 children, 3,174 had surgery for pyloric stenosis. The authors found pyloric stenosis to be significantly associated with male sex, age between 2 and 7 weeks, early study period, being first born, maternal smoking during pregnancy, preterm delivery, small weight for gestational age, cesarean section, and congenital malformations. Among cases, 2,595 were males and 579 were females. Lower male predominance was associated with age at diagnosis outside the peak ages, early study period, no maternal smoking during pregnancy, preterm delivery, and congenital malformations. The authors have previously found a strong familial aggregation of pyloric stenosis indicating a genetic influence. This study shows that environmental factors during and shortly after pregnancy also play a role and that several of these modify the strong male predominance.

    View details for DOI 10.1093/aje/kwr493

    View details for Web of Science ID 000305827500001

    View details for PubMedID 22553083

  • Detectable clonal mosaicism from birth to old age and its relationship to cancer NATURE GENETICS Laurie, C. C., Laurie, C. A., Rice, K., Doheny, K. F., Zelnick, L. R., McHugh, C. P., Ling, H., Hetrick, K. N., Pugh, E. W., Amos, C., Wei, Q., Wang, L., Lee, J. E., Barnes, K. C., Hansel, N. N., Mathias, R., Daley, D., Beaty, T. H., Scott, A. F., Ruczinski, I., Scharpf, R. B., Bierut, L. J., Hartz, S. M., Landi, M. T., Freedman, N. D., Goldin, L. R., Ginsburg, D., Li, J., Desch, K. C., Strom, S. S., Blot, W. J., Signorello, L. B., Ingles, S. A., Chanock, S. J., Berndt, S. I., Le Marchand, L., Henderson, B. E., Monroe, K. R., Heit, J. A., de Andrade, M., Armasu, S. M., Regnier, C., Lowe, W. L., Hayes, M. G., Marazita, M. L., Feingold, E., Murray, J. C., Melbye, M., Feenstra, B., Kang, J. H., Wiggs, J. L., Jarvik, G. P., McDavid, A. N., Seshan, V. E., Mirel, D. B., Crenshaw, A., Sharopova, N., Wise, A., Shen, J., Crosslin, D. R., Levine, D. M., Zheng, X., Udren, J. I., Bennett, S., Nelson, S. C., Gogarten, S. M., Conomos, M. P., Heagerty, P., Manolio, T., Pasquale, L. R., Haiman, C. A., Caporaso, N., Weir, B. S. 2012; 44 (6): 642-U58

    Abstract

    We detected clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells with the same abnormal karyotype (>5-10%; presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rapidly rises to 2-3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions with genes previously associated with these cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer before DNA sampling, those without a previous diagnosis have an estimated tenfold higher risk of a subsequent hematological cancer (95% confidence interval = 6-18).

    View details for DOI 10.1038/ng.2271

    View details for Web of Science ID 000304551100010

    View details for PubMedID 22561516

    View details for PubMedCentralID PMC3366033

  • Vaccination against pandemic A/H1N1 2009 influenza in pregnancy and risk of fetal death: cohort study in Denmark BRITISH MEDICAL JOURNAL Pasternak, B., Svanstrom, H., Molgaard-Nielsen, D., Krause, T. G., Emborg, H., Melbye, M., Hviid, A. 2012; 344

    Abstract

    To investigate whether an adjuvanted pandemic A/H1N1 2009 influenza vaccine in pregnancy was associated with an increased risk of fetal death.Nationwide register based cohort study.Denmark.All clinically recognised singleton pregnancies that ended between November 2009 and September 2010. Individual level data on exposure to an inactivated AS03 pandemic A/H1N1 2009 influenza vaccine (Pandemrix) and potential confounders were linked to the study cohort using a unique person identifier.The primary outcome measure was risk of fetal death (spontaneous abortion and stillbirth combined) in H1N1 vaccinated compared with unvaccinated pregnancies, adjusting for propensity scores. Secondary outcome measures were spontaneous abortion (between seven and 22 weeks' gestation) and stillbirth (after 22 completed weeks' gestation).The cohort comprised 54,585 pregnancies; 7062 (12.9%) women were vaccinated against pandemic A/H1N1 2009 influenza during pregnancy. Overall, 1818 fetal deaths occurred (1678 spontaneous abortions and 140 stillbirths). Exposure to the H1N1 vaccine was not associated with an increased risk of fetal death (adjusted hazard ratio 0.79, 95% confidence interval 0.53 to 1.16), or the secondary outcomes of spontaneous abortion (1.11, 0.71 to 1.73) and stillbirth (0.44, 0.20 to 0.94). Estimates for fetal death were similar in pregnant women with (0.82, 0.44 to 1.53) and without comorbidities (0.77, 0.47 to 1.25).This large cohort study found no evidence of an increased risk of fetal death associated with exposure to an adjuvanted pandemic A/H1N1 2009 influenza vaccine during pregnancy.

    View details for DOI 10.1136/bmj.e2794

    View details for Web of Science ID 000303817200001

    View details for PubMedID 22551713

    View details for PubMedCentralID PMC3342154

  • Common variants at 12q15 and 12q24 are associated with infant head circumference NATURE GENETICS Taal, H. R., St Pourcain, B., Thiering, E., Das, S., Mook-Kanamori, D. O., Warrington, N. M., Kaakinen, M., Kreiner-Moller, E., Bradfield, J. P., Freathy, R. M., Geller, F., Guxens, M., Cousminer, D. L., Kerkhof, M., Timpson, N. J., Ikram, M. A., Beilin, L. J., Bonnelykke, K., Buxton, J. L., Charoen, P., Chawes, B. L., Eriksson, J., Evans, D. M., Hofman, A., Kemp, J. P., Kim, C. E., Klopp, N., Lahti, J., Lye, S. J., McMahon, G., Mentch, F. D., Mueller-Nurasyid, M., O'Reilly, P. F., Prokopenko, I., Rivadeneira, F., Steegers, E. A., Sunyer, J., Tiesler, C., Yaghootkar, H., Breteler, M. M., Debette, S., Fornage, M., Gudnason, V., Launer, L. J., van der Lugt, A., Mosley, T. H., Seshadri, S., Smith, A. V., Vernooij, M. W., Blakemore, A. I., Chiavacci, R. M., Feenstra, B., Fernandez-Banet, J., Grant, S. F., Hartikainen, A., van der Heijden, A. J., Iniguez, C., Lathrop, M., McArdle, W. L., Molgaard, A., Newnham, J. P., Palmer, L. J., Palotie, A., Pouta, A., Ring, S. M., Sovio, U., Standl, M., Uitterlinden, A. G., Wichmann, H., Vissing, N. H., DeCarli, C., van Duijn, C. M., McCarthy, M. I., Koppelman, G. H., Estivill, X., Hattersley, A. T., Melbye, M., Bisgaard, H., Pennell, C. E., Widen, E., Hakonarson, H., Smith, G. D., Heinrich, J., Jarvelin, M., Jaddoe, V. W., Adair, L. S., Ang, W., Atalay, M., van Beijsterveldt, T., Bergen, N., Benke, K., Berry, D., Bradfield, J. P., Charoen, P., Coin, L., Cousminer, D. L., Das, S., Davis, O. S., Elliott, P., Evans, D. M., Feenstra, B., Flexeder, C., Frayling, T., Freathy, R. M., Gaillard, R., Geller, F., Groen-Blokhuis, M., Goh, L., Guxens, M., Haworth, C. M., Hadley, D., Hedebrand, J., Hinney, A., Hirschhorn, J. N., Holloway, J. W., Holst, C., Hottenga, J. J., Horikoshi, M., Huikari, V., Hypponen, E., Iniguez, C., Kaakinen, M., Kilpelainen, T. O., Kirin, M., Kowgier, M., Lakka, H., Lange, L. A., Lawlor, D. A., Lehtimaki, T., Lewin, A., Lindgren, C., Lindi, V., Maggi, R., Marsh, J., Middeldorp, C., Millwood, I., Mook-Kanamori, D. O., Murray, J. C., Nivard, M., Nohr, E. A., Ntalla, I., Oken, E., O'Reilly, P. F., Palmer, L. J., Panoutsopoulou, K., Pararajasingham, J., Prokopenko, I., Rodriguez, A., Salem, R. M., Sebert, S., Siitonen, N., Sovio, U., St Pourcain, B., Strachan, D. P., Sunyer, J., Taal, H. R., Teo, Y., Thiering, E., Tiesler, C., Uitterlinden, A. G., Valcarcel, B., Warrington, N. M., White, S., Willemsen, G., Yaghootkar, H., Zeggini, E., Boomsma, D. I., Cooper, C., Estivill, X., Gillman, M., Grant, S. F., Hakonarson, H., Hattersley, A. T., Heinrich, J., Hocher, B., Jaddoe, V. W., Jarvelin, M., Lakka, T. A., McCarthy, M. I., Melbye, M., Mohlke, K. L., Dedoussis, G. V., Ong, K. K., Pearson, E. R., Pennell, C. E., Price, T. S., Power, C., Raitakari, O. T., Saw, S., Scherag, A., Simell, O., Sorensen, T. I., Timpson, N. J., Widen, E., Wilson, J. F., Ang, W., van Beijsterveldt, T., Bergen, N., Benke, K., Berry, D., Bradfield, J. P., Charoen, P., Coin, L., Cousminer, D. L., Das, S., Elliott, P., Evans, D. M., Frayling, T., Freathy, R. M., Gaillard, R., Groen-Blokhuis, M., Guxens, M., Hadley, D., Hottenga, J. J., Huikari, V., Hypponen, E., Kaakinen, M., Kowgier, M., Lawlor, D. A., Lewin, A., Lindgren, C., Marsh, J., Middeldorp, C., Millwood, I., Mook-Kanamori, D. O., Nivard, M., O'Reilly, P. F., Palmer, L. J., Prokopenko, I., Rodriguez, A., Sebert, S., Sovio, U., St Pourcain, B., Standl, M., Strachan, D. P., Sunyer, J., Taal, H. R., Thiering, E., Tiesler, C., Uitterlinden, A. G., Valcarcel, B., Warrington, N. M., White, S., Willemsen, G., Yaghootkar, H., Boomsma, D. I., Estivill, X., Grant, S. F., Hakonarson, H., Hattersley, A. T., Heinrich, J., Jaddoe, V. W., Jarvelin, M., McCarthy, M. I., Pennell, C. E., Power, C., Timpson, N. J., Widen, E., Ikram, M. A., Fornage, M., Smith, A. V., Seshadri, S., Schmidt, R., Debette, S., Vrooman, H. A., Sigurdsson, S., Ropele, S., Coker, L. H., Longstreth, W. T., Niessen, W. J., DeStefano, A. L., Beiser, A., Zijdenbos, A. P., Struchalin, M., Jack, C. R., Nalls, M. A., Au, R., Hofman, A., Gudnason, H., van der Lugt, A., Harris, T. B., Meeks, W. M., Vernooij, M. W., van Buchem, M. A., Catellier, D., Gudnason, V., Windham, B. G., Wolf, P. A., van Duijn, C. M., Mosley, T. H., Schmidt, H., Launer, L. J., Breteler, M. M., DeCarli, C. 2012; 44 (5): 532-?

    Abstract

    To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 × 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height, their effects on infant head circumference were largely independent of height (P = 3.8 × 10(-7) for rs7980687 and P = 1.3 × 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume, Parkinson's disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.

    View details for DOI 10.1038/ng.2238

    View details for Web of Science ID 000303416300013

    View details for PubMedID 22504419

    View details for PubMedCentralID PMC3773913

  • RT-PCR Screening for ETV6-RUNX1-positive Clones in Cord Blood From Newborns in the Danish National Birth Cohort JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Olsen, M., Hjalgrim, H., Melbye, M., Madsen, H. O., Schmiegelow, K. 2012; 34 (4): 301-303

    Abstract

    Several large biobanks comprising umbilical cord blood samples have been established allowing efforts to characterize the prevalence and risk factors for preleukemic cell clones in healthy newborns. This study explores the feasibility of demonstrating translocation ETV6-RUNX1 transcripts by reverse transcription polymerase chain reaction in newborns enrolled in a large Danish National Birth Cohort.The study emphasizes the necessity of either storing viable cord blood cells or preparation of the RNA within 1 to 2 days of birth, in large scale studies of the natural history of childhood acute lymphoblastic leukemia. Finally, the estimated frequency of translocation ETV6-RUNX1-positive cells was below 10.

    View details for DOI 10.1097/MPH.0b013e3182332268

    View details for Web of Science ID 000303652500027

    View details for PubMedID 22217495

  • Use of Calcium Channel Blockers and Parkinson's Disease AMERICAN JOURNAL OF EPIDEMIOLOGY Pasternak, B., Svanstrom, H., Nielsen, N. M., Fugger, L., Melbye, M., Hviid, A. 2012; 175 (7): 627-635

    Abstract

    Experimental evidence and case-control studies suggest that dihydropyridine calcium channel blockers (DiCCBs) may protect against Parkinson's disease. The authors conducted a historical cohort study in Denmark to investigate the association between DiCCB use and risk of Parkinson's disease (1998-2006). Individual-level data on filled drug prescriptions, diagnostic information, and covariates were linked between nationwide registries. Among DiCCB users, 173 incident cases of Parkinson's disease were detected during 461,984 person-years of follow-up, compared with 5,538 cases during 17,343,641 person-years of follow-up among nonusers. After adjustment for age, sex, year, propensity score, and use of other antihypertensive drugs and statins, DiCCB use was associated with a reduced risk of Parkinson's disease (rate ratio (RR) = 0.71, 95% confidence interval (CI): 0.60, 0.82). This association was not present in patients who had previously used DiCCBs (RR = 1.04, 95% CI: 0.87, 1.24). DiCCB users aged ≥65 years were at lower risk of Parkinson's disease than DiCCB users aged <65 years (RR = 0.59, 95% CI: 0.40, 0.85). Among patients with Parkinson's disease, DiCCB use was associated with reduced risk of death (adjusted RR = 0.66, 95% CI: 0.47, 0.91) but not dementia (adjusted RR = 0.97, 95% CI: 0.60, 1.56). In conclusion, DiCCB exposure was associated with a reduced risk of incident Parkinson's disease, particularly in older patients, and with reduced mortality among patients with Parkinson's disease.

    View details for DOI 10.1093/aje/kwr362

    View details for Web of Science ID 000302483500007

    View details for PubMedID 22387374

  • Using Family Data as a Verification Standard to Evaluate Copy Number Variation Calling Strategies for Genetic Association Studies GENETIC EPIDEMIOLOGY Zheng, X., Shaffer, J. R., McHugh, C. P., Laurie, C. C., Feenstra, B., Melbye, M., Murray, J. C., Marazita, M. L., Feingold, E. 2012; 36 (3): 253-262

    Abstract

    A major concern for all copy number variation (CNV) detection algorithms is their reliability and repeatability. However, it is difficult to evaluate the reliability of CNV-calling strategies due to the lack of gold-standard data that would tell us which CNVs are real. We propose that if CNVs are called in duplicate samples, or inherited from parent to child, then these can be considered validated CNVs. We used two large family-based genome-wide association study (GWAS) datasets from the GENEVA consortium to look at concordance rates of CNV calls between duplicate samples, parent-child pairs, and unrelated pairs. Our goal was to make recommendations for ways to filter and use CNV calls in GWAS datasets that do not include family data. We used PennCNV as our primary CNV-calling algorithm, and tested CNV calls using different datasets and marker sets, and with various filters on CNVs and samples. Using the Illumina core HumanHap550 single nucleotide polymorphism (SNP) set, we saw duplicate concordance rates of approximately 55% and parent-child transmission rates of approximately 28% in our datasets. GC model adjustment and sample quality filtering had little effect on these reliability measures. Stratification on CNV size and DNA sample type did have some effect. Overall, our results show that it is probably not possible to find a CNV-calling strategy (including filtering and algorithm) that will give us a set of "reliable" CNV calls using current chip technologies. But if we understand the error process, we can still use CNV calls appropriately in genetic association studies.

    View details for DOI 10.1002/gepi.21618

    View details for Web of Science ID 000303319700009

    View details for PubMedID 22714937

    View details for PubMedCentralID PMC3696390

  • Common variants near MBNL1 and NKX2-5 are associated with infantile hypertrophic pyloric stenosis NATURE GENETICS Feenstra, B., Geller, F., Krogh, C., Hollegaard, M. V., Gortz, S., Boyd, H. A., Murray, J. C., Hougaard, D. M., Melbye, M. 2012; 44 (3): 334-U1601

    Abstract

    Infantile hypertrophic pyloric stenosis (IHPS) is a severe condition characterized by hypertrophy of the pyloric sphincter muscle. We conducted a genome-wide association study (GWAS) on 1,001 surgery-confirmed cases and 2,401 controls from Denmark. The six most strongly associated loci were tested in a replication set of 796 cases and 876 controls. Three SNPs reached genome-wide significance. One of these SNPs, rs11712066 (odds ratio (OR) = 1.61; P = 1.5 × 10(-17)) at 3p25.1, is located 150 kb upstream of MBNL1, which encodes a factor that regulates splicing transitions occurring shortly after birth. The second SNP, rs573872 (OR = 1.41; P = 4.3 × 10(-12)), maps to an intergenic region at 3p25.2 approximately 1.3 Mb downstream of MBNL1. The third SNP, rs29784 (OR = 1.42; P = 1.5 × 10(-15)) at 5q35.2, is 64 kb downstream of NKX2-5, which is involved in development of cardiac muscle tissue and embryonic gut development.

    View details for DOI 10.1038/ng.1067

    View details for Web of Science ID 000300843600022

    View details for PubMedID 22306654

    View details for PubMedCentralID PMC3693399

  • Effectiveness of the Targeted Hepatitis B Vaccination Program in Greenland AMERICAN JOURNAL OF PUBLIC HEALTH Borresen, M. L., Koch, A., Biggar, R. J., Ladefoged, K., Melbye, M., Wohlfahrt, J., Krause, T. G. 2012; 102 (2): 277-284

    Abstract

    To evaluate the effectiveness of the hepatitis B virus (HBV) vaccination program in Greenland, which targets children born to mothers who are positive for HBV surface antigen (HBsAg), we determined vaccination coverage, levels of postvaccination antibodies, and frequency of breakthrough infections in at-risk children.We conducted a population-based retrospective cohort study with data from nationwide registries. We identified all children born to HBsAg-positive mothers from 1992 to 2007 and collected data on their HBV vaccination status. In 2008 to 2010, we tested the children for HBV core antibody, HBsAg, and anti-HBsAg antibody (HBsAb).Of 4050 pregnant women, 3.2% were HBsAg positive. Of 207 children born to these women, 20% received no vaccinations, and only 58% received at least 3 vaccinations. At follow-up, HBsAb levels in vaccinated children were much lower than expected, and 8 (6%) of 140 at-risk children had breakthrough infections, with 4 chronically infected (persistently HBsAg positive).The prevention program targeting children at risk for HBV in Greenland is ineffective. HBV vaccination should be included in the universal childhood vaccination program, and postvaccination HBsAb levels should be monitored.

    View details for DOI 10.2105/AJPH.2011.300239

    View details for Web of Science ID 000299717500019

    View details for PubMedID 21940914

    View details for PubMedCentralID PMC3483978

  • Genome-Wide Association Study of Classical Hodgkin Lymphoma and Epstein-Barr Virus Status-Defined Subgroups JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Urayama, K. Y., Jarrett, R. F., Hjalgrim, H., Diepstra, A., Kamatani, Y., Chabrier, A., Gaborieau, V., Boland, A., Nieters, A., Becker, N., Foretova, L., Benavente, Y., Maynadie, M., Staines, A., Shield, L., Lake, A., Montgomery, D., Taylor, M., Smedby, K. E., Amini, R., Adami, H., Glimelius, B., Feenstra, B., Nolte, I. M., Visser, L., van Imhoff, G. W., Lightfoot, T., Cocco, P., Kiemeney, L., Vermeulen, S. H., Holcatova, I., Vatten, L., Macfarlane, G. J., Thomson, P., Conway, D. I., Benhamou, S., Agudo, A., Healy, C. M., Overvad, K., Tjonneland, A., Melin, B., Canzian, F., Khaw, K., Travis, R. C., Peeters, P. H., Gonzalez, C. A., Quiros, J. R., Sanchez, M., Maria Huerta, J., Ardanaz, E., Dorronsoro, M., Clavel-Chapelon, F., Bueno-de-Mesquita, H. B., Riboli, E., Roman, E., Boffetta, P., de Sanjose, S., Zelenika, D., Melbye, M., van den Berg, A., Lathrop, M., Brennan, P., McKay, J. D. 2012; 104 (3): 240-253

    Abstract

    Accumulating evidence suggests that risk factors for classical Hodgkin lymphoma (cHL) differ by tumor Epstein-Barr virus (EBV) status. This potential etiological heterogeneity is not recognized in current disease classification.We conducted a genome-wide association study of 1200 cHL patients and 6417 control subjects, with validation in an independent replication series, to identify common genetic variants associated with total cHL and subtypes defined by tumor EBV status. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) assuming a log-additive genetic model for the variants. All statistical tests were two-sided.Two novel loci associated with total cHL irrespective of EBV status were identified in the major histocompatibility complex region; one resides adjacent to MICB (rs2248462: OR = 0.61, 95% CI = 0.53 to 0.69, P = 1.3 × 10(-13)) and the other at HLA-DRA (rs2395185: OR = 0.56, 95% CI = 0.50 to 0.62, P = 8.3 × 10(-25)) with both results confirmed in an independent replication series. Consistent with previous reports, associations were found between EBV-positive cHL and genetic variants within the class I region (rs2734986, HLA-A: OR = 2.45, 95% CI = 2.00 to 3.00, P = 1.2 × 10(-15); rs6904029, HCG9: OR = 0.46, 95% CI = 0.36 to 0.59, P = 5.5 × 10(-10)) and between EBV-negative cHL and rs6903608 within the class II region (rs6903608, HLA-DRA: OR = 2.08, 95% CI = 1.84 to 2.35, P = 6.1 × 10(-31)). The association between rs6903608 and EBV-negative cHL was confined to the nodular sclerosis histological subtype. Evidence for an association between EBV-negative cHL and rs20541 (5q31, IL13: OR = 1.53, 95% CI = 1.32 to 1.76, P = 5.4 x 10(-9)), a variant previously linked to psoriasis and asthma, was observed; however, the evidence for replication was less clear. Notably, one additional psoriasis-associated variant, rs27524 (5q15, ERAP1), showed evidence of an association with cHL in the genome-wide association study (OR = 1.21, 95% CI = 1.10 to 1.33, P = 1.5 × 10(-4)) and replication series (P = .03).Overall, these results provide strong evidence that EBV status is an etiologically important classification of cHL and also suggest that some components of the pathological process are common to both EBV-positive and EBV-negative patients.

    View details for DOI 10.1093/jnci/djr516

    View details for Web of Science ID 000300343000012

    View details for PubMedID 22286212

    View details for PubMedCentralID PMC3274508

  • Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis NATURE GENETICS Paternoster, L., Standl, M., Chen, C., Ramasamy, A., Bonnelykke, K., Duijts, L., Ferreira, M. A., Alves, A. C., Thyssen, J. P., Albrecht, E., Baurecht, H., Feenstra, B., Sleiman, P. M., Hysi, P., Warrington, N. M., Curjuric, I., Myhre, R., Curtin, J. A., Groen-Blokhuis, M. M., Kerkhof, M., Saaf, A., Franke, A., Ellinghaus, D., Foelster-Holst, R., Dermitzakis, E., Montgomery, S. B., Prokisch, H., Heim, K., Hartikainen, A., Pouta, A., Pekkanen, J., Blakemore, A. I., Buxton, J. L., Kaakinen, M., Duffy, D. L., Madden, P. A., Heath, A. C., Montgomery, G. W., Thompson, P. J., Matheson, M. C., Le Souef, P., St Pourcain, B., Smith, G. D., Henderson, J., Kemp, J. P., Timpson, N. J., Deloukas, P., Ring, S. M., Wichmann, H., Mueller-Nurasyid, M., Novak, N., Klopp, N., Rodriguez, E., McArdle, W., Linneberg, A., Menne, T., Nohr, E. A., Hofman, A., Uitterlinden, A. G., van Duijin, C. M., Rivadeneira, F., de Jongste, J. C., van der Valk, R. J., Wjst, M., Jogi, R., Geller, F., Boyd, H. A., Murray, J. C., Kim, C., Mentch, F., March, M., Mangino, M., Spector, T. D., Bataille, V., Pennell, C. E., Holt, P. G., Sly, P., Tiesler, C. M., Thiering, E., Illig, T., Imboden, M., Nystad, W., Simpson, A., Hottenga, J., Postma, D., Koppelman, G. H., Smit, H. A., Soderhall, C., Chawes, B., Kreiner-Moller, E., Bisgaard, H., Melen, E., Boomsma, D. I., Custovic, A., Jacobsson, B., Probst-Hensch, N. M., Palmer, L. J., Glass, D., Hakonarson, H., Melbye, M., Jarvis, D. L., Jaddoe, V. W., Gieger, C., Strachan, D. P., Martin, N. G., Jarvelin, M., Heinrich, J., Evans, D. M., Weidinger, S. 2012; 44 (2): 187-192

    Abstract

    Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.

    View details for DOI 10.1038/ng.1017

    View details for Web of Science ID 000299664400018

    View details for PubMedID 22197932

    View details for PubMedCentralID PMC3272375

  • Helminth infection does not reduce risk for chronic inflammatory disease in a population-based cohort study. Gastroenterology Bager, P., Vinkel Hansen, A., Wohlfahrt, J., Melbye, M. 2012; 142 (1): 55-62

    Abstract

    Parasitic helminth infections can suppress symptoms of allergy, type 1 diabetes, arthritis, and inflammatory bowel disease in animal models. We analyzed data from a large, population-based cohort study to determine whether common childhood enterobiasis protects against these diseases.We collected information on individual prescriptions filled for the drug mebendazole against Enterobius vermicularis for all children born in Denmark 1995-2008 from the National Register of Medicinal Product Statistics (n = 924,749; age 0-14 years); 132,383 of these children (14%) filled a prescription for mebendazole, 102,482 of the children (11%) had a household peer who was registered with a filled mebendazole prescription, and the remaining 689,884 children (75%) comprised the reference group. Children diagnosed with asthma, type 1 diabetes, juvenile arthritis, ulcerative colitis, or Crohn's disease were identified from the National Patient Registry. We used Poisson regression to estimate confounder-adjusted incidence rate ratios for first in- or outpatient hospital diagnosis of chronic inflammatory disease according to history of mebendazole treatment prescribed to children in the study.Chronic inflammatory disease was diagnosed in 10,352 children during 6.4 million person-years of follow-up. The incidence rate ratios was 1.07 for asthma (95% confidence interval [CI]: 1.00-1.13), 1.05 for type 1 diabetes (95% CI: 0.79-1.12), 1.13 for juvenile arthritis (95% CI: 0.94-1.37), 0.77 for ulcerative colitis (95% CI: 0.41-1.46), and 1.44 for Crohn's disease (95% CI: 0.82-2.53). Results were not modified by number of treatments or age at treatment.Based on a population-based analysis, enterobiasis does not reduce risk for asthma, type 1 diabetes, arthritis, or inflammatory bowel disease.

    View details for DOI 10.1053/j.gastro.2011.09.046

    View details for PubMedID 21983081

  • Replication of a Genome-Wide Association Study of Birth Weight in Preterm Neonates JOURNAL OF PEDIATRICS Ryckman, K. K., Feenstra, B., Shaffer, J. R., Bream, E. N., Geller, F., Feingold, E., Weeks, D. E., Gadow, E., Cosentino, V., Saleme, C., Simhan, H. N., Merrill, D., Fong, C., Busch, T., Berends, S. K., Comas, B., Camelo, J. L., Boyd, H., Laurie, C. C., Crosslin, D., Zhang, Q., Doheny, K. F., Pugh, E., Melbye, M., Marazita, M. L., Dagle, J. M., Murray, J. C. 2012; 160 (1): 19-U56

    Abstract

    To examine associations between rs9883204 in ADCY5 and rs900400 near LEKR1 and CCNL1 with birth weight in a preterm population. Both markers were associated with birth weight in a term population in a recent genome-wide association study of Freathy et al.A meta-analysis of mother and infant samples was performed for associations of rs900400 and rs9883204 with birth weight in 393 families from the US, 265 families from Argentina, and 735 mother-infant pairs from Denmark. Z-scores adjusted for infant sex and gestational age were generated for each population separately and regressed on allele counts. Association evidence was combined across sites by inverse-variance weighted meta-analysis.Each additional C allele of rs900400 (LEKR1/CCNL1) in infants was marginally associated with a 0.069 SD lower birth weight (95% CI, -0.159 to 0.022; P = .068). This result was slightly more pronounced after adjusting for smoking (P = .036). No significant associations were identified with rs9883204 or in maternal samples.These results indicate the potential importance of this marker on birth weight regardless of gestational age.

    View details for DOI 10.1016/j.jpeds.2011.07.038

    View details for Web of Science ID 000298143000007

    View details for PubMedID 21885063

    View details for PubMedCentralID PMC3237813

  • Helminth Infection Does Not Reduce Risk for Chronic Inflammatory Disease in a Population-Based Cohort Study GASTROENTEROLOGY Bager, P., Hansen, A. V., Wohlfahrt, J., Melbye, M. 2012; 142 (1): 55-62
  • Cancer Risk Among Patients With Myotonic Muscular Dystrophy JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Gadalla, S. M., Lund, M., Pfeiffer, R. M., Gortz, S., Mueller, C. M., Moxley, R. T., Kristinsson, S. Y., Bjoerkholm, M., Shebl, F. M., Hilbert, J. E., Landgren, O., Wohlfahrt, J., Melbye, M., Greene, M. H. 2011; 306 (22): 2480-2486

    Abstract

    Myotonic muscular dystrophy (MMD) is an autosomal-dominant multisystem neuromuscular disorder characterized by unstable nucleotide repeat expansions. Case reports have suggested that MMD patients may be at increased risk of malignancy, putative risks that have never been quantified.To quantitatively evaluate cancer risk in patients with MMD, overall and by sex and age.We identified 1658 patients with an MMD discharge diagnosis in the Swedish Hospital Discharge Register or Danish National Patient Registry between 1977 and 2008. We linked these patients to their corresponding cancer registry. Patients were followed up from date of first MMD-related inpatient or outpatient contact to first cancer diagnosis, death, emigration, or completion of cancer registration.Risks of all cancers combined and by anatomic site, stratified by sex and age.One hundred four patients with an inpatient or outpatient discharge diagnosis of MMD developed cancer during postdischarge follow-up. This corresponds to an observed cancer rate of 73.4 per 10,000 person-years in MMD vs an expected rate of 36.9 per 10,000 person-years in the general Swedish and Danish populations combined (standardized incidence ratio [SIR], 2.0; 95% CI, 1.6-2.4). Specifically, we observed significant excess risks of cancers of the endometrium (n = 11; observed rate, 16.1/10,000 person-years; SIR, 7.6; 95% CI, 4.0-13.2), brain (n = 7; observed rate, 4.9/10,000 person-years; SIR, 5.3; 95% CI, 2.3-10.4), ovary (n = 7; observed rate, 10.3/10,000 person-years; SIR, 5.2; 95% CI, 2.3-10.2), and colon (n = 10; observed rate, 7.1/10,000 person-years; SIR, 2.9; 95% CI, 1.5-5.1). Cancer risks were similar in women and men after excluding genital organ tumors (SIR, 1.9; 95% CI, 1.4-2.5, vs SIR, 1.8; 95% CI, 1.3-2.5, respectively; P = .81 for heterogeneity; observed rates, 64.5 and 47.7 per 10,000 person-years in women and men, respectively). The same pattern of cancer excess was observed first in the Swedish and then in the Danish cohorts, which were studied sequentially and initially analyzed independently.Patients with MMD identified from the Swedish and Danish patient registries were at increased risk of cancer both overall and for selected anatomic sites.

    View details for DOI 10.1001/jama.2011.1796

    View details for Web of Science ID 000297983300021

    View details for PubMedID 22166607

    View details for PubMedCentralID PMC3286183

  • Genome-wide Association Scan for Childhood Caries Implicates Novel Genes JOURNAL OF DENTAL RESEARCH Shaffer, J. R., Wang, X., Feingold, E., Lee, M., Begum, F., Weeks, D. E., Cuenco, K. T., Barmada, M. M., Wendell, S. K., Crosslin, D. R., Laurie, C. C., Doheny, K. F., Pugh, E. W., Zhang, Q., Feenstra, B., Geller, F., Boyd, H. A., Zhang, H., Melbye, M., Murray, J. C., Weyant, R. J., Crout, R., McNeil, D. W., Levy, S. M., Slayton, R. L., Willing, M. C., Broffitt, B., Vieira, A. R., Marazita, M. L. 2011; 90 (12): 1457-1462

    Abstract

    Dental caries is the most common chronic disease in children and a major public health concern due to its increasing incidence, serious health and social co-morbidities, and socio-demographic disparities in disease burden. We performed the first genome-wide association scan for dental caries to identify associated genetic loci and nominate candidate genes affecting tooth decay in 1305 US children ages 3-12 yrs. Affection status was defined as 1 or more primary teeth with evidence of decay based on intra-oral examination. No associations met strict criteria for genome-wide significance (p < 10E-7); however, several loci (ACTN2, MTR, and EDARADD, MPPED2, and LPO) with plausible biological roles in dental caries exhibited suggestive evidence for association. Analyses stratified by home fluoride level yielded additional suggestive loci, including TFIP11 in the low-fluoride group, and EPHA7 and ZMPSTE24 in the sufficient-fluoride group. Suggestive loci were tested but not significantly replicated in an independent sample (N = 1695, ages 2-7 yrs) after adjustment for multiple comparisons. This study reinforces the complexity of dental caries, suggesting that numerous loci, mostly having small effects, are involved in cariogenesis. Verification/replication of suggestive loci may highlight biological mechanisms and/or pathways leading to a fuller understanding of the genetic risks for dental caries.

    View details for DOI 10.1177/0022034511422910

    View details for Web of Science ID 000296982800015

    View details for PubMedID 21940522

    View details for PubMedCentralID PMC3215757

  • Epstein-Barr virus-associated gastric carcinoma among patients with pernicious anemia INTERNATIONAL JOURNAL OF CANCER Boysen, T., Friborg, J., Stribolt, K., Hamilton-Dutoit, S., Goertz, S., Wohlfahrt, J., Melbye, M. 2011; 129 (11): 2756-2760

    Abstract

    Approximately 9% of gastric carcinomas worldwide are associated with Epstein-Barr virus (EBV), making it the most frequent EBV-associated malignancy. Pernicious anemia, a condition with chronic gastritis and achlorhydria, is strongly associated with gastric carcinoma. Both chronic inflammation and the lack of stomach acid may influence the likelihood of EBV infection of the neoplastic gastric epithelium, but the prevalence of EBV-associated gastric carcinoma among patients with pernicious anemia is unknown. Therefore, we conducted a Danish nationwide case-control study comparing gastric carcinoma patients with pernicious anemia (PA-GC) with those without pernicious anemia (nonPA-GC), frequency matched 1:2. Tumor tissues were reclassified by expert histopathologists blinded to pernicious anemia and EBV status. In total, 186 samples (55 PA-GC and 131 nonPA-GC) were identified. EBV-associated gastric carcinoma (EBV-GC) was more common among PA-GC compared with nonPA-GC, adjusted odds ratio (OR) = 2.53 (CI: 0.88; 7.14), p = 0.08, with further adjustment for lymphocytic infiltrate OR = 2.94 (0.99-8.67), p = 0.05. Gastric carcinomas with signet-ring cell morphology were significantly less common in patients with PA-GC compared with nonPA-GC (OR = 0.05, CI 0.01; 0.24). Although these conditions are rare, we found suggestive evidence that EBV-associated gastric carcinomas are more common among gastric carcinoma patients with pernicious anemia compared with those without.

    View details for DOI 10.1002/ijc.25925

    View details for Web of Science ID 000296449900022

    View details for PubMedID 21225628

  • Cancer in first-degree relatives and risk of testicular cancer in Denmark INTERNATIONAL JOURNAL OF CANCER Nordsborg, R. B., Meliker, J. R., Wohlfahrt, J., Melbye, M., Raaschou-Nielsen, O. 2011; 129 (10): 2485-2491

    Abstract

    Familial aggregation of testicular cancer has been reported consistently, but it is less clear if there is any association between risk of testicular cancer and other cancers in the family. We conducted a population-based case-control study to examine the relationship between risk of testicular cancer and 22 different cancers in first-degree relatives. We included 3,297 cases of testicular cancer notified to the Danish Cancer Registry between 1991 and 2003. A total of 6,594 matched controls were selected from the Danish Civil Registration System, which also provided the identity of 40,104 first-degree relatives of case and controls. Familial cancer was identified by linkage to the Danish Cancer Registry, and we used conditional logistic regression to analyze whether cancer among first-degree relatives was associated with higher risk of testicular cancer. Rate ratio for testicular cancer was 4.63 (95% CI: 2.41-8.87) when a father, 8.30 (95% CI: 3.81-18.10) when a brother and 5.23 (95% CI: 1.35-20.26) when a son had testicular cancer compared to no familial testicular cancer. Results were similar when analyses were stratified by histologic subtypes of testicular cancer. Familial non-Hodgkin lymphoma and esophageal cancer were associated with testicular cancer; however, these may be chance findings. The familial aggregation of testicular and possibly other cancers may be explained by shared genes and/or shared environmental factors, but the mutual importance of each of these is difficult to determine.

    View details for DOI 10.1002/ijc.25897

    View details for Web of Science ID 000295231000020

    View details for PubMedID 21207375

    View details for PubMedCentralID PMC3178684

  • Hepatocellular Carcinoma and Other Liver Disease Among Greenlanders Chronically Infected with Hepatitis B Virus: A Population-Based Study JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Borresen, M. L., Koch, A., Biggar, R. J., Andersson, M., Wohlfahrt, J., Ladefoged, K., Melbye, M. 2011; 103 (22): 1676-1685

    Abstract

    In Greenland, the prevalence of hepatitis B surface antigen carriers, reflecting chronic hepatitis B virus (HBV) infection, is 5%-10%. However, the incidence of cirrhosis and hepatocellular carcinoma in this population has been reported to be low. We investigated this discrepancy in a large population-based cohort study.In total, 8879 Greenlanders (16% of the population) were recruited for population-based surveys performed from May 5 to July 7, 1987, and from November 1 to November 21, 1998, with follow-up until March 31, 2010. HBV status was based on serological testing, supplemented by data from all available HBV registries in Greenland to determine changes in HBV status over time. Information on morbidity and mortality was obtained from the Patient Discharge Registry, the Cancer Registry, and the Central Registration System. Sex, age, ethnicity, and period-adjusted incidence rate ratios (IRRs) were estimated using Poisson regression. World standardized rates were derived from these and World Health Organization data.The 650 chronically HBV-infected persons had higher rates of hepatocellular carcinoma (adjusted IRR = 8.70; 95% CI = 2.06 to 36.7), liver disease (adjusted IRR = 5.73, 95% CI = 3.52 to 9.34), and all-cause mortality (adjusted IRR = 1.47; 95% CI = 1.21 to 1.79) than the 5160 HBV-negative persons. However, the world standardized incidence rates of hepatocellular carcinoma (38.5 cancers per 100 000 person-years) and cirrhosis (24 cases per 100 000 person-years) among chronically HBV-infected persons were low compared with results from population-based studies from countries with low, intermediate, and high rates of endemic HBV infection.The relatively low incidence of hepatocellular carcinoma and other HBV-related morbidity among chronic HBV-infected persons in Greenland suggest a more benign course of HBV among the Greenlandic Inuit than in populations in other parts of the world.

    View details for DOI 10.1093/jnci/djr405

    View details for Web of Science ID 000297209000009

    View details for PubMedID 22021665

  • Risk factors for Mycobacterium tuberculosis infection among children in Greenland BULLETIN OF THE WORLD HEALTH ORGANIZATION Soborg, B., Andersen, A. B., Melbye, M., Wohlfahrt, J., Anderssbn, M., Biggar, R. J., Ladefoged, K., Thomsen, V. O., Koch, A. 2011; 89 (10): 741-748

    Abstract

    To examine the risk factors for Mycobacterium tuberculosis infection (MTI) among Greenlandic children for the purpose of identifying those at highest risk of infection.Between 2005 and 2007, 1797 Greenlandic schoolchildren in five different areas were tested for MTI with an interferon gamma release assay (IGRA) and a tuberculin skin test (TST). Parents or guardians were surveyed using a standardized self-administered questionnaire to obtain data on crowding in the household, parents' educational level and the child's health status. Demographic data for each child--i.e. parents' place of birth, number of siblings, distance between siblings (next younger and next older), birth order and mother's age when the child was born--were also extracted from a public registry. Logistic regression was used to check for associations between these variables and MTI, and all results were expressed as odds ratios (ORs) and 95% confidence intervals (CIs). Children were considered to have MTI if they tested positive on both the IGRA assay and the TST.The overall prevalence of MTI was 8.5% (152/1797). MTI was diagnosed in 26.7% of the children with a known TB contact, as opposed to 6.4% of the children without such contact. Overall, the MTI rate was higher among Inuit children (OR:  4.22; 95% CI: 1.55-11.5) and among children born less than one year after the birth of the next older sibling (OR:  2.48; 95% CI: 1.33-4.63). Self-reported TB contact modified the profile to include household crowding and low mother's education. Children who had an older MTI-positive sibling were much more likely to test positive for MTI themselves (OR:  14.2; 95% CI: 5.75-35.0) than children without an infected older sibling.Ethnicity, sibling relations, number of household residents and maternal level of education are factors associated with the risk of TB infection among children in Greenland. The strong household clustering of MTI suggests that family sources of exposure are important.

    View details for DOI 10.2471/BLT.10.084152

    View details for Web of Science ID 000295707700012

    View details for PubMedID 22084512

    View details for PubMedCentralID PMC3209970

  • Genome-Wide Association Study Identifies Four Loci Associated with Eruption of Permanent Teeth PLOS GENETICS Geller, F., Feenstra, B., Zhang, H., Shaffer, J. R., Hansen, T., Esserlind, A., Boyd, H. A., Nohr, E. A., Timpson, N. J., Fatemifar, G., Paternoster, L., Evans, D. M., Weyant, R. J., Levy, S. M., Lathrop, M., Smith, G. D., Murray, J. C., Olesen, J., Werge, T., Marazita, M. L., Sorensen, T. I., Melbye, M. 2011; 7 (9)

    Abstract

    The sequence and timing of permanent tooth eruption is thought to be highly heritable and can have important implications for the risk of malocclusion, crowding, and periodontal disease. We conducted a genome-wide association study of number of permanent teeth erupted between age 6 and 14 years, analyzed as age-adjusted standard deviation score averaged over multiple time points, based on childhood records for 5,104 women from the Danish National Birth Cohort. Four loci showed association at P<5×10(-8) and were replicated in four independent study groups from the United States and Denmark with a total of 3,762 individuals; all combined P-values were below 10(-11). Two loci agreed with previous findings in primary tooth eruption and were also known to influence height and breast cancer, respectively. The two other loci pointed to genomic regions without any previous significant genome-wide association study results. The intronic SNP rs7924176 in ADK could be linked to gene expression in monocytes. The combined effect of the four genetic variants was most pronounced between age 10 and 12 years, where children with 6 to 8 delayed tooth eruption alleles had on average 3.5 (95% confidence interval: 2.9-4.1) fewer permanent teeth than children with 0 or 1 of these alleles.

    View details for DOI 10.1371/journal.pgen.1002275

    View details for Web of Science ID 000295419100028

    View details for PubMedID 21931568

    View details for PubMedCentralID PMC3169538

  • Symptoms after Ingestion of Pig Whipworm Trichuris suis Eggs in a Randomized Placebo-Controlled Double-Blind Clinical Trial PLOS ONE Bager, P., Kapel, C., Roepstorff, A., Thamsborg, S., Arnved, J., Ronborg, S., Kristensen, B., Poulsen, L. K., Wohlfahrt, J., Melbye, M. 2011; 6 (8)

    Abstract

    Symptoms after human infection with the helminth Trichuris suis have not previously been described. Exposure to helminths has been suggested as immune therapy against allergy and autoimmune diseases. We randomized adults with allergic rhinitis to ingest a dose of 2500 T. suis eggs or placebo every 21 days for 168 days (total 8 doses) in a double-blind clinical trial. In a previous publication, we reported a lack of efficacy and a high prevalence of adverse gastrointestinal reactions. The aim of the present study was to present a detailed description of the adverse event data and post-hoc analyses of gastrointestinal reactions. Adverse events and severity (mild, moderate, severe) were recorded daily by subjects, classified by organ using MedDRA 10.0, and event rates compared between subjects on T. suis treatment vs. subjects on placebo. T. suis-specific serum IgG antibodies were measured by a fluoroenzymeimmunoassay (Phadia ApS). During 163 days complete follow-up, subjects ingesting T. suis eggs (N = 49) had a three to 19-fold higher rate of events (median duration, 2 days) with gastrointestinal reactions (moderate to severe flatulence, diarrhea, and upper abdominal pain) compared with placebo subjects (N = 47). The highest incidence of affected subjects was seen from the first few days and until day 42 (3(rd) dose): 63% vs. 29% for placebo; day 163: 76% vs. 49% for placebo. Seroprevalences increased concurrently in the T. suis group: Day 59, 50%; day 90, 91%; day 170, 93%. The combined duration of episodes with onset before day 42 was ≤ 14 days in 80% of affected subjects. Age, gender, total IgE, and recent intestinal symptoms at baseline did not predict gastrointestinal side effects. In conclusion, during the first 2 months, repeated ingestions of 2500 T. suis eggs caused frequent gastrointestinal reactions lasting up to 14 days, whereas 4 months further treatment mainly provoked a subclinical stimulation.University hospital Medical Information Network trial registry Reg. no. R000001298, Trial ID UMIN000001070.

    View details for DOI 10.1371/journal.pone.0022346

    View details for Web of Science ID 000293511900005

    View details for PubMedID 21829616

    View details for PubMedCentralID PMC3149054

  • Genome partitioning of genetic variation for complex traits using common SNPs NATURE GENETICS Yang, J., Manolio, T. A., Pasquale, L. R., Boerwinkle, E., Caporaso, N., Cunningham, J. M., de Andrade, M., Feenstra, B., Feingold, E., Hayes, M. G., Hill, W. G., Landi, M. T., Alonso, A., Lettre, G., Lin, P., Ling, H., Lowe, W., Mathias, R. A., Melbye, M., Pugh, E., Cornelis, M. C., Weir, B. S., Goddard, M. E., Visscher, P. M. 2011; 43 (6): 519-U44

    Abstract

    We estimate and partition genetic variation for height, body mass index (BMI), von Willebrand factor and QT interval (QTi) using 586,898 SNPs genotyped on 11,586 unrelated individuals. We estimate that ∼45%, ∼17%, ∼25% and ∼21% of the variance in height, BMI, von Willebrand factor and QTi, respectively, can be explained by all autosomal SNPs and a further ∼0.5-1% can be explained by X chromosome SNPs. We show that the variance explained by each chromosome is proportional to its length, and that SNPs in or near genes explain more variation than SNPs between genes. We propose a new approach to estimate variation due to cryptic relatedness and population stratification. Our results provide further evidence that a substantial proportion of heritability is captured by common SNPs, that height, BMI and QTi are highly polygenic traits, and that the additive variation explained by a part of the genome is approximately proportional to the total length of DNA contained within genes therein.

    View details for DOI 10.1038/ng.823

    View details for Web of Science ID 000291017000007

    View details for PubMedID 21552263

    View details for PubMedCentralID PMC4295936

  • Digoxin Use and the Risk of Breast Cancer in Women JOURNAL OF CLINICAL ONCOLOGY Biggar, R. J., Wohlfahrt, J., Oudin, A., Hjuler, T., Melbye, M. 2011; 29 (16): 2165-2170

    Abstract

    Digoxin resembles estrogen chemically and may have estrogenic effect. We hypothesized that digoxin use might increase breast cancer incidence and examined if use might be associated with risk of breast cancer, categorized by estrogen receptor (ER) status. To determine if being under care for heart disease biased the findings, rate ratios in users of angina drugs were similarly evaluated as a control exposure group.Women using digoxin and angina drugs were identified in the nationwide Danish Prescription Database, available between 1995 and 2008. Incident breast cancers were identified in the Danish Cancer Registry and further classifying by ER status. Relative risks (RR) were compared to nonusers using age- and period-adjusted incidence rate ratios.Two thousand one hundred forty-four of 104,648 women using digoxin developed breast cancer. Current digoxin users were at increased risk of breast cancer (RR, 1.39; 95% CI, 1.32 to 1.46), but risk was not increased in former users (RR, 0.91; 95% CI, 0.83 to 1.00). The increased risks in digoxin users were marginally higher for ER-positive breast cancers (RR, 1.35; 95% CI, 1.26 to 1.45) and ER unknown breast cancers (RR, 1.51; 95% CI, 1.38 to 1.64) than for ER-negative breast cancers (RR, 1.20; 95% CI, 1.03 to 1.40). Among 137,493 women exposed to angina drugs only (a comparison group with cardiovascular disease; n = 2,658 breast cancers), incidence was not increased in current or former users.Women currently using digoxin had a significantly increased risk of breast cancer. Risk normalized when digoxin was stopped. No risk increases were observed in women using angina drugs only. The higher risk of developing ER-positive breast cancers supports an estrogen-mimicking mechanism.

    View details for DOI 10.1200/JCO.2010.32.8146

    View details for Web of Science ID 000291032200025

    View details for PubMedID 21422417

  • Sequence variants at CYP1A1-CYP1A2 and AHR associate with coffee consumption HUMAN MOLECULAR GENETICS Sulem, P., Gudbjartsson, D. F., Geller, F., Prokopenko, I., Feenstra, B., Aben, K. K., Franke, B., den Heijer, M., Kovacs, P., Stumvoll, M., Maegi, R., Yanek, L. R., Becker, L. C., Boyd, H. A., Stacey, S. N., Walters, G. B., Jonasdottir, A., Thorleifsson, G., Holm, H., Gudjonsson, S. A., Rafnar, T., Bjornsdottir, G., Becker, D. M., Melbye, M., Kong, A., Toenjes, A., Thorgeirsson, T., Thorsteinsdottir, U., Kiemeney, L. A., Stefansson, K. 2011; 20 (10): 2071-2077

    Abstract

    Coffee is the most commonly used stimulant and caffeine is its main psychoactive ingredient. The heritability of coffee consumption has been estimated at around 50%. We performed a meta-analysis of four genome-wide association studies of coffee consumption among coffee drinkers from Iceland (n = 2680), The Netherlands (n = 2791), the Sorbs Slavonic population isolate in Germany (n = 771) and the USA (n = 369) using both directly genotyped and imputed single nucleotide polymorphisms (SNPs) (2.5 million SNPs). SNPs at the two most significant loci were also genotyped in a sample set from Iceland (n = 2430) and a Danish sample set consisting of pregnant women (n = 1620). Combining all data, two sequence variants significantly associated with increased coffee consumption: rs2472297-T located between CYP1A1 and CYP1A2 at 15q24 (P = 5.4 · 10(-14)) and rs6968865-T near aryl hydrocarbon receptor (AHR) at 7p21 (P = 2.3 · 10(-11)). An effect of ∼0.2 cups a day per allele was observed for both SNPs. CYP1A2 is the main caffeine metabolizing enzyme and is also involved in drug metabolism. AHR detects xenobiotics, such as polycyclic aryl hydrocarbons found in roasted coffee, and induces transcription of CYP1A1 and CYP1A2. The association of these SNPs with coffee consumption was present in both smokers and non-smokers.

    View details for DOI 10.1093/hmg/ddr086

    View details for Web of Science ID 000289837400018

    View details for PubMedID 21357676

    View details for PubMedCentralID PMC3080612

  • Use of Angiotensin Receptor Blockers and the Risk of Cancer CIRCULATION Pasternak, B., Svanstrom, H., Callreus, T., Melbye, M., Hviid, A. 2011; 123 (16): 1729-U77

    Abstract

    A recent meta-analysis of randomized trials suggested that use of angiotensin receptor blockers (ARBs) may be associated with a modestly increased risk of incident cancer, particularly lung cancer.We linked individual-level data from Danish registries on filled drug prescriptions, diagnostic information, and covariates. In a nationwide cohort of new users of ARBs and angiotensin-converting enzyme inhibitors ≥35 years of age during 1998 to 2006, we compared incidence rates of all cancer, cancer subgroups by anatomic site, and cancer mortality. Among 107 466 ARB users, 3954 cases of cancer were detected during 312 753 person-years of follow-up compared with 6214 cases during 435 207 person-years of follow-up in 209 692 angiotensin-converting enzyme inhibitor users (adjusted rate ratio, 0.99; 95% confidence interval, 0.95 to 1.03). Cancer risk did not increase with increasing duration of ARB exposure (increase in rate ratio per year, 0.99; 95% confidence interval, 0.99 to 1.00,) and was similar across individual ARBs. In subgroup analyses, there was a significant association between ARB use and cancer of male genital organs (rate ratio, 1.15; 95% confidence interval, 1.02 to 1.28), but no significantly increased risk of any of the other 15 cancer subgroups, including lung cancer (rate ratio, 0.92; 95% confidence interval, 0.82 to 1.02). For cancer mortality, the rate ratio was 0.77 (95% confidence interval, 0.72 to 0.82).In this large nationwide cohort, use of ARBs was not significantly associated with increased risk of incident cancer overall or of lung cancer.

    View details for DOI 10.1161/CIRCULATIONAHA.110.007336

    View details for Web of Science ID 000289833500009

    View details for PubMedID 21482967

  • GWAS of Follicular Lymphoma Reveals Allelic Heterogeneity at 6p21.32 and Suggests Shared Genetic Susceptibility with Diffuse Large B-cell Lymphoma PLOS GENETICS Smedby, K. E., Foo, J. N., Skibola, C. F., Darabi, H., Conde, L., Hjalgrim, H., Kumar, V., Chang, E. T., Rothman, N., Cerhan, J. R., Brooks-Wilson, A. R., Rehnberg, E., Irwan, I. D., Ryder, L. P., Brown, P. N., Bracci, P. M., Agana, L., Riby, J., Cozen, W., Davis, S., Hartge, P., Morton, L. M., Severson, R. K., Wang, S. S., Slager, S. L., Fredericksen, Z. S., Novak, A. J., Kay, N. E., Habermann, T. M., Armstrong, B., Kricker, A., Milliken, S., Purdue, M. P., Vajdic, C. M., Boyle, P., Lan, Q., Zahm, S. H., Zhang, Y., Zheng, T., Leach, S., Spinelli, J. J., Smith, M. T., Chanock, S. J., Padyukov, L., Alfredsson, L., Klareskog, L., Glimelius, B., Melbye, M., Liu, E. T., Adami, H., Humphreys, K., Liu, J. 2011; 7 (4)

    Abstract

    Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL-associated locus on 6p21.32, rs2647012 (OR(combined)  = 0.64, P(combined)  = 2 × 10(-21)) located 962 bp away from rs10484561 (r(2)<0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012:OR(adjusted)  = 0.70, P(adjusted)  =  4 × 10(-12); rs10484561:OR(adjusted)  = 1.64, P(adjusted)  = 5 × 10(-15)). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL-associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (OR(combined)  = 1.36, P(combined)  =  1.4 × 10(-7)). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL.

    View details for DOI 10.1371/journal.pgen.1001378

    View details for Web of Science ID 000289977000026

    View details for PubMedID 21533074

    View details for PubMedCentralID PMC3080853

  • Chronic Suppurative Otitis Media in a Birth Cohort of Children in Greenland Population-based Study of Incidence and Risk Factors PEDIATRIC INFECTIOUS DISEASE JOURNAL Koch, A., Homoe, P., Pipper, C., Hjuler, T., Melbye, M. 2011; 30 (1): 25-29

    Abstract

    Inuits of the Arctic experience very high rates of chronic suppurative otitis media (CSOM), yet world-wide, very little is known about the epidemiology of CSOM. The study aims were to determine incidence, median age at debut, risk factors, and associated population attributable risks for CSOM in young children in Sisimiut, the second biggest town of Greenland (population 5400), where living conditions are relatively western and approximately 90% are Inuits.A population-based birth cohort of 465 children aged between 0 and 4 years was followed for a 2-year period (1996 to 1998), and cases of CSOM were registered based on medical history and clinical examinations. Kaplan-Meier curves were used for estimations of cumulative risk and Cox regression analyses for hazard rates associated with risk factors.Cumulative risk of CSOM at 4 years of age was 14%, and median age at debut was 336 days. Risk factors were attending childcare centers (hazard ratio [HR]: 3.18, 95% confidence interval [CI]: 1.53- 6.61), having smokers in the household (HR: 4.56, 95% CI: 1.07-19.4), having a mother who reported a history of purulent ear discharge (3.27, 95% CI: 1.74-6.13), having a high burden of upper respiratory tract infections (HR: 1.19, 95% CI: 1.03-1.37), and being Inuit (HR: 5.56, 95% CI: 0.78-50).Greenlandic children have high rates of CSOM with debut early in life, but the identified risk factors and the associated population attributable risks indicate that preventive measures regarding use of childcare centers and passive smoking may reduce the high frequency of CSOM in this high-risk population.

    View details for DOI 10.1097/INF.0b013e3181efaa11

    View details for Web of Science ID 000285498800008

    View details for PubMedID 20700079

  • Vitamin D Receptor Genotypes, Ultraviolet Radiation Exposure, and Risk of Non-Hodgkin Lymphoma AMERICAN JOURNAL OF EPIDEMIOLOGY Smedby, K. E., Eloranta, S., Duvefelt, K., Melbye, M., Humphreys, K., Hjalgrim, H., Chang, E. T. 2011; 173 (1): 48-54

    Abstract

    Ultraviolet radiation (UVR) exposure may influence risk of non-Hodgkin lymphoma (NHL) through vitamin D, with antineoplastic effects mediated through the vitamin D receptor (VDR). To explore the role of vitamin D in NHL risk and the potential interaction with UVR, the authors genotyped 10 VDR polymorphisms in 2,448 NHL patients and 1,981 controls from Denmark and Sweden who were recruited in 1999-2002. Odds ratios and 95% confidence intervals were computed with logistic regression. P values were 2-sided. Most VDR variants (e.g., rs731236/TaqI, rs15444410/BsmI) were not associated with overall risk of NHL, but there was some evidence of a positive association between rs4760655 and follicular lymphoma risk (nominal P(trend) = 0.004, corrected P(trend) = 0.24). There was no support for an effect of interaction between VDR variants and UVR exposure on risk of overall NHL or B-cell lymphoma subtypes. However, there was some evidence that rs731236 altered associations between UVR and T-cell NHL risk; while increasing UVR frequency lowered T-cell NHL risk among rs731236 TT carriers, an elevated risk was observed among rs731236 CC carriers (nominal P(interaction) ≤ 0.008, corrected P(interaction) ≥ 0.12). VDR does not appear to harbor major determinants of NHL risk, except perhaps for follicular lymphoma. Possible heterogeneity in effects of UVR exposure on T-cell lymphoma risk by VDR rs731236 genotype merits further investigation.

    View details for DOI 10.1093/aje/kwq340

    View details for Web of Science ID 000285412200005

    View details for PubMedID 21076051

  • Testosterone Levels in Umbilical-Cord Blood and Risk of Pyloric Stenosis PEDIATRICS Krogh, C., Cohen, A. S., Basit, S., Hougaard, D. M., Biggar, R. J., Wohlfahrt, J., Melbye, M., Fischer, T. K. 2011; 127 (1): E197-E201

    Abstract

    The risk of infantile hypertrophk pylonc stenosis is ∼5 times more common in male than female infants. It has been hypothesized that the higher risk among male infants is associated with high levels of testosterone causing hypertrophy of the pylorus muscle. To test this hypothesis, we examined the association between the testosterone levels in the umbilical-cord blood and the risk of infantile hypertrophic pyloric stenosis.We conducted a matched case-control study nested in the Danish National Birth Cohort using risk-set sampling. From a cohort of 101 042 pregnancies, we identified umbilical-cord blood samples from 46 case subjects (43 male and 3 female infants) who developed infantile hypertrophic pyloric stenosis in the first year of life and 150 gender- and gestational age-matched control subjects. The testosterone levels were measured by liquid chromatography-tandem mass spectrometry. Rate ratios were estimated by using conditional logistic regression.In male infants, the mean testosterone level at birth was 0.78 nmol/L in case subjects and 0.91 nmol/L in control subjects. The rate of infantile hypertrophic pyloric stenosis was inversely, albeit insignificantly, associated with the testosterone levels in male infants; there was a 29% (95% confidence interval: -46% to 65%; P = 35) lower rate per nmol/L. The association was not modified according to age, gestational age, or birth order.We found no support for the hypothesis that high testosterone levels in the umbilical-cord blood are strongly associated with a subsequently higher risk for infantile hypertrophic pyloric stenosis in male infants.

    View details for DOI 10.1542/peds.2010-2127

    View details for Web of Science ID 000285782200025

    View details for PubMedID 21172998

  • Risk of Gastric Cancer and Peptic Ulcers in Relation to ABO Blood Type: A Cohort Study AMERICAN JOURNAL OF EPIDEMIOLOGY Edgren, G., Hjalgrim, H., Rostgaard, K., Norda, R., Wikman, A., Melbye, M., Nyren, O. 2010; 172 (11): 1280-1285

    Abstract

    Blood group A was found to be associated with gastric cancer in the 1950s. Strikingly, for peptic ulcers an increased risk has been shown for blood group O. However, previous investigations have generally been poorly conducted and have failed to take a unifying approach to these observations. Using the Scandinavian Donations and Transfusions (referred to as "SCANDAT") database, the authors established a cohort of Swedish and Danish blood donors with known blood type and followed these for the occurrence of gastric cancer and peptic ulcers through December 31, 2002. Cases were ascertained by using nationwide cancer and hospital registers. Altogether, 1,089,022 donors were followed for up to 35 years, during which 688 gastric cancer cases and 5,667 peptic ulcer cases accrued. Poisson regression analyses confirmed an increased risk of gastric cancer among individuals with blood group A (incidence rate ratio = 1.20, 95% confidence interval: 1.02, 1.42) and conversely that peptic ulcer risk was instead highest among those with blood group O. In this large, population-based cohort study, the authors have confirmed the association between blood group A and gastric cancer. In addition, they give further support to the notion that individuals with blood group O have a higher risk of peptic ulcers than those with other blood groups.

    View details for DOI 10.1093/aje/kwq299

    View details for Web of Science ID 000284634900007

    View details for PubMedID 20937632

  • A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3) NATURE GENETICS Enciso-Mora, V., Broderick, P., Ma, Y., Jarrett, R. F., Hjalgrim, H., Hemminki, K., van den Berg, A., Olver, B., Lloyd, A., Dobbins, S. E., Lightfoot, T., van Leeuwen, F. E., Foersti, A., Diepstra, A., Broeks, A., Vijayakrishnan, J., Shield, L., Lake, A., Montgomery, D., Roman, E., Engert, A., von Strandmann, E. P., Reiners, K. S., Nolte, I. M., Smedby, K. E., Adami, H., Russell, N. S., Glimelius, B., Hamilton-Dutoit, S., de Bruin, M., Ryder, L. P., Molin, D., Sorensen, K. M., Chang, E. T., Taylor, M., Cooke, R., Hofstra, R., Westers, H., van Wezel, T., van Eijk, R., Ashworth, A., Rostgaard, K., Melbye, M., Swerdlow, A. J., Houlston, R. S. 2010; 42 (12): 1126-?

    Abstract

    To identify susceptibility loci for classical Hodgkin's lymphoma (cHL), we conducted a genome-wide association study of 589 individuals with cHL (cases) and 5,199 controls with validation in four independent samples totaling 2,057 cases and 3,416 controls. We identified three new susceptibility loci at 2p16.1 (rs1432295, REL, odds ratio (OR) = 1.22, combined P = 1.91 × 10(-8)), 8q24.21 (rs2019960, PVT1, OR = 1.33, combined P = 1.26 × 10(-13)) and 10p14 (rs501764, GATA3, OR = 1.25, combined P = 7.05 × 10(-8)). Furthermore, we confirmed the role of the major histocompatibility complex in disease etiology by revealing a strong human leukocyte antigen (HLA) association (rs6903608, OR = 1.70, combined P = 2.84 × 10(-50)). These data provide new insight into the pathogenesis of cHL.

    View details for DOI 10.1038/ng.696

    View details for Web of Science ID 000284578800017

    View details for PubMedID 21037568

  • Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies NATURE GENETICS Elks, C. E., Perry, J. R., Sulem, P., Chasman, D. I., Franceschini, N., He, C., Lunetta, K. L., Visser, J. A., Byrne, E. M., Cousminer, D. L., Gudbjartsson, D. F., Esko, T., Feenstra, B., Hottenga, J., Koller, D. L., Kutalik, Z., Lin, P., Mangino, M., Marongiu, M., McArdle, P. F., Smith, A. V., Stolk, L., Van Wingerden, S. H., Zhao, J. H., Albrecht, E., Corre, T., Ingelsson, E., Hayward, C., Magnusson, P. K., Smith, E. N., Ulivi, S., Warrington, N. M., Zgaga, L., Alavere, H., Amin, N., Aspelund, T., Bandinelli, S., Barroso, I., Berenson, G. S., Bergmann, S., Blackburn, H., Boerwinkle, E., Buring, J. E., Busonero, F., Campbell, H., Chanock, S. J., Chen, W., Cornelis, M. C., Couper, D., Coviello, A. D., D'Adamo, P., de Faire, U., de Geus, E. J., Deloukas, P., Doering, A., Smith, G. D., Easton, D. F., Eiriksdottir, G., Emilsson, V., Eriksson, J., Ferrucci, L., Folsom, A. R., Foroud, T., Garcia, M., Gasparini, P., Geller, F., Gieger, C., Gudnason, V., Hall, P., Hankinson, S. E., Ferreli, L., Heath, A. C., Hernandez, D. G., Hofman, A., Hu, F. B., Illig, T., Jaervelin, M., Johnson, A. D., Karasik, D., Khaw, K., Kiel, D. P., Kilpelaeinen, T. O., Kolcic, I., Kraft, P., Launer, L. J., Laven, J. S., Li, S., Liu, J., Levy, D., Martin, N. G., McArdle, W. L., Melbye, M., Mooser, V., Murray, J. C., Murray, S. S., Nalls, M. A., Navarro, P., Nelis, M., Ness, A. R., Northstone, K., Oostra, B. A., Peacock, M., Palmer, L. J., Palotie, A., Pare, G., Parker, A. N., Pedersen, N. L., Peltonen, L., Pennell, C. E., Pharoah, P., Polasek, O., Plump, A. S., Pouta, A., Porcu, E., Rafnar, T., Rice, J. P., Ring, S. M., Rivadeneira, F., Rudan, I., Sala, C., Salomaa, V., Sanna, S., Schlessinger, D., Schork, N. J., Scuteri, A., Segre, A. V., Shuldiner, A. R., Soranzo, N., Sovio, U., Srinivasan, S. R., Strachan, D. P., Tammesoo, M., Tikkanen, E., Toniolo, D., Tsui, K., Tryggvadottir, L., Tyrer, J., Uda, M., van Dam, R. M., van Meurs, J. B., Vollenweider, P., Waeber, G., Wareham, N. J., Waterworth, D. M., Weedon, M. N., Wichmann, H. E., Willemsen, G., Wilson, J. F., Wright, A. F., Young, L., Zhai, G., Zhuang, W. V., Bierut, L. J., Boomsma, D. I., Boyd, H. A., Crisponi, L., Demerath, E. W., van Duijn, C. M., Econs, M. J., Harris, T. B., Hunter, D. J., Loos, R. J., Metspalu, A., Montgomery, G. W., Ridker, P. M., Spector, T. D., Streeten, E. A., Stefansson, K., Thorsteinsdottir, U., Uitterlinden, A. G., Widen, E., Murabito, J. M., Ong, K. K., Murray, A. 2010; 42 (12): 1077-U73

    Abstract

    To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.

    View details for DOI 10.1038/ng.714

    View details for Web of Science ID 000284578800010

    View details for PubMedID 21102462

    View details for PubMedCentralID PMC3140055

  • Both high and low serum vitamin D concentrations are associated with tuberculosis: a case-control study in Greenland BRITISH JOURNAL OF NUTRITION Nielsen, N. O., Skifte, T., Andersson, M., Wohlfahrt, J., Soborg, B., Koch, A., Melbye, M., Ladefoged, K. 2010; 104 (10): 1487-1491

    Abstract

    Vitamin D deficiency has been associated with increased risk of tuberculosis (TB). Changes from a traditional to a Westernised diet among Greenlanders have resulted in reduced serum vitamin D, leading to considerations of whether preventive vitamin D supplementation should be introduced. The association between vitamin D status and TB was examined to assess the feasibility of vitamin D supplementation in Greenland. This was examined in a case-control study involving seventy-two matched pairs of TB patients (cases) and controls aged 8-74 years. Cases were diagnosed with TB during 2004-6 based on clinical findings in combination with either (1) positive Mycobacterium tuberculosis culture, (2) characteristic X-ray abnormalities together with a positive tuberculin skin test or a positive interferon-γ release assay or (3) characteristic histology. Controls were individually matched on age ( ± 5 years), sex and district. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were measured and OR of TB were the outcome. Compared with individuals with 25(OH)D concentrations between 75 and 140 nmol/l, individuals with concentrations < 75 nmol/l (OR 6.5; 95% CI 1.8, 23.5) or > 140 nmol/l (OR 6.5; 95% CI 1.9, 22.2) had higher risks of active TB (P = 0.003; adjustment for alcohol and ethnicity). Supplementing individuals with low vitamin D to normalise serum 25(OH)D concentrations was estimated to result in a 29% reduction in the number of TB cases. The study indicated that vitamin D supplementation may be beneficial to individuals with insufficient vitamin D concentrations but may increase the risk of TB among individuals with normal or high concentrations.

    View details for DOI 10.1017/S0007114510002333

    View details for Web of Science ID 000284034900010

    View details for PubMedID 20553638

  • Photosensitizing Medication Use and Risk of Skin Cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Kaae, J., Boyd, H. A., Hansen, A. V., Wulf, H. C., Wohlfahrt, J., Melbye, M. 2010; 19 (11): 2942-2949

    Abstract

    Many commonly used medications, including both medications for long-term (daily) use and short-term use (treatment courses of finite duration), have photosensitizing properties. Whether use of these medications affects skin cancer risk, however, is unclear.Using a cohort of all Danish residents ≥15 years old in 1995 to 2006 (n = 4,761,749) and information from Danish national registers, we examined associations between use of photosensitizing medications and risk of basal cell carcinoma, cutaneous malignant melanoma, Merkel cell carcinoma, and squamous cell carcinoma.Users of only 2 of 19 medications for long-term use (methyldopa and furosemide) had both a ≥20% increased risk of skin cancer (compared with nonusers) and an increase in risk with increasing duration of use; these effects were limited to basal cell carcinoma and squamous cell carcinoma, respectively. In contrast, 8 of 10 medications for short-term use were associated with both a ≥20% increased risk of skin cancer and an increase in risk with increasing use for at least one of the four cancers.We found little evidence of an increased risk of skin cancer among users of photosensitizing medications for long-term daily use, but could not rule out the possibility that users of some photosensitizing medications for short-term use may have an increased risk of skin cancer.Previous studies have been limited to specific medication types (e.g., antidiuretics). Our study examined the effect of a wide range of photosensitizing medications on skin cancer risk and suggests that future work should focus on photosensitizing medications for short-term use.

    View details for DOI 10.1158/1055-9965.EPI-10-0652

    View details for Web of Science ID 000283991600028

    View details for PubMedID 20861398

  • Ongoing tuberculosis transmission to children in Greenland EUROPEAN RESPIRATORY JOURNAL Soborg, B., Koch, A., Thomsen, V. O., Ladefoged, K., Andersson, M., Wohlfahrt, J., Melbye, M., Andersen, A. B. 2010; 36 (4): 878-884

    Abstract

    Inuit in the Arctic are experiencing an increase in tuberculosis cases, reaching levels in Greenland comparable to high-incidence countries. This prompted us to study the level of tuberculosis transmission to Greenlandic children. Specifically, we estimated the current prevalence of Mycobacterium tuberculosis infection (MTI) and the underlying annual risk of MTI. 2,231 Greenlandic school children aged 5-17 yrs (∼25% of the Greenlandic population in the relevant age group) were tested for MTI using the tuberculin skin test and the QuantiFERON®-TB Gold in-tube test. Subjects with dual-positive results were considered infected and subjects with dual-negative results uninfected. The children with discordant test results were classified as probably having MTI and analysed separately. 8.1% of the children had dual-positive test results. The annual risk of MTI was estimated as 0.80% (95% CI 0.67-0.92%) giving a cumulative risk at the 18th birthday of 13.4%. The annual risk of MTI varied substantially by ethnicity (0.87% in Inuit children, 0.02% in non-Inuit children; p<0.001) and by location (0.13% on the west coast, 1.68% on the south coast; p<0.001). M. tuberculosis transmission occurs at a very high level in Inuit children with pronounced geographic differences emphasising the need for immediate public health interventions.

    View details for DOI 10.1183/09031936.00015510

    View details for Web of Science ID 000282473700030

    View details for PubMedID 20516050

  • Perinatal risk factors for strabismus INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Torp-Pedersen, T., Boyd, H. A., Poulsen, G., Haargaard, B., Wohlfahrt, J., Holmes, J. M., Melbye, M. 2010; 39 (5): 1229-1239

    Abstract

    Little is known about the aetiological factors underlying strabismus. We undertook a large cohort study to investigate perinatal risk factors for strabismus, overall and by subtype.Orthoptists reviewed ophthalmological records for Danish National Birth Cohort (DNBC) children examined for strabismus in hospital ophthalmology departments or by ophthalmologists in private practice. Information on perinatal characteristics was obtained from national registers. We used log-linear binomial regression and polytomous logistic regression to estimate risk ratios for strabismus overall and by strabismus subtype, respectively.Among 96,842 DNBC children born in Denmark between 1996 and 2003, we identified 8783 children who had been evaluated for strabismus. Ophthalmological records were available for 5655 of these children, of whom 1321 were diagnosed with strabismus. In multivariable analysis, low birth weight, prematurity, large head circumference and presence of congenital abnormalities were all associated with increased risk of strabismus. Presence of congenital abnormalities was more strongly associated with exotropia than with esotropia. Of 183 exotropia cases, 40 (22%) had congenital abnormality. Although not associated with esotropia, delivery by Caesarean section was associated with exotropia (relative risk = 1.65; 95% confidence interval 1.16-2.34). After adjustment for birth weight, Apgar score at 5 min, multiple gestation and parental ages were not associated with strabismus overall.Congenital abnormalities, low birth weight, prematurity and large head circumference were independent risk factors for strabismus. Differences in risk factors for esotropia and exotropia suggest that strabismus subtypes may have different underlying aetiologies. The proportion of exotropic children with congenital abnormalities suggests that a large angle constant exotropia in an infant should alert physicians to the possibility of a congenital abnormality.

    View details for DOI 10.1093/ije/dyq092

    View details for Web of Science ID 000283932000018

    View details for PubMedID 20525734

  • Prospective Study of Human Papillomavirus (HPV) Types, HPV Persistence, and Risk of Squamous Cell Carcinoma of the Cervix CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Sundstrom, K., Eloranta, S., Sparen, P., Dahlstrom, L. A., Gunnell, A., Lindgren, A., Palmgren, J., Ploner, A., Sanjeevi, C. B., Melbye, M., Dillner, J., Adami, H., Ylitalo, N. 2010; 19 (10): 2469-2478

    Abstract

    The link between squamous cell cervical carcinoma and human papillomavirus (HPV) 16/18 is well established, but the magnitude of the risk association is uncertain and the importance of other high-risk HPV (HRHPV) types is unclear.In two prospective nested case-control series among women participating in cytologic screening in Sweden, we collected 2,772 cervical smears from 515 women with cancer in situ (CIS), 315 with invasive squamous cell carcinoma (SCC), and individually matched controls. All smears were tested for HPV with PCR assays, and the median follow-up until diagnosis was 5 to 7 years. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (95% CI).The presence of HPV16/18 in the first smear was associated with 8.5-fold (95% CI, 5.3-13.7) and 18.6-fold (95% CI, 9.0-38.9) increased risks of CIS and SCC, respectively, compared with women negative for HPV. Infection with other HRHPV types in the first smear was also associated with significantly increased risks for both CIS and SCC. Persistence of HPV16 infection conferred a RR of 18.5 (95% CI, 6.5-52.9) for CIS and 19.5 (95% CI, 4.7-81.7) for SCC. The HPV16/18 attributable risk proportion was estimated at 30% to 50% for CIS, and 41% to 47% for SCC. Other HRHPV types also conferred significant proportions.Our large population-based study provides quantification of risks for different HPV types and prospective evidence that non-16/18 HRHPV types increase the risk for future cervical cancer.This study gives further insights into cervical cancer risk stratification with implications for HPV-based prevention strategies.

    View details for DOI 10.1158/1055-9965.EPI-10-0424

    View details for Web of Science ID 000282590500008

    View details for PubMedID 20671136

    View details for PubMedCentralID PMC2952359

  • Birth Order and Risk of Non-Hodgkin Lymphoma-True Association or Bias? AMERICAN JOURNAL OF EPIDEMIOLOGY Grulich, A. E., Vajdic, C. M., Falster, M. O., Kane, E., Smedby, K. E., Bracci, P. M., de Sanjose, S., Becker, N., Turner, J., Martinez-Maza, O., Melbye, M., Engels, E. A., Vineis, P., Costantini, A. S., Holly, E. A., Spinelli, J. J., La Vecchia, C., Zheng, T., Chiu, B. C., Franceschi, S., Cocco, P., Maynadie, M., Foretova, L., Staines, A., Brennan, P., Davis, S., Severson, R. K., Cerhan, J. R., Breen, E. C., Birmann, B., Cozen, W. 2010; 172 (6): 621-630

    Abstract

    There is inconsistent evidence that increasing birth order may be associated with risk of non-Hodgkin lymphoma (NHL). The authors examined the association between birth order and related variables and NHL risk in a pooled analysis (1983-2005) of 13,535 cases and 16,427 controls from 18 case-control studies within the International Lymphoma Epidemiology Consortium (InterLymph). Overall, the authors found no significant association between increasing birth order and risk of NHL (P-trend = 0.082) and significant heterogeneity. However, a significant association was present for a number of B- and T-cell NHL subtypes. There was considerable variation in the study-specific risks which was partly explained by study design and participant characteristics. In particular, a significant positive association was present in population-based studies, which had lower response rates in cases and controls, but not in hospital-based studies. A significant positive association was present in higher-socioeconomic-status (SES) participants only. Results were very similar for the related variable of sibship size. The known correlation of high birth order with low SES suggests that selection bias related to SES may be responsible for the association between birth order and NHL.

    View details for DOI 10.1093/aje/kwq167

    View details for Web of Science ID 000281949100001

    View details for PubMedID 20720098

    View details for PubMedCentralID PMC2950815

  • Pattern of declining hemoglobin concentration before cancer diagnosis INTERNATIONAL JOURNAL OF CANCER Edgren, G., Bagnardi, V., Bellocco, R., Hjalgrim, H., Rostgaard, K., Melbye, M., Reilly, M., Adami, H., Hall, P., Nyren, O. 2010; 127 (6): 1429-1436

    Abstract

    Although anemia is widely considered an early sign of malignant disease, little is known about the pattern of hemoglobin decline before diagnosis. As an approach to understanding the duration of the preclinical phase of different types of malignant diseases, we investigated prediagnostic hemoglobin concentration changes in a large cohort of blood donors. Using a nested case-control design, we analyzed a population-based cohort comprising 1.1 million Scandinavian blood donors with complete follow-up through record linkage to population and cancer registers. A total of 16,375 cancer cases were identified, for whom we selected 161,995 controls. We used conditional logistic regression to estimate the risk of cancer in relation to hemoglobin concentration during the 5 years preceding the cancer diagnosis. Hemoglobin concentration decline began already 3 years before diagnosis of stomach cancer, multiple myeloma, and lymphatic leukemia; 2 years before diagnosis of small intestinal and colon cancer as well as of Hodgkin lymphoma. A decline was evident during the last year for non-Hodgkin lymphoma and myeloid/monocytic leukemia, whereas no change was found for cancer of the esophagus, breast or prostate. In conclusion, in this study, we have demonstrated that the pattern of declining hemoglobin concentration before cancer diagnosis varies considerably between malignancies without being a suitable screening tool for any of them. For some malignancies, however, the long duration of hemoglobin decline before clinical diagnosis suggests a substantial lead-time with systemic effects, during which earlier diagnosis should be achievable by emerging diagnostic tools.

    View details for DOI 10.1002/ijc.25122

    View details for Web of Science ID 000281340100018

    View details for PubMedID 20020493

  • Mannose-Binding Lectin Genotypes and Susceptibility to Epstein-Barr Virus Infection in Infancy CLINICAL AND VACCINE IMMUNOLOGY Friborg, J. T., Jarrett, R. F., Koch, A., Garred, P., Freeland, J. M., Andersen, A., Melbye, M. 2010; 17 (9): 1484-1487

    Abstract

    In a cohort study of children < 4 years of age in Greenland, mannose-binding lectin (MBL2) genotypes and Epstein-Barr virus (EBV) antibody levels were determined. EBV seropositivity was significantly lower and time to seroconversion increased in MBL-insufficient compared with MBL-sufficient children, indicating that MBL may be involved in primary EBV infection in infancy.

    View details for DOI 10.1128/CVI.00527-09

    View details for Web of Science ID 000281444300027

    View details for PubMedID 20610664

    View details for PubMedCentralID PMC2944456

  • Trichinella infection in a hunting community in East Greenland EPIDEMIOLOGY AND INFECTION Moller, L. N., Koch, A., Petersen, E., Hjuler, T., Kapel, C. M., Andersen, A., Melbye, M. 2010; 138 (9): 1252-1256

    Abstract

    Trichinella nativa infection (trichinellosis) is highly prevalent in Arctic wildlife, but the human burden of trichinellosis in present-day Greenland is unknown. The study aimed to determine Trichinella seroprevalence in an eastern Greenlandic hunting community and to evaluate risk factors for seropositivity. Overall, 998 inhabitants aged 10 years in the Ammassalik municipality were tested for Trichinella-specific IgG antibodies. Background information was obtained from questionnaires. Seropositivity was 1.4% in persons aged <40 years and increased to >12% in those aged 60 years. Older age, occupation as hunter or fisherman, and consumption of polar bear meat significantly increased the risk of Trichinella seropositivity. The seropositivity age pattern probably reflects changes in dietary preferences, but could also reflect mandatory meat inspection since 1966. However, preventive measures against Trichinella infection should be strengthened in Greenland.

    View details for DOI 10.1017/S0950268810000282

    View details for Web of Science ID 000281275300005

    View details for PubMedID 20144253

  • Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32 NATURE GENETICS Conde, L., Halperin, E., Akers, N. K., Brown, K. M., Smedby, K. E., Rothman, N., Nieters, A., Slager, S. L., Brooks-Wilson, A., Agana, L., Riby, J., Liu, J., Adami, H., Darabi, H., Hjalgrim, H., Low, H., Humphreys, K., Melbye, M., Chang, E. T., Glimelius, B., Cozen, W., Davis, S., Hartge, P., Morton, L. M., Schenk, M., Wang, S. S., Armstrong, B., Kricker, A., Milliken, S., Purdue, M. P., Vajdic, C. M., Boyle, P., Lan, Q., Zahm, S. H., Zhang, Y., Zheng, T., Becker, N., Benavente, Y., Boffetta, P., Brennan, P., Butterbach, K., Cocco, P., Foretova, L., Maynadie, M., de Sanjose, S., Staines, A., Spinelli, J. J., Achenbach, S. J., Call, T. G., Camp, N. J., Glenn, M., Caporaso, N. E., Cerhan, J. R., Cunningham, J. M., Goldin, L. R., Hanson, C. A., Kay, N. E., Lanasa, M. C., Leis, J. F., Marti, G. E., Rabe, K. G., Rassenti, L. Z., Spector, L. G., Strom, S. S., Vachon, C. M., Weinberg, J. B., Holly, E. A., Chanock, S., Smith, M. T., Bracci, P. M., Skibola, C. F. 2010; 42 (8): 661-664

    Abstract

    To identify susceptibility loci for non-Hodgkin lymphoma subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma at 6p21.32 (rs10484561, combined P = 1.12 x 10(-29) and rs7755224, combined P = 2.00 x 10(-19); r(2) = 1.0), supporting the idea that major histocompatibility complex genetic variation influences follicular lymphoma susceptibility. We also found confirmatory evidence of a previously reported association between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined P = 4.24 x 10(-9)).

    View details for DOI 10.1038/ng.626

    View details for Web of Science ID 000280524000008

    View details for PubMedID 20639881

    View details for PubMedCentralID PMC2913472

  • Tonsillitis, tonsillectomy and Hodgkin's lymphoma INTERNATIONAL JOURNAL OF CANCER Vestergaard, H., Westergaard, T., Wohlfahrt, J., Hjalgrim, H., Melbye, M. 2010; 127 (3): 633-637

    Abstract

    It has been debated whether the reported increased risk of Hodgkin's lymphoma (HL) after tonsillectomy could be due to some underlying factor rather than the surgery itself. We studied whether not only tonsillectomy but also tonsillitis was associated with HL. This nationwide cohort study included all Danish residents during 1977-2001. Information on a diagnosis of tonsillitis, tonsillectomy, or HL was obtained from national registries. During 124 million person-years we observed 2,988 HL patients of whom 58 were tonsillectomized (most with preceding tonsillitis) and 14 were diagnosed with only tonsillitis at more than 1 year before HL diagnosis. Tonsillectomy was associated with a significantly increased HL risk in persons under 15 years of age as follows: 1-4 years after tonsillectomy, relative risk (RR) = 3.9 [95% CI: 1.4-11; n = 4]; >5 years after tonsillectomy, RR = 3.5 [1.4-8.5; n = 5]. No young cases of HL occurred among persons diagnosed with only tonsillitis. In contrast, 1-4 years after a hospital diagnosis of tonsillitis without subsequent tonsillectomy we found an increased HL risk in persons aged 15 years or above as follows: 15-34 years of age at HL diagnosis, RR = 3.5 [1.6-7.7; n = 6]; 35+ years, RR = 5.9 [2.2-16; n = 4]. Age at tonsillitis or tonsillectomy did not modify HL risk within the 3 age strata. An increased HL risk was found both after tonsillectomy and after an isolated diagnosis of tonsillitis. These results suggest that tonsillitis is a risk factor for HL and not that, as previously reported, only the surgical removal of tonsils is a risk factor.

    View details for DOI 10.1002/ijc.24973

    View details for Web of Science ID 000279131300014

    View details for PubMedID 19839050

  • Familial Aggregation and Heritability of Pyloric Stenosis JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Krogh, C., Fischer, T. K., Skotte, L., Biggar, R. J., Oyen, N., Skytthe, A., Goertz, S., Christensen, K., Wohlfahrt, J., Melbye, M. 2010; 303 (23): 2393-2399

    Abstract

    Pyloric stenosis is the most common condition requiring surgery in the first months of life. Case reports have suggested familial aggregation, but to what extent this is caused by common environment or inheritance is unknown.To investigate familial aggregation of pyloric stenosis from monozygotic twins to fourth-generation relatives according to sex and maternal and paternal contributions and to estimate disease heritability.Population-based cohort study of 1,999,738 children born in Denmark between 1977 and 2008 and followed up for the first year of life, during which 3362 children had surgery for pyloric stenosis.Familial aggregation of pyloric stenosis, evaluated by rate ratios.The incidence rate (per 1000 person-years) of pyloric stenosis in the first year of life was 1.8 for singletons and 3.1 for twins. The rate ratios of pyloric stenosis were 182 (95% confidence interval [CI], 70.7-467) for monozygotic twins, 29.4 (95% CI, 9.45-91.5) for dizygotic twins, 18.5 (95% CI, 13.7-25.1) for siblings, 4.99 (95% CI, 2.59-9.65) for half-siblings, 3.06 (95% CI, 2.10-4.44) for cousins, and 1.60 (95% CI, 0.51-4.99) for half-cousins. We found no difference in rate ratios for maternal and paternal relatives of children with pyloric stenosis and no difference according to sex of cohort member or sex of relative. The heritability of pyloric stenosis was 87%.Pyloric stenosis in Danish children shows strong familial aggregation and heritability.

    View details for DOI 10.1001/jama.2010.784

    View details for Web of Science ID 000278759200029

    View details for PubMedID 20551410

  • Merkel Cell Carcinoma: Incidence, Mortality, and Risk of Other Cancers JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Kaae, J., Hansen, A. V., Biggar, R. J., Boyd, H. A., Moore, P. S., Wohlfahrt, J., Melbye, M. 2010; 102 (11): 793-801

    Abstract

    Merkel cell carcinoma (MCC) is a rare skin cancer that was recently found to be associated with a polyomavirus and with immunosuppression, provoking new interest in its epidemiology. We conducted a nationwide study in Denmark to describe MCC incidence and mortality and the association between MCC and other cancers.We used data from Danish national health and population registers on MCC diagnoses, deaths, and population counts during the study period (1978-2006) to calculate MCC incidence rates, cumulative risks of MCC at age 100 years, and MCC mortality rates by tumor stage. We used Poisson regression to estimate the excess mortality rate ratio attributable to MCC and examined associations between MCC and other cancers diagnosed before and after the MCC diagnosis using standardized incidence rate ratios (SIRs). All statistical tests were two-sided.Between January 1, 1978, and December 31, 2006, 185 persons were diagnosed with MCC in Denmark. MCC incidence between 1995 and 2006 was 2.2 cases per million person-years. In the first year after MCC diagnosis, 22% of persons with localized disease died compared with 54% of patients with nonlocalized disease; by 5 years after diagnosis, the proportions of MCC patients who had died increased to 55% and 84%, respectively. MCC incidence was statistically significantly increased more than 1 year after a diagnosis of squamous cell carcinoma of the skin (SIR = 14.6, 95% confidence interval [CI] = 8.4 to 25.6), basal cell carcinoma (SIR = 4.3, 95% CI = 2.7 to 6.6), malignant melanoma (SIR = 3.3, 95% CI = 1.1 to 10.3), chronic lymphocytic leukemia (SIR = 12.0, 95% CI = 3.8 to 37.8), Hodgkin lymphoma (SIR = 17.6, 95% CI = 2.5 to 126), and non-Hodgkin lymphoma (SIR = 5.6, 95% CI = 1.4 to 22.4). Squamous cell carcinoma (SIR = 12.1, 95% CI = 5.1 to 29.1) and chronic lymphocytic leukemia (SIR = 14.7, 95% CI = 3.7 to 58.8) occurred in statistically significant excess more than 1 year after MCC diagnosis.These results support the existence of shared risk factors for MCC and other cancers. Heightened awareness of the association between MCC and other cancers, particularly squamous cell carcinoma and chronic lymphocytic leukemia, may facilitate earlier clinical detection and treatment of MCC, thereby improving patient survival.

    View details for DOI 10.1093/jnci/djq120

    View details for Web of Science ID 000278440900008

    View details for PubMedID 20424236

  • A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4 NATURE GENETICS Beaty, T. H., Murray, J. C., Marazita, M. L., Munger, R. G., Ruczinski, I., Hetmanski, J. B., Liang, K. Y., Wu, T., Murray, T., Fallin, M. D., Redett, R. A., Raymond, G., Schwender, H., Jin, S., Cooper, M. E., Dunnwald, M., Mansilla, M. A., Leslie, E., Bullard, S., Lidral, A. C., Moreno, L. M., Menezes, R., Vieira, A. R., Petrin, A., Wilcox, A. J., Lie, R. T., Jabs, E. W., Wu-Chou, Y. H., Chen, P. K., Wang, H., Ye, X., Huang, S., Yeow, V., Chong, S. S., Jee, S. H., Shi, B., Christensen, K., Melbye, M., Doheny, K. F., Pugh, E. W., Ling, H., Castilla, E. E., Czeizel, A. E., Ma, L., Field, L. L., Brody, L., Pangilinan, F., Mills, J. L., Molloy, A. M., Kirke, P. N., Scott, J. M., Arcos-Burgos, M., Scott, A. F. 2010; 42 (6): 525-U76

    Abstract

    Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635-0.778, P = 1.44 x 10(-11); and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292-1.587, P = 5.01 x 10(-12)) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes remained similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24, whereas Asian families showed stronger evidence for association with MAFB and ABCA4. Expression studies support a role for MAFB in palatal development.

    View details for DOI 10.1038/ng.580

    View details for Web of Science ID 000278081500019

    View details for PubMedID 20436469

    View details for PubMedCentralID PMC2941216

  • Duration of red blood cell storage and survival of transfused patients (CME) TRANSFUSION Edgren, G., Kamper-Jorgensen, M., Eloranta, S., Rostgaard, K., Custer, B., Ullum, H., Murphy, E. L., Busch, M. P., Reilly, M., Melbye, M., Hjalgrim, H., Nyren, O. 2010; 50 (6): 1185-1195

    Abstract

    Disquieting reports of increased complication and death rates after transfusions of red blood cells (RBCs) stored for more than 14 days prompted us to perform an observational retrospective cohort study of mortality in relation to storage time.We conducted a cohort study utilizing data on all recipients of at least one RBC transfusion in Sweden and Denmark between 1995 and 2002, as recorded in the Scandinavian Donations and Transfusions (SCANDAT) database. Relative risks of death in relation to storage time were estimated using Cox regression, adjusted for several possible confounding factors.After various exclusions, 404,959 transfusion episodes remained for analysis. The 7-day risk of death was similar in all exposure groups, but a tendency for a higher risk emerged among recipients of blood stored for 30 to 42 days (hazard ratio, 1.05; 95% confidence interval [CI], 0.97-1.12), compared to recipients of blood stored for 10 to 19 days. With 2-year follow-up, this excess remained at the same level (hazard ratio, 1.05; 95% CI, 1.02-1.08). No dose-response pattern was revealed and no differential effect was seen when the analyses were restricted to recipients of leukoreduced units only.Although a small excess mortality was noted in recipients of the oldest RBCs, the risk pattern was more consistent with weak confounding than with an effect of the momentary exposure to stored RBCs. It seems, thus, that any excess mortality conferred by older RBCs in the combined Swedish and Danish transfusion recipient population is likely less than 5%, which is considerably smaller than in the hitherto largest investigation.

    View details for DOI 10.1111/j.1537-2995.2010.02583.x

    View details for Web of Science ID 000278316500007

    View details for PubMedID 20158690

    View details for PubMedCentralID PMC3201703

  • Genetic variation in chromosomal translocation breakpoint and immune function genes and risk of non-Hodgkin lymphoma CANCER CAUSES & CONTROL Fernberg, P., Chang, E. T., Duvefelt, K., Hjalgrim, H., Eloranta, S., Sorensen, K. M., Porwit, A., Humphreys, K., Melbye, M., Smedby, K. E. 2010; 21 (5): 759-769

    Abstract

    Tumor necrosis factor (TNF) and interleukin 10 (IL10) are promising candidate susceptibility genes for non-Hodgkin lymphoma (NHL). Chromosomal translocation breakpoint genes are of interest, given their documented involvement in lymphoma progression.We analyzed 11 polymorphisms in BCL2, CCND1, MYC, TNF, and IL10 in a large, population-based, Danish-Swedish case-control study including 2,449 NHL cases and 1,980 controls. Relative risk of NHL was computed as odds ratios (OR).There was no clear evidence of associations between variants in BCL2, CCND1, and MYC and risk of NHL overall or subtypes. TNF rs1800629 was associated with risk of NHL (OR 1.53, 95% confidence interval, CI, 1.06-2.19 for minor allele homozygosity), T-cell lymphoma (OR 2.54, CI 1.27-5.09) and mantle cell lymphoma (OR 2.84, CI 1.38-5.87). IL10 rs1800890 was associated with risk of diffuse large B-cell lymphoma (OR 1.41, CI 1.08-1.85 for minor allele homozygosity) and mantle cell lymphoma (OR 1.77, CI 1.04-3.00). We did not replicate a previously reported interaction with autoimmunity.We found no support for a role of the studied variants in BCL2, CCND1, or MYC in risk of NHL or subtypes, but we provide further evidence of putative susceptibility loci in TNF and IL10 for specific NHL subtypes.

    View details for DOI 10.1007/s10552-010-9504-y

    View details for Web of Science ID 000276768500012

    View details for PubMedID 20087644

  • In-Utero Exposure to Smoking, Alcohol, Coffee, and Tea and Risk of Strabismus AMERICAN JOURNAL OF EPIDEMIOLOGY Torp-Pedersen, T., Boyd, H. A., Poulsen, G., Haargaard, B., Wohlfahrt, J., Holmes, J. M., Melbye, M. 2010; 171 (8): 868-875

    Abstract

    In a prospective, population-based cohort study, the authors investigated the effect of in-utero exposure to maternal smoking and consumption of alcohol, coffee, and tea on the risk of strabismus. They reviewed medical records for children in the Danish National Birth Cohort identified through national registers as possibly having strabismus. Relative risk estimates were adjusted for year of birth, social class, maternal smoking, maternal age at birth, and maternal coffee and tea consumption. The authors identified 1,321 cases of strabismus in a cohort of 96,842 Danish children born between 1996 and 2003. Maternal smoking was associated with a significantly elevated risk of strabismus in the child, increasing with number of cigarettes smoked per day (<5 cigarettes/day: relative risk (RR) = 0.95, 95% confidence interval (CI): 0.80, 1.14; 5-<10 cigarettes/day: RR = 1.38, 95% CI: 1.12, 1.70; > or =10 cigarettes/day: RR = 1.90, 95% CI: 1.57, 2.30). Nicotine replacement therapy was not associated with strabismus risk (RR = 1.22, 95% CI: 0.92, 1.61). Light maternal alcohol consumption was inversely associated with strabismus risk, whereas maternal coffee and tea drinking were not associated with strabismus risk. In conclusion, smoking during pregnancy is associated with an increased risk of strabismus in the offspring. Conversely, light alcohol consumption is associated with decreased risk.

    View details for DOI 10.1093/aje/kwq010

    View details for Web of Science ID 000277078300003

    View details for PubMedID 20338975

  • HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Hjalgrim, H., Rostgaard, K., Johnson, P. C., Lake, A., Shield, L., Little, A., Ekstrom-Smedby, K., Adami, H., Glimelius, B., Hamilton-Dutoit, S., Kane, E., Taylor, G. M., McConnachie, A., Ryder, L. P., Sundstrom, C., Andersen, P. S., Chang, E. T., Alexander, F. E., Melbye, M., Jarrett, R. F. 2010; 107 (14): 6400-6405

    Abstract

    A proportion of classical Hodgkin lymphoma (HL) is believed to be causally related to infection with the ubiquitous lymphotropic EBV. The determining factors for development of EBV-related HL remain poorly understood, but likely involve immunological control of the viral infection. Accordingly, markers of the HLA class I region have been associated with risk of EBV-related HL. To study the host genetic component of EBV-related HL further, we investigated the lymphoma's association with HLA-A*01 and HLA-A*02 simultaneously in the setting of infectious mononucleosis (IM), a risk factor for EBV-related HL, in a case-series analysis including 278 EBV-related and 656 EBV-unrelated cases of HL. By logistic regression, HLA-A*01 alleles [odds ratio (OR) per allele, 2.15; 95% CI, 1.60-2.88] were associated with increased and HLA-A*02 alleles (OR per allele, 0.70; 95% CI, 0.51-0.97) with decreased risk of EBV-related HL. These allele-specific associations corresponded to nearly 10-fold variation in risk of EBV-related HL between HLA-A*01 and HLA-A*02 homozygotes. History of IM was also associated with risk of EBV-related HL (OR, 3.40; 95% CI, 1.74-6.66). The association between history of IM and EBV-related HL was not seen in the presence of HLA-A*02 because this allele appeared to neutralize the effect of IM on EBV-related HL risk. Our findings suggest that HLA class I-restricted EBV-specific cytotoxic T-cell responses and events in the early immune response to EBV infection in IM play critical roles in the pathogenesis of EBV-related HL.

    View details for DOI 10.1073/pnas.0915054107

    View details for Web of Science ID 000276374400050

    View details for PubMedID 20308568

    View details for PubMedCentralID PMC2851961

  • Recurrence of Discordant Congenital Heart Defects in Families CIRCULATION-CARDIOVASCULAR GENETICS Oyen, N., Poulsen, G., Wohlfahrt, J., Boyd, H. A., Jensen, P. K., Melbye, M. 2010; 3 (2): 122-U17

    Abstract

    Variation within a single gene might produce different congenital heart defects (CHDs) within a family, which could explain the previously reported familial aggregation of discordant CHDs. We investigated whether certain groups of discordant CHDs are more common in families than others.Using Danish national population and health registers, we identified CHDs among all singletons born in Denmark during 1977-2005 and their first-degree relatives. In a cohort of 1 711 641 persons, 16 777 had CHDs, which we classified into 14 phenotypes. We estimated relative risks of discordant CHDs by history of specific CHDs in first-degree relatives. The relative risk of any dissimilar CHD given the specified CHD in first-degree relatives was as follows: heterotaxia, 2.00 (95% CI, 0.96 to 4.17); conotruncal defects, 2.78 (95% CI, 2.12 to 3.66); atrioventricular septal defects, 2.25 (95% CI, 1.39 to 3.66); anomalous pulmonary venous return, 1.76 (95% CI, 0.66 to 4.64); left- and right-ventricular outflow tract obstruction, 2.55 (95% CI, 1.87 to 3.48) and 3.09 (95% CI, 2.03 to 4.71), respectively; isolated atrial septal defects, 2.76 (95% CI, 2.11 to 3.61); isolated ventricular septal defects, 2.27 (95% CI, 1.75 to 2.94); persistent ductus arteriosus, 1.92 (95% CI, 1.32 to 2.79); other specified CHDs, 3.29 (95% CI, 2.51 to 4.32); and unspecified CHDs, 2.30 (95% CI, 1.76 to 3.00). Relative risks for all pairwise combinations of discordant CHD phenotypes gave no indications that certain constellations of CHDs cluster more in families than others.We documented strong familial aggregation of discordant CHD phenotypes. However, we observed no excess clustering of specific CHD phenotypes among the first-degree relatives.

    View details for DOI 10.1161/CIRCGENETICS.109.890103

    View details for Web of Science ID 000276876400002

    View details for PubMedID 20173214

  • Spontaneous labor onset: is it immunologically mediated? AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Biggar, R. J., Poulsen, G., Melbye, M., Ng, J., Boyd, H. A. 2010; 202 (3)

    Abstract

    The investigators tested the hypothesis that maternal-fetal immune interactions could be important in initiating spontaneous labor onset by examining if labor was delayed when fetuses share maternal HLA antigen types.HLA antigen types A, B, and DR in 200 Danish mother-infant pairs delivering in 42-44 weeks (postterm) were compared with 195 mother-infant pairs delivering in 37-40 weeks (term).Sharing of HLA A and B antigens was more common than expected in postterm deliveries. Odds ratios were 1.54 (95% confidence interval [CI], 1.01-2.35) and 1.75 (95% CI, 0.87-3.52), respectively (risk per shared antigen: 1.40 [95% CI, 1.04-1.90] per unit increase). Adding stringent birth-length criteria for postmaturity (92 cases; 168 controls) strengthened risks associated with antigen sharing to 1.57 (95% CI, 0.90-2.74) and 2.60 (95% CI, 1.15-5.88), respectively (risk per shared antigen: 1.60 (95% CI, 1.10-2.32).Postterm-delivered infants had more HLA A and B antigens in common with their mothers, suggesting that recognition of HLA antigen differences by adaptive immunity may have a role in triggering labor onset.

    View details for DOI 10.1016/j.ajog.2009.10.875

    View details for Web of Science ID 000275516900021

    View details for PubMedID 20045503

  • Lack of association between the MDM2 promoter polymorphism SNP309 and clinical outcome in chronic lymphocytic leukemia LEUKEMIA RESEARCH Kaderi, M. A., Mansouri, M., Zainuddin, N., Cahill, N., Gunnarsson, R., Jansson, M., Kimby, E., Aleskog, A., Lundin, J., Glimelius, B., Melbye, M., Juliusson, G., Jurlander, J., Rosenquist, R. 2010; 34 (3): 335-339

    Abstract

    The 309T>G polymorphism in the promoter region of the MDM2 gene, known as SNP309, has recently been suggested as an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL) although this has been questioned. To investigate this further, we analyzed the MDM2 SNP309 genotypes in 418 CLL patients and correlated the results with established CLL prognostic factors, time to treatment and overall survival. In this Swedish cohort, no association existed between any particular MDM2 SNP309 genotype, overall survival and time to treatment. Furthermore, no correlation was shown between the MDM2 SNP309 genotypes and Binet stage, IGHV mutational status and recurrent genomic aberrations. In summary, this study argues against the use of the MDM2 SNP309 as a prognostic marker in CLL.

    View details for DOI 10.1016/j.leukres.2009.06.006

    View details for Web of Science ID 000274529600013

    View details for PubMedID 19573916

  • HLA antigen sharing between mother and fetus as a risk factor for eclampsia and preeclampsia HUMAN IMMUNOLOGY Biggar, R. J., Poulsen, G., Ng, J., Melbye, M., Boyd, H. A. 2010; 71 (3): 263-267

    Abstract

    Immune maladaption between mother and infant has been suggested to induce preeclampsia/eclampsia. When fetuses share more human leukocyte antigen (HLA) types with their mother, immune differences would be limited and thereby could affect this risk. Data from Danish women (1996-2002) with single live-birth pregnancies complicated by severe preeclampsia/eclampsia were compared to women with term pregnancies uncomplicated by hypertension. HLA A, B, and DR types were resolved at the intermediate-level typing (antigen). A total of 201 cases and 195 control mother-infant pairs had complete HLA types. The odds ratios of preeclampsia/eclampsia in mothers sharing both HLA antigens with their infants were 1.19 (95% confidence interval: 0.81-1.76) for HLA A, 0.91 (0.59-1.42) for HLA B, and 1.05 (0.5-1.59) for HLA DR antigens. No specific HLA antigens in either mother or infant appeared important after Bonferroni correction, except possibly DR01 in mothers (protective). Thus, maladaption mediated by adaptive immunity between mother and infant is not the basis for the mother developing preeclampsia/eclampsia.

    View details for DOI 10.1016/j.humimm.2010.01.006

    View details for Web of Science ID 000275488500005

    View details for PubMedID 20074602

  • Familial Coaggregation of Cryptorchidism, Hypospadias, and Testicular Germ Cell Cancer: A Nationwide Cohort Study JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Schnack, T. H., Poulsen, G., Myrup, C., Wohlfahrt, J., Melbye, M. 2010; 102 (3): 187-192

    Abstract

    Cryptorchidism, hypospadias, and testicular germ cell cancer (TGCC) may be symptoms of a testicular dysgenesis syndrome that manifests during fetal life. To address the inheritability of this syndrome, we examined whether family history of cryptorchidism or hypospadias is associated with an increased risk of TGCC.A total of 2,159,883 men born since 1953, identified through Danish health registers, were followed from April 2, 1968, through May 31, 2008. First-, second-, and third-degree relatives were identified in the Danish Family Relations Database; cryptorchidism and hypospadias patients were identified in the Danish Hospital Discharge Register; and TGCC patients were identified in the Danish Cancer Register. Poisson regression was used to calculate the risk ratio for TGCC by family history of cryptorchidism or hypospadias.A total of 5441 patients developed TGCC. A personal history of cryptorchidism or hypospadias was associated with an increased relative risk (RR) of developing TGCC (RR = 3.71, 95% confidence interval [CI] = 3.29 to 4.19; and RR = 2.13, 95% CI = 1.26 to 3.61, respectively). For example, in men in their thirties, the overall rate per 100 000 is 25.1 in the cohort, but 88.6 and 55.4 in men born with cryptorchidism or hypospadias, respectively. In contrast, relatives of a hypospadias patient did not have a statistically significantly increased risk of TGCC nor did the first- and second-degree relatives of cryptorchidism patients. However, we found a small increased risk of TGCC for third-degree relatives of patients with cryptorchidism.Having hypospadias or cryptorchidism was associated with an increased risk of developing TGCC. However, our finding that family history of hypospadias or cryptorchidism generally was not associated with increased risk of developing TGCC does not support the hypothesis of shared inheritability of cryptorchidism, hypospadias, and TGCC.

    View details for DOI 10.1093/jnci/djp457

    View details for Web of Science ID 000274345800009

    View details for PubMedID 20026812

  • Risk of testicular cancer according to birthplace and birth cohort in Denmark INTERNATIONAL JOURNAL OF CANCER Myrup, C., Wohlfahrt, J., Oudin, A., Schnack, T., Melbye, M. 2010; 126 (1): 217-223

    Abstract

    Based on the intriguing finding of an east-west gradient of testicular cancer risk in the Nordic countries with a low risk in Finland, intermediate in Sweden, and high risk in Denmark, it was suggested that national practices rather than individual behavior may be important in the etiology of this cancer. We investigated the risk of testicular cancer in all men born in Denmark, 1931-1969 according to birthplace. Testicular cancer information was derived from the Danish Cancer Registry and population data from Statistics Denmark. There was a several fold geographical variation in testicular cancer risk within Denmark. Among men born in the early period, 1931-39, the highest risk was primarily observed in the western part of Denmark whereas no such gradient was observed in more recent cohorts. The incidence of testicular cancer increased in all counties from the earliest to the latest birth cohort, but the increase was highest in the eastern parts of Denmark. The heterogeneity in risk according to place of birth within Denmark suggests that individual behavior plays an important role for the risk of testicular cancer. Based on the Danish data, the factor that may have caused the east-west gradient in testicular cancer risk appears to have been more unevenly distributed in the early part of the past century compared to more recent times.

    View details for DOI 10.1002/ijc.24736

    View details for Web of Science ID 000272496700024

    View details for PubMedID 19588505

  • Trichuris suis ova therapy for allergic rhinitis: A randomized, double-blind, placebo-controlled clinical trial JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Bager, P., Arnved, J., Ronborg, S., Wohlfahrt, J., Poulsen, L. K., Westergaard, T., Petersen, H. W., Kristensen, B., Thamsborg, S., Roepstorff, A., Kapel, C., Melbye, M. 2010; 125 (1): 123-130

    Abstract

    Parasitic helminth infections can protect against allergic airway inflammation in experimental models and have been associated with a reduced risk of atopy and a reduced course of asthma in some observational studies. Although no clinical evidence exists to support the use of helminth therapy for allergic disease, the helminth Trichuris suis has demonstrated efficacy in treatment of inflammatory bowel disease.To determine efficacy of helminth therapy for allergic rhinitis.We conducted a double-blind, placebo-controlled, parallel group trial in which 100 subjects age 18 to 65 years with grass pollen-induced allergic rhinitis were randomly assigned to ingest a total of 8 doses with 2500 live T suis ova or placebo with an interval of 21 days. The primary outcome was a change in mean daily total symptom score for runny, itchy, sneezing nose (maximum change, 9.0) or in percentage of well days during the grass pollen season.Treatment with T suis ova (N = 49) compared with placebo (N = 47) caused transient diarrhea peaking at day 41 in 33% of participants (placebo, 2%), and increased eosinophil counts (P < .001) and T suis-specific IgE (P < .05), IgG (P < .001), IgG(4) (P < .003), and IgA (P < .001), whereas there was no significant change in symptom scores (0.0; 95% CI, -0.5 to 0.4; P = .87), well days (3%; 95% CI, -9% to 14%; P = .63), total histamine (P = .44), grass-specific IgE (P = .76), or diameter of wheal reaction on skin prick testing with grass (P = .85) or 9 other allergens.Repeated treatment with the helminth T suis induced a substantial clinical and immunologic response as evidence of infection, but had no therapeutic effect on allergic rhinitis.

    View details for DOI 10.1016/j.jaci.2009.08.006

    View details for Web of Science ID 000273660500014

    View details for PubMedID 19800680

  • Familial Coaggregation of Cryptorchidism and Hypospadias EPIDEMIOLOGY Schnack, T. H., Poulsen, G., Myrup, C., Wohlfahrt, J., Melbye, M. 2010; 21 (1): 109-113

    Abstract

    It has been suggested that cryptorchidism and hypospadias may be the result of a common pathologic pathway that causes testicular dysgenesis during fetal life. To address the potential heritability of this pathway, we specifically examined to what extent a family history of cryptorchidism increases the risk of developing hypospadias and vice versa.By using Danish health registers, we identified 27,762 boys diagnosed with cryptorchidism and 4832 boys diagnosed with hypospadias in a cohort of 1,018,517 boys born during 1977-2005. Using binomial log-linear regression, we estimated risk ratios of cryptorchidism and hypospadias in male twin pairs and first-, second-, and third-degree relatives with a family history of hypospadias and cryptorchidism, respectively.After adjusting for birth period and personal hypospadias/cryptorchidism status, there was little evidence of increased risk of cryptorchidism given a family history of hypospadias, and vice versa. However, cryptorchidism and hypospadias was associated on an individual level.We found no persuasive evidence that a family history of hypospadias increases the risk of cryptorchidism and vice versa. Thus, we found no support for shared heritability of hypospadias and cryptorchidism.

    View details for DOI 10.1097/EDE.0b013e3181c15a50

    View details for Web of Science ID 000272872900019

    View details for PubMedID 19901839

  • Expensive blood safety initiatives may offer less benefit than we think TRANSFUSION Kamper-Jorgensen, M., Hjalgrim, H., Edgren, G., Titlestad, K., Ullum, H., Shanwell, A., Reilly, M., Melbye, M., Nyren, O., Rostgaard, K. 2010; 50 (1): 240-242

    Abstract

    Various blood safety initiatives have ensured a historically low risk of infection transmission through blood transfusion. Although further prevention of infection transmission is possible through, for example, nucleic acid testing and future introduction of pathogen inactivation, such initiatives are very costly in relation to the benefit they offer. Although estimation of the cost-effectiveness requires detailed information about the survival of transfusion recipients, previous cost-effectiveness analyses have relied on incorrect survival assumptions.Based on empirical data of more than 1 million Scandinavian transfusion recipients followed for up to 20 years, we present two new survival functions. In a fictitious example we assessed the impact of survival assumptions on the estimated costs per quality-adjusted life-year (QALY) gained, by using the survival functions of three previous cost-effectiveness analyses along with the two new survival functions.We conclude that despite considerable costs, previous cost-effectiveness studies may have underestimated the costs per QALY gained by as much as 44%.

    View details for DOI 10.1111/j.1537-2995.2009.02374.x

    View details for Web of Science ID 000273171000035

    View details for PubMedID 19761551

  • Maternal Contributions to Preterm Delivery AMERICAN JOURNAL OF EPIDEMIOLOGY Boyd, H. A., Poulsen, G., Wohlfahrt, J., Murray, J. C., Feenstra, B., Melbye, M. 2009; 170 (11): 1358-1364

    Abstract

    Preterm delivery (PTD) is a complex trait with a significant familial component. However, no specific inheritance patterns have been established. The authors examined the contribution of PTDs in both the woman's family and her partner's family to her risk of PTD. The authors linked birth information from Danish national registers with pedigree information from the Danish Family Relations Database for 1,107,124 live singleton deliveries occurring from 1978 to 2004. Risk ratios were estimated comparing women with and without various PTD histories. Women with previous PTDs were at greatly increased risk of recurrent PTD (risk ratio = 5.6, 95% confidence interval: 5.5, 5.8); however, their PTD risk was unaffected by a partner's history of preterm children with other women. PTDs to a woman's mother, full sisters, or maternal half-sisters also increased her PTD risk (risk ratio = 1.6, 95% confidence interval: 1.5, 1.6), whereas PTDs in her paternal half-sisters, the female partners of her male relatives, or members of her partner's family did not affect her PTD risk. Inheritance patterns were similar for all gestational ages from very early through late PTD. The substantial portion of PTD risk explained by effects passed through the female line suggests a role for either imprinting or mitochondrial inheritance.

    View details for DOI 10.1093/aje/kwp324

    View details for Web of Science ID 000272069900004

    View details for PubMedID 19854807

    View details for PubMedCentralID PMC2800264

  • The Clustering of Premature Deaths in Families EPIDEMIOLOGY Oyen, N., Boyd, H. A., Poulsen, G., Wohlfahrt, J., Melbye, M. 2009; 20 (5): 757-765

    Abstract

    Infant deaths cluster in families, but beyond infancy, little is known about familial aggregation of premature deaths. We hypothesized that an individual's risk of premature death would be influenced by prior premature deaths of any age in family members.For all Danish residents registered in the Civil Registration System, 1968-2005, information was linked to the Causes of Death Register and the Danish Family Relation Database, yielding a cohort of 4,870,821 persons linked to one or more relatives (93 million persons-years and 73,278 deaths). We used log-linear Poisson regression to estimate mortality rate ratios (relative risks) for premature death (before age 40 years) in persons with a family history of premature death, compared with persons without such a history.Persons with a family history of premature death were 46% more likely themselves to die prematurely than persons without such a family history (relative risk [RR] = 1.46 [95% confidence interval = 1.42-1.50]). Relative risks were higher for concordant age at death, a close kinship relation, and similar causes of death. As expected, certain natural causes clustered among first-degree relatives (RRs ranged from 1.81-618), but unnatural causes of death, such as nonsimultaneous motor vehicle injuries, other injuries, and suicides, also clustered (RRs = 1.80, 3.53, and 4.23, respectively). Previous family history of premature death in a first-degree relative also increased the risk of dying from another cause (overall RR = 2.08 in infancy and 1.33 between ages 1 and 39).Premature deaths cluster in families, for both similar and dissimilar causes.

    View details for DOI 10.1097/EDE.0b013e3181ad5444

    View details for Web of Science ID 000269103500024

    View details for PubMedID 19602981

  • Atopic Disease and Risk of Non-Hodgkin Lymphoma: An InterLymph Pooled Analysis CANCER RESEARCH Vajdic, C. M., Falster, M. O., de Sanjose, S., Martinez-Maza, O., Becker, N., Bracci, P. M., Melbye, M., Smedby, K. E., Engels, E. A., Turner, J., Vineis, P., Costantini, A. S., Holly, E. A., Kane, E., Spinelli, J. J., La Vecchia, C., Zheng, T., Chiu, B. C., Dal Maso, L., Cocco, P., Maynadie, M., Foretova, L., Staines, A., Brennan, P., Davis, S., Severson, R., Cerhan, J. R., Breen, E. C., Birmann, B., Cozen, W., Grulich, A. E. 2009; 69 (16): 6482-6489

    Abstract

    We performed a pooled analysis of data on atopic disease and risk of non-Hodgkin lymphoma (NHL) from 13 case-control studies, including 13,535 NHL cases and 16,388 controls. Self-reported atopic diseases diagnosed 2 years or more before NHL diagnosis (cases) or interview (controls) were analyzed. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were computed in two-stage random-effects or joint fixed-effects models, and adjusted for age, sex, and study center. When modeled individually, lifetime history of asthma, hay fever, specific allergy (excluding hay fever, asthma, and eczema), and food allergy were associated with a significant reduction in NHL risk, and there was no association for eczema. When each atopic condition was included in the same model, reduced NHL risk was only associated with a history of allergy (OR, 0.80; 95% CI, 0.68-0.94) and reduced B-cell NHL risk was associated with history of hay fever (OR, 0.85; 95% CI, 0.77-0.95) and allergy (OR, 0.84; 95% CI, 0.76-0.93). Significant reductions in B-cell NHL risk were also observed in individuals who were likely to be truly or highly atopic-those with hay fever, allergy, or asthma and at least one other atopic condition over their lifetime. The inverse associations were consistent for the diffuse large B-cell and follicular subtypes. Eczema was positively associated with lymphomas of the skin; misdiagnosis of lymphoma as eczema is likely, but progression of eczema to cutaneous lymphoma cannot be excluded. This pooled study shows evidence of a modest but consistent reduction in the risk of B-cell NHL associated with atopy.

    View details for DOI 10.1158/0008-5472.CAN-08-4372

    View details for Web of Science ID 000269064600016

    View details for PubMedID 19654312

    View details for PubMedCentralID PMC2758272

  • Recurrence of Congenital Heart Defects in Families CIRCULATION Oyen, N., Poulsen, G., Boyd, H. A., Wohlfahrt, J., Jensen, P. K., Melbye, M. 2009; 120 (4): 295-301

    Abstract

    Knowledge of the familial contribution to congenital heart diseases (CHD) on an individual and population level is sparse. We estimated an individual's risk of CHD given a family history of CHD, as well as the contribution of CHD family history to the total number of CHD cases in the population.In a national cohort study, we linked all Danish residents to the National Patient Register, the Causes of Death Register, the Danish Central Cytogenetic Register, and the Danish Family Relations Database, yielding 1 763 591 persons born in Denmark between 1977 and 2005, of whom 18 708 had CHD. Individuals with CHD were classified by phenotype. We estimated recurrence risk ratios and population-attributable risk. Among first-degree relatives, the recurrence risk ratio was 79.1 (95% confidence interval [CI] 32.9 to 190) for heterotaxia, 11.7 (95% CI, 8.0 to 17.0) for conotruncal defects, 24.3 (95% CI,12.2 to 48.7) for atrioventricular septal defect, 12.9 (95% CI, 7.48 to 22.2) for left ventricular outflow tract obstruction, 48.6 (95% CI, 27.5 to 85.6) for right ventricular outflow tract obstruction, 7.1 (95% CI, 4.5 to 11.1) for isolated atrial septal defect, and 3.4 (95% CI, 2.2 to 5.3) for isolated ventricular septal defect. The overall recurrence risk ratio for the same defect was 8.15 (95% CI, 6.95 to 9.55), whereas it was 2.68 (95% CI, 2.43 to 2.97) for different heart defects. Only 2.2% of heart defect cases in the population (4.2% after the exclusion of chromosomal aberrations) were attributed to CHD family history in first-degree relatives.Specific CHDs showed highly variable but strong familial clustering in first-degree relatives, ranging from 3-fold to 80-fold compared with the population prevalence, whereas the crossover risks between dissimilar cases of CHD were weaker. Family history of any CHD among first-degree relatives accounted for a small proportion of CHD cases in the population.

    View details for DOI 10.1161/CIRCULATIONAHA.109.857987

    View details for Web of Science ID 000268377500006

    View details for PubMedID 19597048

  • Familial Recurrence of Midline Birth Defects-A Nationwide Danish Cohort Study AMERICAN JOURNAL OF EPIDEMIOLOGY Oyen, N., Boyd, H. A., Poulsen, G., Wohlfahrt, J., Melbye, M. 2009; 170 (1): 46-52

    Abstract

    If birth defects resulting from fusion failure in the midline have a common etiology, as previously hypothesized, persons with a family history of 1 type of midline defect should have an increased risk of dissimilar midline defects. The authors examined this hypothesis by linking information from the National Patient Register, the Causes of Death Register, and the Danish Family Relations Database for all Danish residents registered in the Civil Registration System during 1977-2005. Linkage yielded a cohort of 1.7 million persons with 1 or more relatives, including 9,063 persons with 1 or more midline defects. The authors investigated familial clustering of midline defects by estimating relative risks of similar and dissimilar midline defects according to family history of midline defects. Given a history of similar defects in first-degree relatives, relative risks for neural tube defects, conotruncal defects, oral facial clefts, anal/rectal defects, and diaphragmatic defects were 8.2 (95% confidence interval (CI): 3.1, 21.7), 7.7 (95% CI: 4.3, 13.8), 13.2 (95% CI: 10.8, 16.2), 10.3 (95% CI: 2.6, 41.1), and 11.2 (95% CI: 1.6, 79.7), respectively. However, given a dissimilar defect in a family member, the relative risk for any midline defect was null. Thus, similar defects but not dissimilar defects clustered in families, providing no evidence of a shared etiology for dissimilar midline defects.

    View details for DOI 10.1093/aje/kwp087

    View details for Web of Science ID 000267440200006

    View details for PubMedID 19414496

  • EBV-associated gastric carcinoma in high- and low-incidence areas for nasopharyngeal carcinoma BRITISH JOURNAL OF CANCER Boysen, T., Mohammadi, M., Melbye, M., Hamilton-Dutoit, S., Vainer, B., HANSEN, A. V., Wohlfahrt, J., Friborg, J. 2009; 101 (3): 530-533

    Abstract

    Approximately 10% of gastric carcinomas are associated with Epstein-Barr virus (EBV). The Inuit in Greenland have a high incidence of EBV-associated nasopharyngeal carcinoma.We conducted a population-based case-control study comparing gastric carcinomas in Greenland and in Denmark.The prevalence rate of EBV-associated gastric carcinomas was 8.5% in both populations.The findings of this study argue against a general susceptibility to EBV-associated carcinomas among the Inuit.

    View details for DOI 10.1038/sj.bjc.6605168

    View details for Web of Science ID 000268439500024

    View details for PubMedID 19603026

    View details for PubMedCentralID PMC2720225

  • Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche NATURE GENETICS Sulem, P., Gudbjartsson, D. F., Rafnar, T., Holm, H., Olafsdottir, E. J., Olafsdottir, G. H., Jonsson, T., Alexandersen, P., Feenstra, B., Boyd, H. A., Aben, K. K., Verbeek, A. L., Roeleveld, N., Jonasdottir, A., Styrkarsdottir, U., Steinthorsdottir, V., Karason, A., Stacey, S. N., Gudmundsson, J., Jakobsdottir, M., Thorleifsson, G., Hardarson, G., Gulcher, J., Kong, A., Kiemeney, L. A., Melbye, M., Christiansen, C., Tryggvadottir, L., Thorsteinsdottir, U., Stefansson, K. 2009; 41 (6): 734-738

    Abstract

    Earlier menarche correlates with shorter adult height and higher childhood body fat. We conducted a genome-wide association study of age at menarche (AAM) on 15,297 Icelandic women. Combined analysis with replication sets from Iceland, Denmark and the Netherlands (N = 10,040) yielded a significant association between rs314280[T] on 6q21, near the LIN28B gene, and AAM (effect = 1.2 months later per allele; P = 1.8 × 10(-14)). A second SNP within the same linkage disequilibrium (LD) block, rs314277, splits rs314280[T] into two haplotypes with different effects (0.9 months and 1.9 months per allele). These variants have been associated with greater adult height. The association with adult height did not account for the association with AAM or vice versa. Other variants, previously associated with height, did not associate significantly with AAM. Given the link between body fat and AAM, we also assessed 11 variants recently associated with higher body mass index (BMI) and 5 of those associated with earlier AAM.

    View details for DOI 10.1038/ng.383

    View details for Web of Science ID 000266411700025

    View details for PubMedID 19448622

  • Immunoglobulin subclass levels in patients with non-Hodgkin lymphoma INTERNATIONAL JOURNAL OF CANCER Biggar, R. J., Christiansen, M., Rostgaard, K., Smedby, K. E., Adami, H., Glimelius, B., Hjalgrim, H., Melbye, M. 2009; 124 (11): 2616-2620

    Abstract

    Allergy/atopy has been suggested to protect against non-Hodgkin lymphoma (NHL) and specific IgE levels are decreased in patients with NHL. We speculated that all immunoglobulin subclass levels might be downregulated in NHL and examined levels of IgM, IgD, IgA, IgE, IgG and IgG(4) in 200 NHL patients and 200 age- and sex-matched controls. Patients with B-cell NHL of many types had consistently lower median immunoglobulin subclass levels than controls. In every subclass except IgD, about 10-15% of B-cell NHL patients had absolute levels below the 2.5 percentile of controls. Subclass levels correlated with each other and many patients had more than one significantly low level. Levels were lowest for IgG(4) and IgE. Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma had especially low total IgE levels. In other B-cell NHL types, total IgE levels were decreased to a similar extent as other immunoglobulin subclasses. In conclusion, low IgE levels are only part of a more generalized loss of immunoglobulins of all subtypes in a wide variety of B-cell NHL types. Low immunoglobulin levels appear to be a consequence of B-cell NHL presence, and we speculate about molecular mechanisms that could reduce all immunoglobulin subclasses in B-cell NHL.

    View details for DOI 10.1002/ijc.24245

    View details for Web of Science ID 000265848600013

    View details for PubMedID 19235925

  • Blood transfusion exposure in Denmark and Sweden TRANSFUSION Kamper-Jorgensen, M., Edgren, G., Rostgaard, K., Biggar, R. J., Nyren, O., Reilly, M., Titlestad, K., Shanwell, A., Melbye, M., Hjalgrim, H. 2009; 49 (5): 888-894

    Abstract

    Although essential for the evaluation of blood transfusion safety, the prevalence of blood transfusion in the general population is not presently known. This study estimated the exposure to blood transfusion in the general Scandinavian population.Population-based registry data of more than 600,000 transfusion recipients and general population data from 2000 to 2002 in Denmark and 1996 to 2002 in Sweden were reviewed. Outcome measures were the unit exposure rate, the 1-year period prevalence, the incidence rate, and the prevalence of exposure to blood transfusion.The unit exposure rate was 71.9 per 1000 population per year in Denmark and 60.9 in Sweden, corresponding to 29 percent more blood units being transfused in Denmark than in Sweden. The 1-year period prevalence was 8.8 and the incidence rate was 7.2 per 1000 population per year in Denmark, being 37 and 25 percent higher than in Sweden, respectively. The prevalences of blood transfusion in Danish males at 20, 40, 60, and 80 years of age were 1.9, 3.1, 7.6, and 18.1 percent, respectively. In Danish females, the corresponding prevalences were 1.6, 5.9, 11.1, and 20.5 percent. A similar but slightly lower prevalence was found in Sweden.Exposure to blood transfusion is frequent in Denmark and Sweden. At age 80 years, approximately one in five persons in the general population had received blood at least once.

    View details for DOI 10.1111/j.1537-2995.2008.02081.x

    View details for Web of Science ID 000265410800013

    View details for PubMedID 19210324

  • National time trends in congenital heart defects, Denmark, 1977-2005 AMERICAN HEART JOURNAL Oyen, N., Poulsen, G., Boyd, H. A., Wohifahrt, J., Jensen, P. K., Melbye, M. 2009; 157 (3): 467-473

    Abstract

    Time trends in congenital heart defects (CHD) by specific phenotype and with long follow-up time are rarely available for an entire population. We present trends in national CHD prevalences over the past 3 decades.We linked information from the National Patient Register, the Causes of Death Register, and the Danish Cytogenetic Central Register for all persons born in Denmark, 1977 to 2005, and registered in the Civil Registration System, yielding a cohort of 1,763,591 persons-18,207 with CHD. Individuals with CHDs were classified by phenotype (heterotaxia, conotruncal defect, atrioventricular septal defect, anomalous pulmonary venous return, left and right ventricular outflow tract obstructions, septal defects, complex defects, associations, patent ductus arteriosus, unspecified, and other specified) by combining International Classification of Diseases codes using a hierarchical approach.From 1977 to 2005, the overall CHD birth prevalence increased from 73 to 113 per 10,000 live births. Generally, prevalence increased for defects diagnosed in infancy, until 1996-1997, and then stabilized. For each 5-year interval, isolated septal defects and severe defects increased by 22% (95% CI, 20%-25%) and 5% (95% CI, 4%-7%), respectively. Among the severe defects, conotruncal defects and atrioventricular septal defect showed the largest prevalence increases. Women had a lower prevalence of severe defects during the 1980s. The CHD prevalence increase was unchanged when persons with extracardiac defects or chromosomal aberrations were excluded.CHD birth prevalence increased from the beginning of the 1980s but stabilized in the late 1990s.

    View details for DOI 10.1016/j.ahj.2008.10.017

    View details for Web of Science ID 000264214700010

    View details for PubMedID 19249416

  • Post-transfusion mortality among recipients of ABO-compatible but non-identical plasma VOX SANGUINIS Shanwell, A., Andersson, T. L., Rostgaard, K., Edgren, G., Hjalgrim, H., Norda, R., Melbye, M., Nyren, O., Reilly, M. 2009; 96 (4): 316-323

    Abstract

    The consequences of ABO-compatible non-identical plasma for patient outcome have not been studied in randomized clinical trials or large cohort studies and use varies widely in the absence of evidence-based policies. We investigated if transfusion with compatible instead of identical plasma confers any short-term survival disadvantage on the recipients.The cohort of all 86 082 Swedish patients who received their first plasma transfusion between 1990 and 2002 was followed for 14 days and the risk of death in patients exposed to compatible non-identical plasma compared to recipients of only identical plasma.After adjustment for potential confounding factors, there was an increased mortality associated with exposure to ABO-compatible non-identical plasma, with the excess risk mostly confined to those receiving 5 or more units (relative risk, 1.15; 95% confidence interval, 1.02-1.29). Stratification by blood group indicated higher risks in group O recipients, especially when the compatible plasma was from a group AB donor.This study suggests that ABO-compatible non-identical plasma is less safe than identical plasma. Subanalyses by blood group suggest a role for circulating immune complexes. Our findings may have policy implications for improving transfusion safety.

    View details for DOI 10.1111/j.1423-0410.2009.01167.x

    View details for Web of Science ID 000265190000007

    View details for PubMedID 19254234

  • Survival after blood transfusion TRANSFUSION Kamper-Jorgensen, M., Ahlgren, M., Rostgaard, K., Melbye, M., Edgren, G., Nyren, O., Reilly, M., Norda, R., Titlestad, K., Tynell, E., Hjalgrim, H. 2008; 48 (12): 2577-2584

    Abstract

    Long-term survival of transfusion recipients has rarely been studied. This study examines short- and long-term mortality among transfusion recipients and reports these as absolute rates and rates relative to the general population.Population-based cohort study of transfusion recipients in Denmark and Sweden followed for up to 20 years after their first blood transfusion. Main outcome measure was all-cause mortality.A total of 1,118,261 transfusion recipients were identified, of whom 62.0 percent were aged 65 years or older at the time of their first registered transfusion. Three months after the first transfusion, 84.3 percent of recipients were alive. One-, 5-, and 20-year posttransfusion survival was 73.7, 53.4, and 27.0 percent, respectively. Survival was slightly poorer in men than in women, decreased with increasing age, and was worst for recipients transfused at departments of internal medicine. The first 3 months after the first transfusion, the standardized mortality ratio (SMR) was 17.6 times higher in transfusion recipients than in the general population. One to 4 years after first transfusion, the SMR was 2.1 and even after 17 years the SMR remained significantly 1.3-fold increased.The survival and relative mortality patterns among blood transfusion recipients were characterized with unprecedented detail and precision. Our results are relevant to assessments of the consequences of possible transfusion-transmitted disease as well as for cost-benefit estimation of new blood safety interventions.

    View details for DOI 10.1111/j.1537-2995.2008.01881.x

    View details for Web of Science ID 000261439900015

    View details for PubMedID 18673342

  • Measles-Mumps-Rubella Vaccination and Asthma-like Disease in Early Childhood AMERICAN JOURNAL OF EPIDEMIOLOGY Hviid, A., Melbye, M. 2008; 168 (11): 1277-1283

    Abstract

    The authors evaluated the association between receipt of measles-mumps-rubella (MMR) vaccine and asthma-like disease in early childhood in a Danish nationwide cohort study (N = 871,234). Two outcomes were included: hospitalizations with asthma diagnoses and use of anti-asthma medications (for a subset of the cohort only). Poisson regression was used to estimate rate ratios according to vaccination status. MMR-vaccinated children were less often hospitalized with an asthma diagnosis (rate ratio (RR) = 0.75, 95% confidence interval (CI): 0.73, 0.78) and used fewer courses of anti-asthma medication (RR = 0.92, 95% CI: 0.91, 0.92) than unvaccinated children. This "protective" effect of MMR vaccine was more pronounced for hospitalizations with severe asthma diagnoses (status asthmaticus: RR = 0.63, 95% CI: 0.49, 0.82) and use of medication that was highly specific for asthma (long-acting beta2-agonist inhalant: RR = 0.68, 95% CI: 0.63, 0.73). MMR vaccine was not negatively associated with anti-asthma medications often used for wheezing illnesses in early childhood (systemic beta2-agonist: RR = 1.02, 95% CI: 1.01, 1.02). These results are compatible not with an increased risk of asthma following MMR vaccination but rather with the hypothesis that MMR vaccination is associated with a reduced risk of asthma-like disease in young children.

    View details for DOI 10.1093/aje/kwn253

    View details for Web of Science ID 000261279600007

    View details for PubMedID 18845551

  • Serum YKL-40 and Interleukin 6 Levels in Hodgkin Lymphoma CLINICAL CANCER RESEARCH Biggar, R. J., Johansen, J. S., Smedby, K. E., Rostgaard, K., Chang, E. T., Adami, H., Glimelius, B., Molin, D., Hamilton-Dutoit, S., Melbye, M., Hjalgrim, H. 2008; 14 (21): 6974-6978

    Abstract

    Serum levels of the inflammatory markers YKL-40 and interleukin 6 (IL-6) are increased in many conditions, including cancers. We examined serum YKL-40 and IL-6 levels in patients with Hodgkin lymphoma, a tumor with strong immunologic reaction to relatively few tumor cells, especially in nodular sclerosis Hodgkin lymphoma.We analyzed Danish and Swedish patients with incident Hodgkin lymphoma (N=470) and population controls from Denmark (n=245 for YKL-40; n=348 for IL-6). Serum YKL-40 and IL-6 levels were determined by ELISA, and log-transformed data were analyzed by linear regression, adjusting for age and sex.Serum levels of YKL-40 and IL-6 increased in Hodgkin lymphoma patients compared with controls (YKL-40, 3.6-fold; IL-6, 8.3-fold; both, P<0.0001). In pretreatment samples from pretreatment Hodgkin lymphoma patients (n=176), levels were correlated with more advanced stages (P(trend), 0.0001 for YKL-40 and 0.013 for IL-6) and in those with B symptoms; however, levels were similar in nodular sclerosis and mixed cellularity subtypes, by EBV status, and in younger (<45 years old) and older patients. Patients tested soon after treatment onset had significantly lower levels than pretreatment patients; however, even >or=6 months after treatment onset, serum YKL-40 and IL-6 levels remained significantly increased compared with controls. In patients who died (n=12), pretreatment levels for YKL-40 and IL-6 were higher than in survivors, although not statistically significantly.Serum YKL-40 and IL-6 levels were increased in untreated Hodgkin lymphoma patients and those with more advanced stages but did not differ significantly by Hodgkin lymphoma histology. Following treatment, serum levels were significantly lower.

    View details for DOI 10.1158/1078-0432.CCR-08-1026

    View details for Web of Science ID 000260732200031

    View details for PubMedID 18980992

    View details for PubMedCentralID PMC2613488

  • Disruption of an AP-2 alpha binding site in an IRF6 enhancer is associated with cleft lip NATURE GENETICS Rahimov, F., Marazita, M. L., Visel, A., Cooper, M. E., Hitchler, M. J., Rubini, M., Domann, F. E., Govil, M., Christensen, K., Bille, C., Melbye, M., Jugessur, A., Lie, R. T., Wilcox, A. J., FitzPatrick, D. R., Green, E. D., Mossey, P. A., Little, J., Steegers-Theunissen, R. P., Pennacchio, L. A., Schutte, B. C., Murray, J. C. 2008; 40 (11): 1341-1347

    Abstract

    Previously we have shown that nonsyndromic cleft lip with or without cleft palate (NSCL/P) is strongly associated with SNPs in IRF6 (interferon regulatory factor 6). Here, we use multispecies sequence comparisons to identify a common SNP (rs642961, G>A) in a newly identified IRF6 enhancer. The A allele is significantly overtransmitted (P = 1 x 10(-11)) in families with NSCL/P, in particular those with cleft lip but not cleft palate. Further, there is a dosage effect of the A allele, with a relative risk for cleft lip of 1.68 for the AG genotype and 2.40 for the AA genotype. EMSA and ChIP assays demonstrate that the risk allele disrupts the binding site of transcription factor AP-2alpha and expression analysis in the mouse localizes the enhancer activity to craniofacial and limb structures. Our findings place IRF6 and AP-2alpha in the same developmental pathway and identify a high-frequency variant in a regulatory element contributing substantially to a common, complex disorder.

    View details for DOI 10.1038/ng.242

    View details for Web of Science ID 000260501500028

    View details for PubMedID 18836445

    View details for PubMedCentralID PMC2691688

  • [Genome-wide association studies]. Ugeskrift for laeger Feenstra, B., Boyd, H. A., Melbye, M. 2008; 170 (41): 3216-3220

    Abstract

    Within the last year, genome-wide association (GWA) studies have identified a large number of robust associations between genetic variants and common diseases. Two key premises underlie this burst of discovery. First, the HapMap project has provided a catalogue of human genetic variation. Second, genotyping microarrays can now assess up to 1 million SNPs, allowing hypothesis-free screening of the entire genome. An important next step will be to elucidate the mechanisms behind genotype-phenotype associations. Ultimately, the goal is improved prevention, diagnosis and therapy.

    View details for PubMedID 18940150

  • Cancer patterns in Inuit populations LANCET ONCOLOGY Friborg, J. T., Melbye, M. 2008; 9 (9): 892-900

    Abstract

    Inuit people inhabit the circumpolar region, with most living in Alaska, northwest Canada, and Greenland. Although malignant diseases were believed to be almost non-existent in Inuit populations during the beginning of the 20th century, the increasing life expectancy within these populations showed a distinct pattern, characterised by a high risk of Epstein-Barr virus-associated carcinomas of the nasopharynx and salivary glands, and a low risk of tumours common in white populations, including cancer of the prostate, testis, and haemopoietic system. Both genetic and environmental factors seem to be responsible for this pattern. During the second half of the 20th century, Inuit societies underwent major changes in lifestyle and living conditions, and the risk of lifestyle-associated tumours, especially cancers of the lung, colon, and breast, increased considerably after changes in smoking, diet, and reproductive factors. This Review will briefly summarise the current knowledge on cancer epidemiology in Inuit populations, with emphasis on the characteristic Inuit types of cancer.

    View details for Web of Science ID 000259060100023

    View details for PubMedID 18760245

  • Maternal and gestational risk factors for hypospadias ENVIRONMENTAL HEALTH PERSPECTIVES Akre, O., Boyd, H. A., Ahlgren, M., Wilbrand, K., Westergaard, T., Hjalgrim, H., Nordenskjoeld, A., Ekborn, A., Melbye, M. 2008; 116 (8): 1071-1076

    Abstract

    An increase in the prevalence of hypospadias has been reported, but the environmental causes remain virtually unknown.Our goal was to assess the association between risk of hypospadias and indicators of placental function and endogenous hormone levels, exposure to exogenous hormones, maternal diet during pregnancy, and other environmental factors.We conducted a case-control study in Sweden and Denmark from 2000 through 2005 using self-administered questionnaires completed by mothers of hypospadias cases and matched controls. The response rate was 88% and 81% among mothers of cases and controls, respectively. The analyses included 292 cases and 427 controls.A diet during pregnancy lacking both fish and meat was associated with a more than 4-fold increased risk of hypospadias [odds ratio (OR) = 4.6; 95% confidence interval (CI), 1.6-13.3]. Boys born to obese [body mass index (BMI) > or = 30] women had a more than 2-fold increased risk of hypospadias (OR = 2.6; 95% CI, 1.2-5.7) compared with boys born to mothers with a normal weight (BMI = 20-24). Maternal hypertension during pregnancy and absence of maternal nausea increased a boy's risk of hypospadias 2.0-fold (95% CI, 1.1-3.7) and 1.8-fold (95% CI, 1.2-2.8), respectively. Nausea in late pregnancy also appeared to be positively associated with hypospadias risk (OR = 7.6; 95% CI, 1.1-53).A pregnancy diet lacking meat and fish appears to increase the risk of hypospadias in the offspring. Other risk associations were compatible with a role for placental insufficiency in the etiology of hypospadias.

    View details for DOI 10.1289/ehp.10791

    View details for Web of Science ID 000258270200029

    View details for PubMedID 18709149

    View details for PubMedCentralID PMC2516569

  • Risks of invasive pneumococcal disease in children with underlying chronic diseases PEDIATRICS Hjuler, T., Wohlfahrt, J., Kaltoft, M. S., Koch, A., Biggar, R. J., Melbye, M. 2008; 122 (1): E26-E32

    Abstract

    The risk of invasive pneumococcal disease is increased among children with some chronic diseases. The objective of this study was to quantify the risk of invasive pneumococcal disease in a wide range of chronic diseases.Cases of invasive pneumococcal disease among children (aged 0-17 years) were identified from 1977 through 2005 by using a national surveillance program in Denmark. Rate ratios were assessed in a case-control study by using 10 age- and gender-matched controls per case. Chronic diseases were defined a priori.Among 1655 children with invasive pneumococcal disease, 19% had a history of chronic disease, according to our definition, versus 5% of controls. An increased risk of invasive pneumococcal disease was observed for children followed >30 days after initial hospital contact for a chronic disease, but it was also increased in children with >or=5 hospital contacts for any other reason. Children with a history of cancer, chronic renal disease, splenectomy, and transplantation were particularly susceptible to invasive pneumococcal disease. Adjusted for number of hospital contacts, the risk for children with other types of chronic disease was 1.4-fold more than for those with hospital contacts for any reason.Cancer, chronic renal diseases, splenectomy, and transplantation were strongly associated with an increased risk of invasive pneumococcal disease in children. For children with other chronic diseases, their excess risk seemed to be attributable mostly to frail children having repeated hospital contact rather than their underlying condition.

    View details for DOI 10.1542/peds.2007-1510

    View details for Web of Science ID 000257271200064

    View details for PubMedID 18595971

  • Autoimmune diseases in patients with multiple sclerosis and their first-degree relatives: a nationwide cohort study in Denmark MULTIPLE SCLEROSIS JOURNAL Nielsen, N. M., Frisch, M., Rostgaard, K., Wohlfahrt, J., Hjalgrim, H., Koch-Henriksen, N., Melbye, M., Westergaard, T. 2008; 14 (6): 823-829

    Abstract

    Multiple sclerosis (MS) and other autoimmune diseases might cluster. Our aim was to estimate the relative risk (RR) of other autoimmune diseases among MS patients and their first-degree relatives in a population-based cohort study.Using the Danish Multiple Sclerosis Register, the Danish Hospital Discharge Register, and the Danish Civil Registration System, we estimated RRs for 42 different autoimmune diseases in a population-based cohort of 12 403 MS patients and 20 798 of their first-degree relatives. Ratios of observed to expected numbers of autoimmune diseases, based on national sex-, age-, and period-specific incidence rates, served as measures of the RRs.Compared with the general population, MS patients were at an increased risk of developing ulcerative colitis (RR = 2.0 (95% confidence interval (CI): 1.4-2.8), n = 29) and pemphigoid (RR = 15.4 (CI: 8.7-27.1), n = 12) but at reduced risk of rheumatoid arthritis (RR = 0.5 (CI: 0.4-0.8), n = 28) and temporal arteritis (RR = 0.5 (CI: 0.3-0.97), n = 11). First-degree relatives of MS patients were at increased risks of Crohn's disease (RR = 1.4 (CI: 1.04-1.9), n = 44), ulcerative colitis (RR = 1.3 (CI: 0.99-1.7), n = 51), Addison's disease (RR = 3.4 (CI: 1.3-9.0), n = 4), and polyarteritis nodosa (RR = 3.7 (CI: 1.4-10.0), n = 4).with MS and their first-degree relatives seem to be at an increased risk of acquiring certain other autoimmune diseases.

    View details for DOI 10.1177/1352458508088936

    View details for Web of Science ID 000258252200016

    View details for PubMedID 18573841

  • Familial aggregation of cryptorchidism - A nationwide cohort study AMERICAN JOURNAL OF EPIDEMIOLOGY Schnack, T. H., Zdravkovic, S., Myrup, C., Westergaard, T., Wohlfahrt, J., Melbye, M. 2008; 167 (12): 1453-1457

    Abstract

    Although cryptorchidism is the most common birth defect in boys affecting 4-9 percent of newborns and 1-2 percent of boys 1 year of age, the etiology remains largely unknown. The authors investigated the contribution of genetic and environmental factors to familial aggregation of cryptorchidism. Using Danish health registers, they identified 25,395 boys diagnosed with cryptorchidism in a cohort of 1,022,713 boys born in 1977-2005. Using binomial log-linear regression, they estimated recurrence risk ratios (RRRs) of cryptorchidism for male twin pairs and first-, second-, and third-degree relatives of a cryptorchidism case. The RRR in same-sex twins was 10.1 (95% confidence interval (CI): 7.78, 13.1). The RRR among first-degree relatives was significantly higher among brothers (RRR = 3.52, 95% CI: 3.26, 3.79) than for offspring of a cryptorchidism case (RRR = 2.31, 95% CI: 2.09, 2.54). The RRR was also found to be significantly higher in maternal (RRR = 2.12, 95% CI: 1.74, 2.60) than paternal (RRR = 1.28, 95% CI: 1.01, 1.61) half brothers. In conclusion, inherited factors were found to have a moderate influence on the risk of cryptorchidism. The data are compatible with the hypothesis that maternal factors operating in utero are important for the risk of cryptorchidism.

    View details for DOI 10.1093/aje/kwn081

    View details for Web of Science ID 000256755900008

    View details for PubMedID 18436537

  • Borrelia infection and risk of non-Hodgkin lymphoma BLOOD Schollkopf, C., Melbye, M., Munksgaard, L., Smedby, K. E., Rostgaard, K., Glimelius, B., Chang, E. T., Roos, G., Hansen, M., Adami, H., Hjalgrim, H. 2008; 111 (12): 5524-5529

    Abstract

    Reports of the presence of Borrelia burgdorferi DNA in malignant lymphomas have raised the hypothesis that infection with B. burgdorferi may be causally related to non-Hodgkin lymphoma (NHL) development. We conducted a Danish-Swedish case-control study including 3055 NHL patients and 3187 population controls. History of tick bite or Borrelia infection was ascertained through structured telephone interviews and through enzyme-linked immunosorbent assay serum analyses for antibodies against B. burgdorferi in a subset of 1579 patients and 1358 controls. Statistical associations with risk of NHL, including histologic subtypes, were assessed by logistic regression. Overall risk of NHL was not associated with self-reported history of tick bite (odds ratio [OR] = 1.0; 95% confidence interval: 0.9-1.1), Borrelia infection (OR = 1.3 [0.96-1.8]) or the presence of anti-Borrelia antibodies (OR = 1.3 [0.9-2.0]). However, in analyses of NHL subtypes, self-reported history of B. burgdorferi infection (OR = 2.5 [1.2-5.1]) and seropositivity for anti-Borrelia antibodies (OR = 3.6 [1.8-7.4]) were both associated with risk of mantle cell lymphoma. Notably, this specific association was also observed in persons who did not recall Borrelia infection yet tested positive for anti-Borrelia antibodies (OR = 4.2 [2.0-8.9]). Our observations suggest a previously unreported association between B. burgdorferi infection and risk of mantle cell lymphoma.

    View details for DOI 10.1182/blood-2007-08-109611

    View details for Web of Science ID 000256786500023

    View details for PubMedID 18424667

    View details for PubMedCentralID PMC2972577

  • The Inuit cancer pattern - The influence of migration INTERNATIONAL JOURNAL OF CANCER Boysen, T., Friborg, J., Andersen, A., Poulsen, G. N., Wohlfahrt, J., Melbye, M. 2008; 122 (11): 2568-2572

    Abstract

    The Inuit cancer pattern is characterized by high frequencies of Epstein-Barr Virus (EBV)-associated carcinomas of the nasopharynx and salivary glands. The reasons are unknown, but genetic and environmental factors are believed to be involved. Using data from the well-defined Inuit population in Greenland we investigated whether migration to Denmark influenced their risk of cancer. Greenland is part of the Danish Kingdom, and population-based registries cover both countries. Using rates for Denmark as reference, sex-specific standardized incidence ratios (SIR) were calculated for Inuit who never lived in Denmark and for those who at least once were registered with a Danish address. During 1973-2003, we observed 3,567 cancers in a cohort of 77,888 persons. Of these, 862 among 26,214 Inuit ever living in Denmark, and 2,705 among 51,674 nonmigrating Inuit. High SIRs for cancers of the nasopharynx [31.7 (CI 22.0-45.5)] and salivary glands [3.1 (CI 1.4-6.9)] observed among Inuit migrating to Denmark were comparable to those observed among Inuit never living in Denmark. Significant higher risk of cancer of the bladder, breast, prostate gland, skin, brain and stomach was observed among Inuit following migration to Denmark. The SIR was not generally influenced by duration of stay. The high risk of carcinoma of the nasopharynx and salivary glands observed in Inuit populations is maintained after migration to a low incidence area. This indicates that genetic factors or environmental factors acting early in life are etiologically important for these cancers.

    View details for DOI 10.1002/ijc.23367

    View details for Web of Science ID 000255466300021

    View details for PubMedID 18214857

  • Risk of glaucoma after pediatric cataract surgery INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Haargaard, B., Ritz, C., Oudin, A., Wohlfahrt, J., Thygesen, J., Olsen, T., Melbye, M. 2008; 49 (5): 1791-1796

    Abstract

    To determine the risk of glaucoma after surgery for pediatric cataract and to evaluate risk factors for glaucoma.A population-based cohort of all children in Denmark aged 0 to 17 years during the period 1977 to 2001, who underwent surgery for pediatric cataract, was established by retrospective chart review. Glaucoma cases were defined as those in which glaucoma surgery (trabeculectomy and/or diode laser transscleral cyclophotocoagulation) was performed and/or permanent medical therapy prescribed after cataract surgery.Of 946 eyes (595 patients) undergoing pediatric cataract surgery, 72 eyes (48 patients) had subsequent development of glaucoma. Early surgery (<9 months of age) was associated with a 7.2-fold increased risk of glaucoma compared with late surgery (> or =9 months of age). Ten years after cataract surgery, glaucoma developed in 31.9% (95% confidence interval [CI], 24.4-41.1) of children undergoing surgery before 9 months of age compared with 4.1% (95% CI, 2.4 to 6.8) of children aged > or =9 months at the time of surgery. Glaucoma cases continued to occur more than 10 years after cataract surgery. After adjustment for age at surgery, no other risk factor appeared important.The risk of glaucoma after surgery for pediatric cataract is substantial and particularly high for those below 9 months of age at the time of surgery. Because the increased risk persists for many years after surgery, careful continuous monitoring for glaucoma is mandatory.

    View details for DOI 10.1167/iovs.07-1156

    View details for Web of Science ID 000255291100009

    View details for PubMedID 18223251

  • Non-Hodgkin lymphoma and obesity: A pooled analysis from the InterLymph consortium INTERNATIONAL JOURNAL OF CANCER Willett, E. V., Morton, L. M., Hartge, P., Becker, N., Bernstein, L., Boffetta, P., Bracci, P., Cerhan, J., Chiu, B. C., Cocco, P., Dal Maso, L., Davis, S., de Sanjose, S., Smedby, K. E., Ennas, M. G., Foretova, L., Holiy, E. A., La Vecchia, C., Matsuo, K., Maynadie, M., Melbye, M., Negri, E., Nieters, A., Severson, R., Slager, S. L., Spinelli, J. J., Staines, A., Talamini, R., Vornanen, M., Weisenburger, D. D., Roman, E. 2008; 122 (9): 2062-2070

    Abstract

    Nutritional status is known to alter immune function, a suspected risk factor for non-Hodgkin lymphoma (NHL). To investigate whether long-term over, or under, nutrition is associated with NHL, self-reported anthropometric data on weight and height from over 10,000 cases of NHL and 16,000 controls were pooled across 18 case-control studies identified through the International Lymphoma Epidemiology Consortium. Study-specific odds ratios (OR) were estimated using logistic regression and combined using a random-effects model. Severe obesity, defined as BMI of 40 kg m(-2) or more, was not associated with NHL overall (pooled OR = 1.00, 95% confidence interval (CI) 0.70-1.41) or the majority of NHL subtypes. An excess was however observed for diffuse large B-cell lymphoma (pooled OR = 1.80, 95% CI 1.24-2.62), although not all study-specific ORs were raised. Among the overweight (BMI 25-29.9 kg m(-2)) and obese (BMI 30-39.9 kg m(-2)), associations were elevated in some studies and decreased in others, while no association was observed among the underweight (BMI < 18.5 kg m(-2)). There was little suggestion of increasing ORs for NHL or its subtypes with every 5 kg m(-2) rise in BMI above 18.5 kg m(-2). BMI components height and weight were also examined, and the tallest men, but not women, were at marginally increased risk (pooled OR = 1.19, 95% CI 1.06-1.34). In summary, whilst we conclude that there is no evidence to support the hypothesis that obesity is a determinant of all types of NHL combined, the association between severe obesity and diffuse large B-cell lymphoma may warrant further investigation.

    View details for DOI 10.1002/ijc.23344

    View details for Web of Science ID 000254224100020

    View details for PubMedID 18167059

    View details for PubMedCentralID PMC3928289

  • Donation frequency, iron loss, and risk of cancer among blood donors JOURNAL OF THE NATIONAL CANCER INSTITUTE Edgren, G., Reilly, M., Hjalgrim, H., Tran, T. N., Rostgaard, K., Adami, J., Titlestad, K., Shanwell, A., Melbye, M., Nyren, O. 2008; 100 (8): 572-579

    Abstract

    Long-term deleterious effects of repeated blood donations may be masked by the donors' healthy lifestyle. To investigate possible effects of blood donation and iron loss through blood donation on cancer incidence while minimizing "healthy donor effects," we made dose-response comparisons within a cohort of Swedish and Danish blood donors.We used a nested case-control study design, in which case patients were defined as all donors who were diagnosed with a malignancy between their first recorded blood donation and study termination (n = 10866). Control subjects (n = 107140) were individually matched on sex, age, and county of residence. Using conditional logistic regression, we estimated relative risks of cancer according to number of blood donations made or estimated iron loss 3-12 years before a case patient was diagnosed with cancer. All statistical tests were two-sided.No clear association was observed between number of donations and risk of cancer overall. However, between the lowest (< or = median, < 0.75 g) and highest (> 90th percentile, > 2.7 g) categories of estimated iron loss, there was a trend (P(trend) < .001) of decreasing risk for cancers of the liver, lung, colon, stomach, and esophagus, which are thought to be promoted by iron overload (combined odds ratio [OR] = 0.70, 95% confidence interval [CI] = 0.58 to 0.84), but only among men and only with a latency of 3-7 years. The risk of non-Hodgkin lymphoma was higher among frequent plasma donors (> 25 vs 0 donations, OR = 2.14, 95% CI = 1.22 to 3.74).Repeated blood donation was not associated with increased or decreased risk of cancer overall. The lack of consistency across latency periods casts doubt on an apparent association between reduced cancer risk and iron loss in men. The positive association between frequent plasma donation and risk of non-Hodgkin lymphoma deserves further exploration.

    View details for DOI 10.1093/jnci/djn084

    View details for Web of Science ID 000255151900012

    View details for PubMedID 18398098

  • Hepatitis C infection and risk of malignant lymphoma INTERNATIONAL JOURNAL OF CANCER Schoellkopf, C., Smedby, K. E., Hjalgrim, H., Rostgaard, K., Panum, I., Vinner, L., Chang, E. T., Glimelius, B., Porwit, A., Sundstroem, C., Hansen, M., Adami, H., Melbye, M. 2008; 122 (8): 1885-1890

    Abstract

    The association between hepatitis C virus (HCV) infection and risk of malignant lymphoma remains controversial, perhaps due to small-sized studies and low prevalence of HCV in the general population. On the basis of a large Danish-Swedish population-based case-control study, 2,819 lymphoma patients and 1,856 controls of second-generation Danish-Swedish origin were screened for HCV infection using an enzyme-linked immunosorbent assay and a confirming recombinant immunoblot assay (RIBA) test. Positive samples were tested with real-time PCR for the presence of HCV RNA. The association between HCV infection and risk of malignant lymphoma was assessed by logistic regression. When intermediate RIBA test results were interpreted as positive, anti-HCV antibody positivity was associated with a nonsignificant increased risk of non-Hodgkin lymphoma (NHL) overall (odds ratio (OR) = 2.2; 95% confidence interval (CI) 0.9-5.3; n = 20 cases), of B-cell lymphomas combined (OR = 2.4 [1.0-5.8]; n = 20) and of lymphoplasmacytic lymphoma (OR = 5.2 [1.0-26.4]; n = 2). No patients with T-cell or Hodgkin lymphoma were HCV-positive. A more conservative definition of HCV positivity (disregarding intermediate RIBA results) resulted in an OR = 1.6 (0.3-8.5; n = 5) for NHL overall. When the definition was further restricted to require HCV RNA positivity, OR was 1.7 (0.2-16.2; n = 3) for NHL overall. Our findings from a population with a low prevalence of HCV suggest a positive association between HCV and risk of NHL, in particular of B-cell origin.

    View details for DOI 10.1002/ijc.23416

    View details for Web of Science ID 000254068300030

    View details for PubMedID 18271005

  • Genetic susceptibility to severe infection in families with invasive pneumococcal disease AMERICAN JOURNAL OF EPIDEMIOLOGY Hjuler, T., Poulsen, G., Wohlfahrt, J., Kaltoft, M., Biggar, R. J., Melbye, M. 2008; 167 (7): 814-819

    Abstract

    Severe infections may be influenced by genetic constitution. The authors examined familial aggregation of invasive infections, using invasive pneumococcal disease (IPD) as the index condition to ascertain families at risk. From Danish national registers, they identified relatives of persons with IPD from 1977 through 2005. Risks of IPD, bacterial meningitis, septicemia, and any invasive infection were analyzed for relatives of IPD cases in a prospective cohort study (23 million person-years). In total, 43,134 persons were found to have an IPD case in the family. The authors observed an increased risk of invasive infections in relatives of IPD cases most likely sharing the same household (parents, offspring, siblings, half-siblings), but only regarding those events within 1 year of the index IPD diagnosis (rate ratio = 7.4, 95% confidence interval: 2.4, 23.0). After 1 year, there were no increased risks of severe infections, including IPD, in close relatives. For other relatives, no increased risks of severe infections were observed at any time. No aggregation of invasive infections in IPD relatives was found, other than for close events among relatives who most likely shared the same household. Thus, at the population level, genetic constitution appears of little importance in the development of IPD and other severe infections.

    View details for DOI 10.1093/aje/kwm376

    View details for Web of Science ID 000254469500008

    View details for PubMedID 18227098

  • Familial aggregation of hypospadias: A cohort study AMERICAN JOURNAL OF EPIDEMIOLOGY Schnack, T. H., Zdravkovic, S., Myrup, C., Westergaard, T., Christensen, K., Wohlfahrt, J., Melbye, M. 2008; 167 (3): 251-256

    Abstract

    Hypospadias is one of the most common birth defects. However, its etiology remains largely unknown. The authors investigated the contribution of genetic and environmental factors to familial aggregation of hypospadias. Using Danish health registers, they identified 5,380 boys diagnosed with hypospadias in a cohort of 1,201,790 boys born in 1973-2005. Using binomial log-linear regression, they estimated recurrence risk ratios of hypospadias for male twin pairs and first-, second-, and third-degree relatives of a hypospadias case, which were 50.8 (95% confidence interval [CI]: 34.2, 75.5), 11.6 (95% CI: 9.75, 13.7), 3.27 (95% CI: 2.47, 4.34), and 1.33 (95% CI: 0.94, 1.88), respectively. Recurrence risk ratios did not differ for family members of a hypospadias case related to the same degree. In addition, the authors found no difference in the recurrence risk ratio for maternal compared with paternal second- and third-degree relatives of a hypospadias case. In conclusion, hypospadias was found to have a strong familial component and also to aggregate within more-distant relatives. Importantly, hypospadias was equally transmitted through the paternal and maternal sides of a family, and recurrence risk ratios for brothers and sons of a hypospadias case were similar. These findings indicate that genetic rather than intrauterine environmental factors have a principal role in causing familial hypospadias.

    View details for DOI 10.1093/aje/kwm317

    View details for Web of Science ID 000252903200001

    View details for PubMedID 18042671

  • Testicular cancer risk in first- and second-generation immigrants to Denmark JOURNAL OF THE NATIONAL CANCER INSTITUTE Myrup, C., Westergaard, T., Schnack, T., Oudin, A., Ritz, C., Wohlfahrt, J., Melbye, M. 2008; 100 (1): 41-47

    Abstract

    Immigrant studies offer insights into the relative importance of environment and genes in disease etiology. There is considerable variation in testicular cancer incidence worldwide. We investigated testicular cancer risk in first- and second-generation immigrants to Denmark, a high-incidence country, to evaluate the relative influence of genes and environment and the potential timing of action of environmental factor(s).A cohort of 2.1 million men who were born since 1930 and lived in Denmark between 1968 and 2003 was established based on information in the Danish Civil Registration System, which included their immigration histories. Cancer histories were obtained from the Danish Cancer Registry. Testicular cancer risk was estimated as rate ratios (RRs) with 95% confidence intervals (CIs) based on log-linear Poisson regression.Overall, 4216 testicular cancer cases occurred during 43 million person-years of follow-up in 2.1 million men. These included 166 cases among 344,444 direct immigrants to Denmark and 13 cases among 56,189 men born in Denmark to immigrant parents. These first- and second-generation immigrants had RRs of testicular cancer of 0.37 (95% CI = 0.31 to 0.43) and 0.88 (95% CI = 0.51 to 1.53), respectively, compared with men born in Denmark of parents born in Denmark. The rate in first-generation immigrants was not modified by age at immigration or duration of stay and reflected that in the country of origin.The testicular cancer risk in first-generation immigrants was lower than that in native-born Danes and reflected that in the countries of origin, whereas the risk in second-generation immigrants was similar to that in natives of Denmark. Together these findings argue for a substantial influence of environmental factors limited to the period early in life, most probably to the period in utero.

    View details for DOI 10.1093/jnci/djm276

    View details for Web of Science ID 000252603600011

    View details for PubMedID 18159067

  • Association between intussusception and tonsil disease in childhood EPIDEMIOLOGY Vestergaard, H., Westergaard, T., Wohlfahrt, J., Pipper, C., Melbye, M. 2008; 19 (1): 71-74

    Abstract

    Intussusception is the most common cause of intestinal obstruction in infancy and early childhood, but its etiology remains unknown. The present study analyzes whether some children with intussusception subsequently have a higher risk of tonsil disease, suggesting an enhanced tendency to lymphoid hyperplasia.This nationwide cohort study included all Danish children younger than age 15 years, who were born in 1977-2001 and diagnosed with intussusception at a hospital (n = 2018). The cohort was followed-up for tonsil disease in the Danish National Patient Registry and the Danish Health Security System.A total of 172 children were identified with tonsil disease following intussusception. The risk of tonsil disease was 48% higher (95% confidence interval = 27%-72%) after intussusception compared with the general population of the same age. Age, sex, age at intussusception, and time since intussusception did not modify risk of tonsil disease. The risks of acute tonsillitis, chronic disease of the tonsils, and tonsillectomy were equally increased after intussusception.Intussusception was associated with an increased risk of tonsil disease in childhood. Children with a general tendency to lymphoid hyperplasia may be at increased risk of intussusception.

    View details for DOI 10.1097/EDE.0b013e31815c1dd3

    View details for Web of Science ID 000251889400012

    View details for PubMedID 18090861

  • Personal sun exposure and risk of non Hodgkin lymphoma: A pooled analysis from the Interlymph Consortium INTERNATIONAL JOURNAL OF CANCER Kricker, A., Armstrong, B. K., Hughes, A. M., Goumas, C., Smedby, K. E., Zheng, T., Spinelli, J. J., De Sanjose, S., Hartge, P., Melbye, M., Willett, E. V., Becker, N., Chiu, B. C., Cerhan, J. R., Maynadie, M., Staines, A., Cocco, P., Boffeta, P. 2008; 122 (1): 144-154

    Abstract

    In 2004-2007 4 independent case-control studies reported evidence that sun exposure might protect against NHL; a fifth, in women only, found increased risks of NHL associated with a range of sun exposure measurements. These 5 studies are the first to examine the association between personal sun exposure and NHL. We report here on the relationship between sun exposure and NHL in a pooled analysis of 10 studies participating in the International Lymphoma Epidemiology Consortium (InterLymph), including the 5 published studies. Ten case-control studies covering 8,243 cases and 9,697 controls in the USA, Europe and Australia contributed original data for participants of European origin to the pooled analysis. Four kinds of measures of self-reported personal sun exposure were assessed at interview. A two-stage estimation method was used in which study-specific odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for potential confounders including smoking and alcohol use, were obtained from unconditional logistic regression models and combined in random-effects models to obtain the pooled estimates. Risk of NHL fell significantly with the composite measure of increasing recreational sun exposure, pooled OR = 0.76 (95% CI 0.63-0.91) for the highest exposure category (p for trend 0.01). A downtrend in risk with increasing total sun exposure was not statistically significant. The protective effect of recreational sun exposure was statistically significant at 18-40 years of age and in the 10 years before diagnosis, and for B cell, but not T cell, lymphomas. Increased recreational sun exposure may protect against NHL.

    View details for DOI 10.1002/ijc.23003

    View details for Web of Science ID 000251193700019

    View details for PubMedID 17708556

  • Cancer incidence in blood transfusion recipients JOURNAL OF THE NATIONAL CANCER INSTITUTE Hjalgrim, H., Edgren, G., Rostgaard, K., Reilly, M., Tran, T. N., Titlestad, K. E., Shanwell, A., Jersild, C., Adami, J., Wikman, A., Gridley, G., Wideroff, L., Nyren, O., Melbye, M. 2007; 99 (24): 1864-1874

    Abstract

    Blood transfusions may influence the recipients' cancer risks both through transmission of biologic agents and by modulation of the immune system. However, cancer occurrence in transfusion recipients remains poorly characterized.We used computerized files from Scandinavian blood banks to identify a cohort of 888,843 cancer-free recipients transfused after 1968. The recipients were followed from first registered transfusion until the date of death, emigration, cancer diagnosis, or December 31, 2002, whichever came first. Relative risks were expressed as ratios of the observed to the expected numbers of cancers, that is, standardized incidence ratios (SIRs), using incidence rates for the general Danish and Swedish populations as a reference. All statistical tests were two-sided.During 5,652,918 person-years of follow-up, 80,990 cancers occurred in the transfusion recipients, corresponding to a SIR of 1.45 (95% confidence interval [CI] = 1.44 to 1.46). The SIR for cancer overall decreased from 5.36 (95% CI = 5.29 to 5.43) during the first 6 months after transfusion to 1.10 or less for follow-up periods more than 2 years after the transfusion. However, the standardized incidence ratios for cancers of the tongue, mouth, pharynx, esophagus, liver, and respiratory and urinary tracts and for squamous cell skin carcinoma remained elevated beyond 10 years after the transfusion.The marked increase in cancer risk shortly after a blood transfusion may reflect the presence of undiagnosed occult cancers with symptoms that necessitated the blood transfusion. The continued increased risk of tobacco- and alcohol-related cancers suggests that lifestyle and other risk factors related to conditions prompting transfusion rather than transfusion-related exposures per se are important to the observed cancer occurrence in the recipients.

    View details for DOI 10.1093/jnci/djm248

    View details for Web of Science ID 000251928200009

    View details for PubMedID 18073377

  • Epstein-Barr virus immune response in high-risk nasopharyngeal carcinoma families in Greenland JOURNAL OF MEDICAL VIROLOGY Friborg, J., Jarrett, R. F., Liu, M., Falk, K. I., Koch, A., Olsen, O. R., Duncan, P., Wohlfarht, J., Chen, J., Melbye, M. 2007; 79 (12): 1877-1881

    Abstract

    Undifferentiated nasopharyngeal carcinoma is associated with Epstein-Barr virus (EBV) infection. Presence of EBV IgA antibodies is rare among healthy individuals and is used as a marker of nasopharyngeal carcinoma in high-incidence populations. Reasons for EBV IgA seropositivity are unknown, but high EBV IgA levels have been found among unaffected close family members and spouses to nasopharyngeal carcinoma patients in Chinese populations. In Greenland, a nasopharyngeal carcinoma-high-incidence area, we compared EBV serology and viral load in high-risk nasopharyngeal carcinoma family members (N = 20) and controls without nasopharyngeal carcinoma-affected relatives (N = 90). There was no significant difference in EBV viral loads between relatives and controls, and EBV was detected in plasma in 5.0% of relatives and 11.4% of controls. There was no significant difference in EBV serology, but the seroprevalence of EBV viral capsid antigen (VCA) IgA was high in both relatives (25.0%) and controls (20.5%). Compared with anti-VCA IgA-negative, anti-VCA IgA-positive individuals had significantly higher EBV viral loads in peripheral blood mononuclear cells (PBMCs) (P < 0.01). The very high prevalence of anti-VCA IgA indicates that this antibody is unsuitable for nasopharyngeal carcinoma screening among Inuits.

    View details for DOI 10.1002/jmv.21014

    View details for Web of Science ID 000250319100013

    View details for PubMedID 17935169

  • Incidence of tonsillectomy in Denmark, 1980 to 2001 PEDIATRIC INFECTIOUS DISEASE JOURNAL Vestergaard, H., Wohlfahrt, J., Westergaard, T., Pipper, C., Rasmussen, N., Melbye, M. 2007; 26 (12): 1117-1121

    Abstract

    Tonsillectomy is one of the most frequent operations performed on children and young adults, but little is known regarding its distribution by age, sex, and calendar period.We designed a population-based cohort study including all Danish residents from 1980 to 2001 to describe national incidence figures for tonsillectomy. Persons undergoing tonsillectomy were identified in the Danish National Patient Registry and from the Danish Health Security System. Overall, the cohort consisted of 6.3 million persons, who were followed up for 106.9 million person-years.During the study period 153,212 patients had tonsillectomies, comprising 84,831 females and 68,381 males. The age-specific incidence of tonsillectomy peaked at 4 years of age for both boys and girls, with 9.7 and 6.9 tonsillectomies per 1000 person-years, respectively. A second peak emerged during teenage years in both sexes, being highest among girls with 8.6 tonsillectomies per 1000 person-years at 16 years of age and 3.1 tonsillectomies per 1000 person-years among 17-year-old boys. The cumulative risk of tonsillectomy during the first 20 years of life increased from 7.9% among females and 6.0% among males in 1980 to 9.2% and 7.7%, respectively, in 2001. Over 90% of the patients less than 20 years of age registered at hospital with chronic disease of the tonsils had tonsillectomies within a year.The incidence of tonsillectomy revealed significant gender differences. Furthermore, 2 incidence peaks emerged at age 4 years and age 16-17 years. The second peak in adolescence was particularly pronounced for females and is unexplained.

    View details for DOI 10.1097/INF.0b013e31814536ba

    View details for Web of Science ID 000251440100007

    View details for PubMedID 18043448

  • Childhood social environment and risk of non-hodgkin lymphoma in adults CANCER RESEARCH Smedby, K. E., Hjalgrim, H., Chang, E. T., Rostgaard, K., Glimelius, B., Adami, H., Melbye, M. 2007; 67 (22): 11074-11082

    Abstract

    Better hygiene and sanitation and decreasing family size parallel the increasing incidence of non-Hodgkin lymphoma (NHL) in many populations around the world. However, whether sibship size, birth order, and crowding are related to adult NHL risk is not clear. We investigated how family structure and childhood social environment were related to the risk of NHL and NHL subtypes in a large Scandinavian population-based case control study with 6,242 participants aged 18 to 74 years. Detailed exposure information was obtained through telephone interviews. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using logistic regression, and all statistical tests were two-sided. Having four or more siblings was associated with a moderately increased risk of NHL, compared with having no siblings (OR 1.34, 95% CI 1.11-1.62, P(trend) < 0.001). Having four or more older siblings was associated with a similar risk increase (OR 1.33, 95% CI 1.12-1.59, P(trend) = 0.003) compared with being the oldest, whereas number of younger siblings was unrelated overall. The associations were independent of other environmental exposures and did not vary by country, age, or sex. High household crowding was also positively associated with risk of NHL. Results were slightly stronger for diffuse large B-cell and T-cell lymphomas than for other major NHL subtypes. Our findings add to the evidence that large sibship size, late birth order, and childhood crowding are associated with an elevated risk of NHL. Effect mechanisms may be related to early age at onset and high frequency of specific infections or total microbial exposure in childhood.

    View details for DOI 10.1158/0008-5472.CAN-07-1751

    View details for Web of Science ID 000251044000054

    View details for PubMedID 18006854

  • The Epidemiology of Viral Meningitis Hospitalization in Childhood EPIDEMIOLOGY Hviid, A., Melbye, M. 2007; 18 (6): 695-701

    Abstract

    There have been few long-term population-based studies of viral meningitis, and only a limited number of potential risk factors have been evaluated.We estimated the incidence of viral meningitis hospitalization in childhood, and assessed risk factors for this disease through a population-based cohort study comprising all children born in Denmark from 1977 through 2001 (n = 1.5 million). Information on sex, number of children and adults in the household, age of parents at child's birth, degree of urbanization, birth weight, gestational age, and possible complications at birth were linked to the children in the cohort, together with information on hospitalization with viral meningitis. We calculated incidence rates of viral meningitis and estimated rate ratios according to the various risk factors using Poisson regression.The incidence rate was highest in the first 6 months of life (38.7 per 100,000 person-years), with a peak right after birth (58.7 per 100,000 person-years). A secondary peak was seen among 5-year-old children (15.6 per 100,000 person-years). Overall incidence rates decreased throughout the study period, with outbreaks occurring every 3 to 5 years [decrease in rate ratio per calendar year = 0.95; 95% confidence interval (CI) = 0.94-0.96]. Summer and early fall peaks were present. We observed independent effects of sex (girls vs. boys: rate ratio = 0.47 [95% CI = 0.43-0.53]), children in the household (eg, living with 3+ younger children vs. living with none: 1.94 [1.22-3.07]), single parenthood (living with 1 parent vs. living with 2 parents: 1.30 [1.12-1.39]), degree of urbanization (children living in the capital vs. children living in small town and rural areas: 1.54 [1.31-1.80]), low birth weight (increase in RR per 500 g reduction in birth weight = 1.05 [1.00-1.09]), prematurity (increase in RR per 1 week reduction in gestational age = 1.03 [1.01-1.04]), and cesarean section (cesarean section vs. vaginal birth: 1.29 [1.12-1.49]).Incidence of viral meningitis hospitalization is highest immediately after birth with a secondary peak at age 5. Lack of passive maternally acquired antibodies and preferential hospitalization are the likely causes for the peak in infancy. Increased transmission in kindergarten, preschool, and day care could explain the secondary peak. The incidence decreased throughout the 25-year study period perhaps due to improved public hygiene. Among the assessed risk factors, we found the strongest to be male sex, a high number of children in the household, and degree of urbanization.

    View details for DOI 10.1097/EDE.0b013e3181567d31

    View details for Web of Science ID 000262285900008

    View details for PubMedID 18062062

  • Improving health profile of blood donors as a consequence of transfusion safety efforts TRANSFUSION Edgren, G., Tran, T. N., Hjalgrim, H., Rostgaard, K., Shanwell, A., Titlestad, K., Wikman, A., Norda, R., Jersild, C., Wideroff, L., Gridley, G., Adami, J., Melbye, M., Nyren, O., Reilly, M. 2007; 47 (11): 2017-2024

    Abstract

    Transfusion safety rests heavily on the health of blood donors. Although they are perceived as being healthier than average, little is known about their long-term disease patterns and to which extent the blood banks' continuous efforts to optimize donor selection has resulted in improvements. Mortality and cancer incidence among blood donors in Sweden and Denmark was investigated.All computerized blood bank databases were compiled into one database, which was linked to national population and health data registers. With a retrospective cohort study design, 1,110,329 blood donors were followed for up to 35 years from first computer-registered blood donation to death, emigration, or December 31, 2002. Standardized mortality and incidence ratios expressed relative risk of death and cancer comparing blood donors to the general population.Blood donors had an overall mortality 30 percent lower (99% confidence interval [CI] 29%-31%) and cancer incidence 4 percent lower (99% CI 2%-5%) than the background population. Mortality rates and cancer incidence were lowest for outcomes that are recognized as being related to lifestyle factors such as smoking or to the selection criteria for blood donation. Blood donors recruited in more recent years exhibited a lower relative mortality than those who started earlier.Blood donors enjoy better than average health. Explicit and informal requirements for blood donation in Scandinavia, although mostly of a simple nature, have successfully refined the selection of a particularly healthy subpopulation.

    View details for DOI 10.1111/j.1537-2995.2007.01425.x

    View details for Web of Science ID 000250364100011

    View details for PubMedID 17958530

  • The impact of autoimmune diseases on the incidence and prognosis of cutaneous malignant melanoma CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Kaae, J., Wohlfahrt, J., Boyd, H. A., Wulf, H. C., Biggar, R. J., Melbye, M. 2007; 16 (9): 1840-1844

    Abstract

    Persons being treated with IFNalpha-2b for advanced cutaneous malignant melanoma (CMM) have been reported to have a greatly improved prognosis if they develop autoantibodies or clinical signs of autoimmunity during therapy. Consequently, we examined whether autoimmune diseases might also be associated with lower CMM incidence and better prognosis.We established a study cohort based on the entire Danish population, obtaining information on CMM and autoimmune diseases from the Danish national registers. Using log-linear regression models adjusting for age, period, and sex, we compared CMM incidence and CMM-specific mortality rates in persons with and without a history of autoimmune disease.Between 1977 and 2003, 20,482 cases of CMM were registered in the Danish Cancer Register. Previously diagnosed autoimmune diseases did not affect the incidence of CMM (incidence rate ratio, 1.0; 95% confidence interval, 0.9-1.1). In the first 5 years after CMM diagnosis, we observed 8,957 deaths in individuals with CMM (5,181 expected). CMM-specific mortality rates 1 to 5 years after diagnosis were similar in CMM patients with and without autoimmune diseases (mortality rate ratio, 0.9; 95% confidence interval, 0.7-1.2).Autoimmune conditions were not associated with CMM incidence or prognosis. The better CMM prognosis previously observed when autoantibodies or clinical signs of autoimmunity developed during IFNalpha-2b therapy may have been related to variation in individual responses to this therapy, with individuals sensitive to treatment exhibiting more signs of autoimmunity but also (independently) experiencing greater antitumor responses as a result of treatment.

    View details for DOI 10.1158/1055-9965.EPI-07-0459

    View details for Web of Science ID 000249643600021

    View details for PubMedID 17855703

  • Cigarette smoking and risk of Hodgkin lymphoma: A population-based case-control study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Hjalgrim, H., Ekstrom-Smedby, K., Rostgaard, K., Amini, R., Molin, D., Hamilton-Dutoit, S., Schollkopf, C., Chang, E. T., Ralfkiaer, E., Adami, H., Glimelius, B., Melbye, M. 2007; 16 (8): 1561-1566

    Abstract

    Studies have inconsistently reported an association between tobacco smoking and Hodgkin lymphoma (HL) risk. The conflicting finding may reflect etiologic heterogeneity between HL subtypes, warranting further characterization of the relationship.We collected information on tobacco-smoking habits in 586 classic HL cases and 3,187 population controls in a Danish-Swedish case-control study. HL EBV status was established for 499 cases by standard techniques. Odds ratios (OR) for an association with cigarette smoking were calculated by logistic regression for HL overall and stratified by age, sex, major histology subtypes, and tumor EBV status, adjusting for known confounders.Compared with never smokers, current cigarette smokers were at an increased overall HL risk [adjusted OR, 1.57; 95% confidence interval (95% CI), 1.22-2.03]. The association was strongest for EBV-positive HL (adjusted OR, 2.36; 95% CI, 1.51-3.71), but also applied to EBV-negative HL (adjusted OR, 1.43; 95% CI, 1.05-1.97; P(homogeneity EBV-pos) versus P(homogeneity EBV-neg) = 0.04). The association did not vary appreciably by age, sex, or histologic subtype, the apparent EBV-related difference present in all strata. There was no evidence of a dose-response pattern, whether by age at smoking initiation, daily cigarette consumption, number of years smoking, or cumulative number of cigarettes smoked. Similar results were obtained in analyses using non-HL patients (n = 3,055) participating in the founding study as comparison group.The observed association between cigarette smoking and HL risk is consistent with previous findings and biologically credible. Although not easily dismissed as an artifact, the limited evidence of a dose-response pattern renders the overall evidence of causality weak.

    View details for DOI 10.1158/1055-9965.EPI-07-0094

    View details for Web of Science ID 000248715100007

    View details for PubMedID 17684129

  • Birth weight and risk of cancer CANCER Ahlgren, M., Wohlfahrt, J., Olsen, L. W., Sorensen, T. I., Melbye, M. 2007; 110 (2): 412-419

    Abstract

    It is well established that prenatal biologic processes are important for the development of some childhood cancers, whereas less is known regarding their influence on adult cancer risk. High birth weight has been associated with risk of breast cancer, whereas studies of other specific cancers and all cancers together have been less conclusive.The authors established a cohort of more than 200,000 men and women who were born between 1936 and 1975. Birth weights were obtained from school health records and information concerning cancer from the Danish Cancer Registry. Follow-up was performed between April 1, 1968 and December 31, 2003. During 6,975,553 person-years of follow-up, a total of 12,540 primary invasive cancers were diagnosed.Analyses of site-specific cancers revealed that the majority of cancers had a positive linear association with birth weight. Departures from a positive linear association were found to be statistically significant for cancers of the pancreas and bladder, which demonstrated a V-shaped association, and testicular cancer, which demonstrated an inverse association with birth weight. Excluding these 3 exceptions, the trends for the individual cancer sites were not heterogeneous, and the overall trend was a relative risk of 1.07 (95% confidence interval, 1.03-1.11) per 1000-g increase in birth weight. This trend was the same in men and women and in all age groups.A 7% increase in cancer risk was observed per 1000-g increase in birth weight. Few cancers demonstrated a nonlinear association with birth weight, and testicular cancer was found to be negatively associated with birth weight. The authors hypothesized that the biologic explanation behind the association between birth weight and cancer at different sites should be sought in a common pathway.

    View details for DOI 10.1002/cncr.22773

    View details for Web of Science ID 000247985600023

    View details for PubMedID 17538980

  • Human antibody recognition of Anisakidae and Trichinella spp. in Greenland CLINICAL MICROBIOLOGY AND INFECTION Moller, L. N., Krause, T. G., Koch, A., Melbye, M., Kapel, C. M., Petersen, E. 2007; 13 (7): 702-708

    Abstract

    High levels of total IgE are observed among children in Greenland. To evaluate the extent to which Anisakidae and Trichinella spp. contribute to the high total IgE level, an ELISA and a western blot were developed for the detection of IgG antibodies to Anisakidae, based on excretory/secretory antigens from Anisakidae larvae. Western blots with Anisakidae and Trichinella antigens discriminated between Anisakidae and Trichinella infections, enabling cross-reactivity between the two parasite infections to be eliminated. Serum samples from 1012 children in Greenland were analysed for specific antibodies to Anisakidae and Trichinella. Eleven children were IgG-positive for Trichinella and nine were IgG-positive for Anisakidae, indicating a relatively low prevalence of both infections among children in Greenland. Faecal samples from 320 children were also examined for other intestinal parasites. Enterobius vermicularis was found in one sample and Blastocystis hominis in 32 samples, but no other intestinal parasites were identified. In total, 304 children had elevated total IgE levels. There was a significant association between Trichinella seropositivity and high levels of total IgE, but not between Anisakidae seropositivity and total IgE. The data indicate that parasitic infections alone do not explain the high level of total IgE observed among children in Greenland.

    View details for DOI 10.1111/j.1469-0691.2007.01730.x

    View details for Web of Science ID 000247114200009

    View details for PubMedID 17484764

  • Reproductive history and cutaneous malignant melanoma: A comparison between women and men AMERICAN JOURNAL OF EPIDEMIOLOGY Kaae, J., Andersen, A., Boyd, H. A., Wohlfahrt, J., Melbye, M. 2007; 165 (11): 1265-1270

    Abstract

    To evaluate whether previously observed associations between parity and cutaneous malignant melanoma (CMM) risk in women reflected a biologic mechanism or resulted from uncontrolled confounding by lifestyle factors associated with parity (e.g., patterns of sun exposure), the authors investigated the effect of reproductive history (parenthood) on CMM risk in both women and men. Using information from Danish national registers (1968-2003), the authors established a population-based cohort of more than 3,500,000 persons with information on parenthood and CMM. Relative risks were estimated using Poisson regression models. Overall, number of children was significantly associated with a woman's risk of CMM (p = 0.004), with the lowest risk being seen among women with many births. Women aged 25 years or older at their first birth had a 24% (95% confidence interval: 16, 33) higher risk of CMM than younger women. Ten or more years after the birth of her youngest child, a woman had a 15% (95% confidence interval: 5, 27) higher risk of CMM than she did in the first 10 years. Similar results were observed in men. The similarity of effects for men and women suggests that lifestyle factors, rather than exposure to pregnancy hormones, may be responsible for the observed associations between reproductive history and CMM risk in women.

    View details for DOI 10.1093/aje/kwm015

    View details for Web of Science ID 000247005500007

    View details for PubMedID 17327217

  • Risk of cancer after blood transfusion from donors with subclinical cancer: a retrospective cohort study LANCET Edgren, G., Hjalgrim, H., Reilly, M., Tran, T. N., Rostgaard, K., Shanwell, A., Titlestad, K., Adami, J., Wikman, A., Jersild, C., Gridley, G., Wideroff, L., Nyren, O., Melbye, M. 2007; 369 (9574): 1724-1730

    Abstract

    Although mechanisms for detection of short-term complications after blood transfusions are well developed, complications with delayed onset, notably transmission of chronic diseases such as cancer, have been difficult to assess. Our aim was to investigate the possible risk of cancer transmission from blood donors to recipients through blood transfusion.We did a register-based retrospective cohort study of cancer incidence among patients who received blood from donors deemed to have a subclinical cancer at the time of donation. These precancerous donors were diagnosed with a cancer within 5 years of the donation. Data from all computerised blood bank registers in Sweden and Denmark gathered between 1968 and 2002 were merged into a common database. Demographic and medical data, including mortality and cancer incidence, were ascertained through linkages with nationwide, and essentially complete, population and health-care registers. The risk of cancer in exposed recipients relative to that in recipients who received blood from non-cancerous donors was estimated with multivariate Poisson regression, adjusting for potential confounding factors.Of the 354 094 transfusion recipients eligible for this analysis, 12,012 (3%) were exposed to blood products from precancerous donors. There was no excess risk of cancer overall (adjusted relative risk 1.00, 95% CI 0.94-1.07) or in crude anatomical subsites among recipients of blood from precancerous donors compared with recipients of blood from non-cancerous donors.Our data provide no evidence that blood transfusions from precancerous blood donors are associated with increased risk of cancer among recipients compared with transfusions from non-cancerous donors.

    View details for Web of Science ID 000246631300028

    View details for PubMedID 17512857

  • Kawasaki syndrome in Denmark PEDIATRIC INFECTIOUS DISEASE JOURNAL Fischer, T. K., Holman, R. C., Yorita, K. L., Belay, E. D., Melbye, M., Koch, A. 2007; 26 (5): 411-415

    Abstract

    To describe the epidemiologic characteristics of Kawasaki syndrome (KS) and to estimate national KS incidence rates among children in Denmark.A retrospective population-based study using hospital discharge records with a KS diagnosis for children younger than 15 years selected from the Danish National Hospital Register for 1981-2004. Incidence rates were calculated using the number of KS patients and corresponding census data.During 1981-2004, 360 children younger than 15 years were hospitalized with KS in Denmark, with 73% younger than 5 years. In this age group, the average annual incidence of KS gradually increased from 1981 to 1999 and thereafter stabilized at 4.5 to 5.0 per 100,000 person-years. The incidence was greater for boys than for girls (RR = 1.6, 95% CI = 1.2-2.0) and was highest among infants younger than 1 year (4.5), declining with increasing age (P = 0.03). However, the age-specific decline in incidence was only observed for boys, whereas the incidence for girls remained unchanged by age. The median length of hospital stay was 12 days, and the incidence peaked in the winter months.Major epidemiologic characteristics identified among Danish childhood KS are consistent with those described in previous studies, such as highest incidence among young children and winter-seasonality. The KS incidence rate among children younger than 5 years in Denmark increased steadily during the early study period (coinciding with global recognition of KS) and seems to have stabilized from 1998-1999 onwards. Although the incidence among Danish children was lower than that reported for several other European countries, differences in methodology challenge definite comparisons.

    View details for DOI 10.1097/01.inf.0000259964.47941.00

    View details for Web of Science ID 000246193400008

    View details for PubMedID 17468651

  • Perinatal and crowding-related risk factors for invasive pneumococcal disease in infants and young children: A population-based case-control study CLINICAL INFECTIOUS DISEASES Hjuler, T., Wohlfahrt, J., Simonsen, J., Kaltoft, M. S., Koch, A., Kamper-Jorgensen, M., Biggar, R. J., Melbye, M. 2007; 44 (8): 1051-1056

    Abstract

    Denmark's systems of registry-based data offer a unique opportunity to examine, on a population basis, risk factors for invasive pneumococcal disease (IPD) relating to perinatal and crowding exposures among children. The main objective of this study was to identify the role of familial and day care factors in the risk of IPD among unvaccinated infants and children.A total of 1381 children aged 0-5 years old who experienced IPD were identified from a national surveillance program of IPD in Denmark. Risk factors were assessed in a matched, nested, case-control study that assigned 10 population control subjects to every case patient. Exposure information was obtained from several population-based, person-identifiable Danish registries.Preterm birth and low birth weight significantly increased the risk of IPD among infants. In infants 0-5 months of age, the risk of IPD was high among infants who had older siblings, compared with infants of the same age who had no older siblings (adjusted rate ratio [aRR], 3.38; 95% confidence interval, 2.11-5.42), whereas the aRR was low (aRR, 0.56; 95% confidence interval, 0.47-0.65) in children aged 6-23 months. Day care attendance, compared with home care, increased the aRR of IPD 0-2 months after enrollment in a day care program (aRR, 2.28; 95% confidence interval, 1.73-3.00), whereas the aRR was 0.70; (95% confidence interval, 0.46-1.06) > or = 6 months after enrollment in children aged 6-23 months.During infancy (age, 0-6 months), risk of IPD is associated with low birth weight, presumably because of lower levels of passively acquired maternal antibody. During early childhood, exposure to other young children (either siblings or through day care attendance) is clearly associated with IPD, but natural exposure appears to occur rapidly and confer durable immunity.

    View details for DOI 10.1086/512814

    View details for Web of Science ID 000244928200006

    View details for PubMedID 17366448

  • The impact of birth weight on infectious disease hospitalization in childhood AMERICAN JOURNAL OF EPIDEMIOLOGY Hviid, A., Melbye, M. 2007; 165 (7): 756-761

    Abstract

    Low birth weight, a result of preterm birth or intrauterine growth restriction, is a well-established indicator of survival in childhood. However, corresponding epidemiologic studies of the association between low birth weight and morbidity from infections throughout childhood are sparse. The authors evaluated the relation between birth weight and infectious diseases throughout childhood in a population-based cohort study comprising all children born in Denmark from 1977 through 2004 (n = 1.7 million). Information on birth weight, gestational age, and potential confounding variables was linked to the children in the cohort, together with information on hospitalization with infectious disease. Poisson regression yielded rate ratios of hospitalization according to birth weight. The authors found that birth weight was inversely associated with risk of infectious disease hospitalization; among children aged 0-14 years, the risk of hospitalization increased 9% for each 500-g reduction in birth weight (increase in rate ratio = 1.09, 95% confidence interval: 1.09, 1.11). The effect was found to peak in infancy and to persist until 10 years of age. It was present also in children born at term (37-41 weeks of gestation). The present study is the first to demonstrate the measurable impact of birth weight on infectious diseases throughout childhood.

    View details for DOI 10.1093/aje/kwk064

    View details for Web of Science ID 000244959600005

    View details for PubMedID 17189591

  • Infectious mononucleosis, childhood social environment, and risk of Hodgkin lymphoma CANCER RESEARCH Hjalgrim, H., Smedby, K. E., Rostgaard, K., Molin, D., Hamilton-Dutoit, S., Chang, E. T., Ralfkiaer, E., Sundstrom, C., Adami, H., Glimelius, B., Melbye, M. 2007; 67 (5): 2382-2388

    Abstract

    Infectious mononucleosis (IM) has been associated with an increased risk of Hodgkin lymphoma (HL), implicating a role for Epstein-Barr virus (EBV) in HL development. Although essential to the understanding of the association, it has remained uncertain if the relationship is restricted to the EBV-positive subset of HL. We collected information on mononucleosis history and childhood socioenvironmental characteristics in a population-based study of 586 patients with classic HL and 3,187 controls in Denmark and Sweden. Tumor EBV status was established for 499 cases by immunohistochemistry and in situ hybridization techniques. Odds ratios (OR) for the relationship between HL risk and mononucleosis and other risk factors were estimated by logistic regression for HL in younger (18-44 years) and older (45-74 years) adults, overall and by tumor EBV status. All analyses were adjusted for country-specific measures of maternal education and mononucleosis history. IM was associated with an increased risk of EBV-positive [OR, 3.23; 95% confidence interval (95% CI) 1.89-5.55] but not EBV-negative HL (OR, 1.35; 95% CI, 0.86-2.14). Risk of EBV-positive HL varied with time since IM and was particularly pronounced in younger adults (OR, 3.96; 95% CI, 2.19-7.18). IM-associated lymphomas occurred with a median of 2.9 years (1.8-4.9 years) after infection. The EBV specificity of the IM association was corroborated by a case-case comparison of IM history between younger adult EBV-positive and EBV-negative HL patients (OR(IM EBV+ HL versus EBV- HL), 2.68; 95% CI, 1.40-5.12). We found further evidence that IM is associated only with EBV-positive HL. This finding is compatible with the notion that EBV-positive and EBV-negative HL may have different etiologies.

    View details for DOI 10.1158/0008-5472.CAN-06-3566

    View details for Web of Science ID 000244738100062

    View details for PubMedID 17332371

  • Atopy and risk of non-Hodgkin lymphoma JOURNAL OF THE NATIONAL CANCER INSTITUTE Melbye, M., Smedby, K. E., Lehtinen, T., Rostgaard, K., Glimelius, B., Munksgaard, L., Schollkopf, C., Sundstrom, C., Chang, E. T., Koskela, P., Adami, H., Hjalgrim, H. 2007; 99 (2): 158-166

    Abstract

    A possible connection between allergy and cancer has been suspected, but allergy-related conditions or atopy have been inconsistently associated with reduced risks of non-Hodgkin lymphoma. We investigated this association in a population-based case-control study and in a prospective study with prediagnostic blood specimens.We carried out a population-based study of 3055 case patients with non-Hodgkin lymphoma and 3187 control subjects in Denmark and Sweden, including questionnaire information on allergy and blood specimens, and a nested case-control study within a prospective cohort of more than 400,000 Finnish women. In the second study, serum specimens from the 198 case patients who developed non-Hodgkin lymphoma within a median of 8.9 years after the blood was drawn were matched with serum specimens from 594 control subjects. In both studies, laboratory-based evidence of allergy (atopy) was determined in serum on the basis of specific IgE reactivity to common inhalant allergens. Dissemination of disease was classified by the Ann Arbor system. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by logistic regression.In the first study, ever having hay fever, but not other allergic conditions, was associated with a reduced risk of non-Hodgkin lymphoma. In particular, subjects with specific IgE reactivity in serum had a 32% (95% CI = 20% to 42%) lower risk of overall non-Hodgkin lymphoma than those without such reactivity. However, among case patients, dissemination of the disease was strongly inversely associated with specific IgE reactivity. In the second (i.e., prospective) study, no association was found between non-Hodgkin lymphoma and specific IgE reactivity, except possibly immediately before a diagnosis of non-Hodgkin lymphoma (> or = 10 years before diagnosis, OR = 1.00, 95% CI = 0.48 to 2.09; 5-9 years before, OR = 0.95, 95% CI = 0.50 to 1.84; 1-4 years before, OR = 0.33, 95% CI = 0.11 to 1.02; and < 1 year before, OR = 0.27, 95% CI = 0.03 to 2.31).Allergy may not be causally associated with the risk of non-Hodgkin lymphoma. The inverse association observed in some case-control studies may arise because non-Hodgkin lymphoma suppresses the immunologic response to allergens.

    View details for DOI 10.1093/inci/djk019

    View details for Web of Science ID 000243528300012

    View details for PubMedID 17227999

  • Nutrient intake and risk of non-Hodgkin's lymphoma AMERICAN JOURNAL OF EPIDEMIOLOGY Chang, E. T., Balter, K. M., Torrang, A., Smedby, K. E., Melbye, M., Sundstrom, C., Glimelius, B., Adami, H. 2006; 164 (12): 1222-1232

    Abstract

    The mechanisms through which diet may influence the development of non-Hodgkin's lymphoma (NHL) are unclear but can be better understood by examining associations between nutrient consumption and NHL risk. Between 2000 and 2002, 591 NHL cases and 460 population-based controls in Sweden completed a semiquantitative food frequency questionnaire. Unconditional logistic regression was performed to estimate odds ratios and 95% confidence intervals for associations with nutrient intake; all statistical tests were two sided. Dietary intake of most macronutrients was not associated with risk of NHL or its common subtypes. Consumption of omega-3 or marine fatty acids was associated with decreased risk of NHL and chronic lymphocytic lymphoma, and dietary fiber was associated with lower risk of all subtypes examined. When the highest and the lowest quartiles of marine fat intake were compared, the odds ratio for NHL risk was 0.6 (95% confidence interval: 0.4, 0.9), ptrend=0.03; for dietary fiber intake, the corresponding odds ratio was 0.5 (95% confidence interval: 0.3, 0.7), ptrend<0.001. Dietary consumption of beta-carotene or alpha-tocopherol was associated with lower NHL risk, whereas intake of calcium or retinol was associated with increased NHL risk. Nutrients that affect inflammation, vitamin D activity, oxidative DNA damage, or DNA methylation may be associated with risk of NHL.

    View details for DOI 10.1093/aje/kwj330

    View details for Web of Science ID 000242714800010

    View details for PubMedID 17005624

  • Maternal serum alpha-fetoprotein level during pregnancy and isolated cryptorchidism in male offspring AMERICAN JOURNAL OF EPIDEMIOLOGY Boyd, H. A., Myrup, C., Wohlfahrt, J., Westergaard, T., Norgaard-Pedersen, B., Melbye, M. 2006; 164 (5): 478-486

    Abstract

    Cryptorchidism is thought to result from a disruption of the androgen-estrogen balance in utero. Alpha-fetoprotein (AFP) interacts with and may modulate fetal responses to estrogens. Using a cohort of boys born to women participating in a Danish maternal serum AFP screening program between 1980 and 1994, the authors explored whether AFP levels (as reflected by maternal serum AFP levels in gestational weeks 14-22) were associated with the risk of isolated cryptorchidism in male offspring. Cryptorchidism diagnoses and covariate information were obtained from Denmark's national health registries. Risk ratios for cryptorchidism by maternal serum AFP multiples of the median were estimated by use of log-linear binomial regression. Of 25,418 boys, 663 (2.6%) were diagnosed with cryptorchidism. After adjustment for confounders, boys with maternal serum AFP levels greater than or equal to 2.5 times the median had a 63% (95% confidence interval: -2, 172) greater risk of cryptorchidism than did boys with maternal serum AFP levels within 25% of the median. High fetal AFP levels may contribute directly to events producing cryptorchidism; alternatively, elevated maternal serum AFP levels may reflect placental dysfunction, some aspect of which contributes to cryptorchidism.

    View details for DOI 10.1093/aje/kwj219

    View details for Web of Science ID 000240286600008

    View details for PubMedID 16790515

  • Type 1 diabetes and multiple sclerosis - A Danish population-based cohort study ARCHIVES OF NEUROLOGY Nielsen, N. M., Westergaard, T., Frisch, M., Rostgaard, K., Wohlfahrt, J., Koch-Henriksen, N., Melbye, M., Hjalgrim, H. 2006; 63 (7): 1001-1004

    Abstract

    Type 1 diabetes mellitus (T1D) and multiple sclerosis (MS) contribute considerably to the burden of autoimmune diseases in young adults. Although HLA patterns of T1D and MS are considered mutually exclusive, individual and familial co-occurrence of the 2 diseases has been reported.To assess the co-occurrence of T1D and MS by estimating the risk for MS in patients with T1D and the risk for T1D in first-degree relatives of patients with MS.Two population-based disease registers, the Danish Hospital Discharge Register and the Danish Multiple Sclerosis Register were used to identify patients with T1D, defined as patients in whom diabetes was diagnosed before age 20 years (N = 6078), and patients with MS (N = 11 862). First-degree relatives (N = 14,771) of patients with MS were identified from family information in the Danish Civil Registration System.Patients with T1D and first-degree relatives of patients with MS were followed up for occurrence of MS and T1D, respectively, and the relative risks were expressed as standardized incidence ratios, that is, ratios of observed to expected numbers of outcomes based on national age, sex, and period-specific MS and T1D incidence rates.Patients with T1D were at more than 3-fold increased risk for development of MS (relative risk, 3.26; 95% confidence interval, 1.80-5.88; n = 11). First-degree relatives of patients with MS were at 63% increased risk (relative risk, 1.63; 95% confidence interval, 1.26-2.12; n = 56) for development of T1D. However, adjusting for familial relationship to patients with T1D reduced the excess risk to 44% (relative risk, 1.44; 95% confidence interval, 1.11-1.88; n = 56).The present nationwide cohort study demonstrates an intraindividual and, to a lesser degree, an intrafamilial co-occurrence of MS and T1D.

    View details for Web of Science ID 000238917100014

    View details for PubMedID 16831970

  • Sibship characteristics and risk of multiple sclerosis: A nationwide cohort study in Denmark AMERICAN JOURNAL OF EPIDEMIOLOGY Bager, P., Nielsen, N. M., Bihrmann, K., Frisch, M., Wohlfart, J., Koch-Henriksen, N., Melbye, M., Westergaard, T. 2006; 163 (12): 1112-1117

    Abstract

    It has been hypothesized that age at infection with a common microbial agent may be associated with the risk of multiple sclerosis (MS). The authors addressed this hypothesis by using number of older siblings and other sibship characteristics as an approximation of age at exposure to common infections. Data on family characteristics and vital status from the Danish Civil Registration System were used to establish a cohort of all Danes whose mothers had been born in Denmark since 1935. Persons diagnosed with MS during the period 1968-1998 were identified through linkage with the Danish Multiple Sclerosis Register. The cohort of 1.9 million Danes was followed for 28.1 million person-years; during that time, 1,036 persons developed MS. Overall, there was no association between number of older siblings, number of younger siblings, total number of siblings, age distance from the nearest younger sibling, or exposure to younger siblings under 2 years of age and risk of MS later in life. There was no association of MS risk with multiple birth (vs. singleton birth) or with the age of the mother or father at birth. These results do not lend support to the hypothesis that number of older siblings or any of the other sibship characteristics studied is associated with risk of MS.

    View details for DOI 10.1093/aje/kwj148

    View details for Web of Science ID 000238424900007

    View details for PubMedID 16675539

  • The impact of pre-school booster vaccination of 4-6-year-old children on pertussis in 0-1-year-old children VACCINE Hviid, A., Stellfeld, M., Wohlfahrt, J., Andersen, P. H., Melbye, M. 2006; 24 (9): 1401-1407

    Abstract

    Pertussis in young children is severe and relatively prevalent in vaccinated populations. We estimated the impact of pre-school booster vaccination of 4-6-year-old children on pertussis in 0-1-year-old children. We conducted a population-based historical cohort study of all children born in Denmark, 1977-2001 (N=1,536,717) using information on place of residence to identify household members and vaccination history from nationwide registers. We estimated rate ratios (RRs) of pertussis hospitalisation among children in the cohort according to number, age, and vaccination status of their household members. This enabled, through population attributable risks, the estimation of the preventable proportion of hospitalisations among 0-1-year-old children according to age at booster vaccination (4-6 years), booster uptake, and the efficacy of the booster against transmission. The preventable proportion of pertussis hospitalisations among 0-1-year-old children ranged from 7% to 33% (most realistic scenario=18%), varying according to age at booster vaccination, uptake, and efficacy of booster against transmission. This relatively limited impact of a pre-school booster was partly a consequence of the actual number of 0-1-year-old children living with children of pre-school age or older and partly the result of significant exposure from children younger than pre-school age in the household. According to our model the effectiveness of pre-school booster vaccination as an intervention to prevent pertussis hospitalisation of 0-1-year-old children is modest.

    View details for DOI 10.1016/j.vaccine.2005.09.019

    View details for Web of Science ID 000235864200022

    View details for PubMedID 16207504

  • Cancer risk among patients with multiple sclerosis: A population-based register study INTERNATIONAL JOURNAL OF CANCER Nielsen, N. M., Rostgaard, K., Rasmussen, S., Koch-Henriksen, N., Storm, H. H., Melbye, M., Hjalgrim, H. 2006; 118 (4): 979-984

    Abstract

    Cancer occurrence in patients with multiple sclerosis (MS) has been little studied, but associations with brain tumours, breast cancer, Hodgkin lymphoma and nasopharyngeal carcinoma have been suggested. We took advantage of population-based registers of MS and cancer to assess the risk of cancer following diagnosis of MS. Patients registered in the Danish Multiple Sclerosis Register were linked with the Danish Cancer Register to obtain information on cancer occurrence. The ratio of the observed to the number of expected cancers based on population-based incidence rates, i.e., the standardised incidence ratio (SIR), served as measure of the relative cancer risk. A database comprising all Danish women born after April 1, 1935, with information on all live-born children, was used in the analyses of breast cancer to adjust for reproductive factors. Overall 1,037 cancers were observed in 11,817 MS patients during 153,875 person-years of follow-up vs. an expected number of 1,098 (SIR = 0.94 [95% confidence interval CI: (0.89-1.00)]. The risk of brain tumours and Hodgkin lymphoma was not increased. A 16% overall reduced cancer risk in men with MS was explained by reduced numbers of cancers of the digestive, respiratory and genital organs. Though the overall cancer risk was not increased [SIR = 1.01(0.94-1.09), n = 676], female MS patients had an increased risk of breast cancer [SIR = 1.21 (1.05-1.39), n = 193]. Adjusting for parity and age at first child delivery did not change this risk estimate materially. In general MS patients are not at increased risk of cancer. Women with MS, however, seem to have a small excess risk of breast cancer, which cannot be attributed to reduced parity or delayed first child birth.

    View details for DOI 10.1002/ijc.21437

    View details for Web of Science ID 000234944000023

    View details for PubMedID 16152598

  • Variation in DNA repair genes ERCC2, XRCC1, and XRCC3 and risk of follicular lymphoma CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Smedby, K. E., Lindgren, C. M., Hjalgrim, H., Humphreys, K., Schollkopf, C., Chang, E. T., Roos, G., Ryder, L. P., Falk, K. I., Palmgren, J., Kere, J., Melbye, M., Glimelius, B., Adami, H. O. 2006; 15 (2): 258-265

    Abstract

    The reasons for the positive association between skin cancer and non-Hodgkin's lymphoma are not known but may be due to common susceptibility involving suboptimal DNA repair. Therefore, we investigated selected polymorphisms and haplotypes in three DNA repair genes, previously associated with skin cancer and DNA repair capacity, in risk of follicular lymphoma, including possible gene interaction with cigarette smoking and sun exposure. We genotyped 19 single nucleotide polymorphisms (SNP) in the ERCC2, XRCC1, and XRCC3 genes in 430 follicular lymphoma patients and 605 controls within a population-based case-control study in Denmark and Sweden. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression and haplotype associations were assessed with a global score test. We observed no associations between variation in the ERCC2 and XRCC1 genes and follicular lymphoma risk. In XRCC3, increased risk of follicular lymphoma was suggested for rare homozygotes of three SNPs [Rs3212024: OR, 1.8 (95% CI, 1.1-2.8); Rs3212038: OR, 1.5 (95% CI, 1.0-2.4); Rs3212090: OR, 1.5 (95% CI, 1.0-2.5)]. These results were strengthened in current cigarette smokers. However, evidence of differences in XRCC3 haplotype distributions between follicular lymphoma cases and controls was weak, both overall and in current smokers. We conclude that polymorphic variation in the XRCC3 gene, but not in ERCC2 or XRCC1, may be of importance for susceptibility to follicular lymphoma, perhaps primarily in current smokers. The link between skin cancer and follicular lymphoma is unlikely to be mediated through common variation in the studied DNA repair gene polymorphisms.

    View details for DOI 10.1158/1055-9965.EPI-05-0583

    View details for Web of Science ID 000235587200010

    View details for PubMedID 16492913

  • Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype JOURNAL OF THE NATIONAL CANCER INSTITUTE Smedby, K. E., Hjalgrim, H., Askling, J., T Chang, E., Gregersen, H., Porwit-MacDonald, A., SUNDSTROM, C., Akerman, M., Melbye, M., Glimelius, B., Adami, H. O. 2006; 98 (1): 51-60

    Abstract

    Some autoimmune and chronic inflammatory disorders are associated with increased risks of non-Hodgkin lymphoma (NHL). Because different NHL subtypes develop at different stages of lymphocyte differentiation, associations of autoimmune and inflammatory disorders with specific NHL subtypes could lead to a better understanding of lymphomagenic mechanisms.In a population-based case-control study in Denmark and Sweden, 3055 NHL patients and 3187 matched control subjects were asked about their history of autoimmune and chronic inflammatory disorders, markers of severity, and treatment. Logistic regression with adjustment for study matching factors was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for NHL overall and for NHL subtypes.Risks of all NHL were increased in association with rheumatoid arthritis (OR = 1.5, 95% CI = 1.1 to 1.9), primary Sjögren syndrome (OR = 6.1, 95% CI = 1.4 to 27), systemic lupus erythematosus (OR = 4.6, 95% CI = 1.0 to 22), and celiac disease (OR = 2.1, 95% CI = 1.0 to 4.8). All of these conditions were also associated with diffuse large B-cell lymphoma, and some were associated with marginal zone, lymphoplasmacytic, or T-cell lymphoma. Ever use of nonsteroidal anti-inflammatory drugs, systemic corticosteroids, and selected immunosuppressants was associated with risk of NHL in rheumatoid arthritis patients but not in subjects without rheumatoid arthritis. Also, multivariable adjustment for treatment had little impact on risk estimates. Psoriasis, sarcoidosis, and inflammatory bowel disorders were not associated with increased risk of NHL overall or of any NHL subtype.Our results confirm the associations between certain autoimmune disorders and risk of NHL and suggest that the associations may not be general but rather mediated through specific NHL subtypes. These NHL subtypes develop during postantigen exposure stages of lymphocyte differentiation, consistent with a role of antigenic drive in autoimmunity-related lymphomagenesis.

    View details for DOI 10.1093/jnci/dj004

    View details for Web of Science ID 000234715800010

    View details for PubMedID 16391371

  • Growth patterns and the risk of breast cancer in women. International journal of gynecological cancer Ahlgren, M., Melbye, M., Wohlfahrt, J., Sørensen, T. I. 2006; 16: 569-575

    Abstract

    Adult height and body mass index (BMI) influence the risk of breast cancer in women. Whether these associations reflect growth patterns of the fetus or growth during childhood and adolescence is unknown. We investigated the association between growth during childhood and the risk of breast cancer in a cohort of 117,415 Danish women. Birth weight, age at menarche, and annual measurements of height and weight were obtained from school health records. We used the data to model individual growth curves. Information on vital status, age at first childbirth, parity, and diagnosis of breast cancer was obtained through linkages to national registries. During 3,333,359 person-years of follow-up, 3340 cases of breast cancer were diagnosed. High birth weight, high stature at 14 years of age, low BMI at 14 years of age, and peak growth at an early age were independent risk factors for breast cancer. Height at 8 years of age and the increase in height during puberty (8-14 years of age) were also associated with breast cancer. The attributable risks of birth weight, height at 14 years of age, BMI at 14 years of age, and age at peak growth were 7%, 15%, 15%, and 9%, respectively. No effect of adjusting for age at menarche, age at first childbirth, and parity was observed. Birth weight and growth during childhood and adolescence influence the risk of breast cancer.

    View details for PubMedID 17010075

  • A population-based binational register for monitoring long-term outcome and possible disease concordance among blood donors and recipients VOX SANGUINIS Edgren, G., Hjalgrim, H., Tran, T. N., Rostgaard, K., Shanwell, A., Titlestad, K., Jakobsson, L., Gridley, G., Wideroff, L., Jersild, C., Adami, J., Melbye, M., Reilly, M., Nyren, O. 2006; 91 (4): 316-323

    Abstract

    Even with appropriate donor deferrals and advanced screening tests, the risk of disease transmission through blood transfusion cannot be completely disregarded. Efficient monitoring of possible disease transmission between blood donors and recipients should be an important component of a comprehensive haemovigilance system.We assembled the Scandinavian Donations and Transfusions (SCANDAT) database, with data on virtually all blood donors and recipients who have been registered at least once in any of the computerized local blood bank databases in Sweden and Denmark since the start of computerized registration in 1966. The records of these individuals, with their entire computerized donation and/or transfusion histories and all donor-component-recipient connections, were linked to nationwide population and health registers to attain essentially complete follow-up for up to 36 years regarding reproduction, hospital morbidity, cancer, and death.After data cleaning, the database contained 1,134,290 blood donors who contributed 15,091,280 records of donations and 1,311,079 recipients who received 11,693,844 transfusions. The data quality in the existing data sources was satisfactory. From the data obtained from local blood banks, 4.6%, 1.6%, and 6.4% of the person, donation, and transfusion records, respectively, had to be discarded after review of the legitimacy of recorded values, and comparisons with independent, external databases.It is possible to use existing computerized data, collected in routine health care, in haemovigilance systems for monitoring long-term outcome and disease concordance in blood donors and transfusion recipients.

    View details for DOI 10.1111/j.1423-0410.2006.00817.x

    View details for Web of Science ID 000241917000007

    View details for PubMedID 17105607

  • Medication use and risk of non-Hodgkin's lymphoma AMERICAN JOURNAL OF EPIDEMIOLOGY Chang, E. T., Smedby, K. E., Hjalgrim, H., Schollkopf, C., Porwit-MacDonald, A., SUNDSTROM, C., Tani, E., d'Amore, F., Melbye, M., Adami, H. O., Glimelius, B. 2005; 162 (10): 965-974

    Abstract

    Conflicting results from previous epidemiologic studies shed little light on whether medication use is associated with risk of non-Hodgkin's lymphoma (NHL). To investigate this question, the authors conducted a population-based case-control study in Denmark and Sweden from 1999 to 2002, including 3,055 incident NHL cases and 3,187 controls. Participants reported their past use of medications and history of particular medical conditions. Unconditional logistic regression was used to estimate multivariate odds ratios and 95% confidence intervals for the associations between medication use and risk of NHL; all statistical tests were two sided. Use of antibiotics more than 10 times during adulthood was positively associated with risk of NHL and most major NHL subtypes; when users were compared with nonusers, the odds ratio for NHL was 1.8 (95% confidence interval: 1.4, 2.3); p(trend) for total antibiotic use <0.001. In addition, high cumulative use of nonsteroidal anti-inflammatory drugs was marginally associated with elevated NHL risk. Other medications evaluated were not associated with risk of NHL or its most common subtypes. Findings suggest that inflammation, infections, susceptibility to infections, and/or use of antibiotics or nonsteroidal anti-inflammatory drugs to treat these conditions may increase the risk of NHL. However, most of the medications examined were not associated with NHL risk.

    View details for DOI 10.1093/aje/kwi311

    View details for Web of Science ID 000233218800004

    View details for PubMedID 16192343

  • Familial risk of multiple sclerosis: A nationwide cohort study AMERICAN JOURNAL OF EPIDEMIOLOGY Nielsen, N. M., Westergaard, T., Rostgaard, K., Frisch, M., Hjalgrim, H., Wohlfahrt, J., Koch-Henriksen, N., Melbye, M. 2005; 162 (8): 774-778

    Abstract

    Multiple sclerosis (MS) is known to accumulate within families. The magnitude of the familial risk, however, remains uncertain. Using a nationwide MS register and other national registers, the authors estimated relative and absolute risks of MS in a population-based cohort that included 19,615 first-degree relatives of 8,205 Danish MS patients followed from 1968 to 1997. The ratio of observed to expected numbers of MS cases served as the measure of the relative risk of MS. Lifetime risks of MS in first-degree relatives were estimated as the product of the relative risk and the national lifetime risk of MS. Overall, first-degree relatives had a sevenfold increased risk of MS (relative risk=7.1, 95% confidence interval: 5.8, 8.8) (n=90) compared with the background population. By modeling the individual incidence rate of MS as the sum of a familial component and a sporadic risk component, the familial excess lifetime risk was found to be 2.5% (95% confidence interval: 2.0, 3.2) among first-degree relatives of MS patients, irrespective of the gender of the proband and the relative. This percentage should be added to a sporadic absolute risk in the general population of 0.5% in women and 0.3% for men. Spouses of MS patients did not experience an increased risk of MS, suggesting no major role for environmental factors acting in adulthood.

    View details for DOI 10.1093/aje/kwi280

    View details for Web of Science ID 000232423000009

    View details for PubMedID 16120694

  • Seroprevalence and risk factors for Helicobacter pylori infection in Greenlanders HELICOBACTER Koch, A., Krause, T. G., Krogfelt, K., Olsen, O. R., Fischer, T. K., Melbye, M. 2005; 10 (5): 433-442

    Abstract

    In contrast to most populations worldwide, the incidence of gastric cancer increases among Inuit in Greenland. Contributing factors to this increase are unknown, but Helicobacter pylori may be involved. However, little is known regarding the epidemiology of H. pylori in Arctic communities. With the aim of determining age-specific prevalence, risk factors, and association with clinical conditions of H. pylori infection, we carried out a population-based study of H. pylori in Sisimiut, the second biggest town of Greenland.A population-based sample of 685 persons had serum drawn that was analyzed for H. pylori IgG antibodies using enzyme-linked immunosorbent assay (ELISA). Risk factors analyses were carried out using multivariate logistic regression models.The seroprevalence was lowest among children aged 0-4 years (6%), but increased rapidly thereafter. In persons aged 15-87 years the seroprevalence had stabilized around 58%. Total number of children in household, number of older, but not younger, siblings and narrow age gap to closest older sibling were associated with H. pylori seropositivity. In contrast, number of adults in household and socioeconomic status did not influence serostatus.The age-specific prevalence pattern in Greenland is intermediate between that of developing and developed countries. The risk factor pattern indicates crowding and older siblings in particular to be key elements in risk of infection.

    View details for Web of Science ID 000231951800010

    View details for PubMedID 16181354

  • Cancer susceptibility in nasopharyngeal carcinoma families - A population-based cohort study CANCER RESEARCH Friborg, J., Wohlfahrt, J., Koch, A., Storm, H., Olsen, O. R., Melbye, M. 2005; 65 (18): 8567-8572

    Abstract

    Undifferentiated nasopharyngeal carcinoma is a result of environmental factors, in particular EBV infection, affecting genetically susceptible individuals. The familial risk of nasopharyngeal carcinoma is among the highest of any malignancy. Whether this susceptibility is restricted to nasopharyngeal carcinoma is unknown as information on the risk of other cancers in relatives is limited. We did a population-based study of the cancer incidence in nasopharyngeal carcinoma families in Greenland, a nasopharyngeal carcinoma-endemic area. Using population-based registers, a cohort of all persons born in Greenland was followed from 1973 to 2002. In this cohort, 134 individuals developed nasopharyngeal carcinoma and their relatives were identified through registers and interviews. Subsequently, the occurrence of cancer was determined by linkage to the population-based cancer register and the risk of cancer in nasopharyngeal carcinoma relatives and nonrelatives compared by relative risks. Among 766 first-degree relatives, the relative risk of nasopharyngeal carcinoma following the family index case was 8.0 [95% confidence interval (95% CI), 4.1-14.0]. Sex and age of the relative or the index case had no modifying effect on the familial risk of nasopharyngeal carcinoma. The relative risks of carcinoma of the salivary glands, 8.4 (95% CI, 2.7-19.5), and uterine cervix, 2.2 (95% CI, 1.1-3.9), were also significantly increased. In families with multiple cases of nasopharyngeal carcinoma, the risk of other cancers than nasopharyngeal carcinoma was further increased. These results indicate that the increased risk of cancer in nasopharyngeal carcinoma families is not restricted to nasopharyngeal carcinoma, but extends to the virally associated cancers of the salivary glands and cervical uteri.

    View details for DOI 10.1158/0008-5472.CAN-04-4208

    View details for Web of Science ID 000231848800063

    View details for PubMedID 16166338

  • Outbreak of trichinellosis associated with consumption of game meat in West Greenland 11th International Conference on Trichinellosis Moller, L. N., Petersen, E., Kapel, C. M., Melbye, M., Koch, A. ELSEVIER SCIENCE BV. 2005: 131–36

    Abstract

    The Inuit population of the Arctic has always been at risk of acquiring trichinellosis and severe outbreaks have been recorded in Alaska and Canada. In West Greenland, a number of large outbreaks took place during the 1940s and 1950s; they involved total 420 cases including 37 deaths. Since then only sporadic cases have been reported. Here, we describe an outbreak of infection with Trichinella spp. after consumption of infected meat presumably from walrus or polar bear caught in western Greenland. Six persons who had eaten of the walrus and polar bear meat were two males and four females, age range 6--47 years. Using ELISA and Western blot analysis (Trichinella-specific IgG antibodies against excreted/secreted antigen and synthetic tyvelose antigen, respectively) four of these persons were found to be sero-positive for Trichinella antibodies, with three of these having clinical symptoms compatible with trichinellosis. On re-test, 12--14 months later one of the two sero-negative persons had sero-converted, probably due to a new, unrelated infection. This study demonstrates that acquiring Trichinella from the consumption of marine mammals remains a possibility in Greenland, and that cases may go undetected. Trichinellosis in Greenland can be prevented by the implementation of public health measures.

    View details for DOI 10.1016/j.vetpar.2005.05.041

    View details for Web of Science ID 000231791600025

    View details for PubMedID 16023294

  • Risk factors for idiopathic congenital/infantile cataract Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology Haargaard, B., Wohlfahrt, J., Rosenberg, T., FLEDELIUS, H. C., Melbye, M. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2005: 3067–73

    Abstract

    To investigate maternal, demographic, and pre- and perinatal risk factors for idiopathic congenital/infantile (ICI) cataract.Based on national registries, a cohort of all children born in Denmark and aged 0 to 17 years during 1977 to 2001 was established, and congenital/infantile cataract cases were identified. Cases of unknown/idiopathic cause were included in the study. Associations between maternal, demographic, and pre- and perinatal factors with the development of cataract were investigated.In a cohort of 2.9 million children, 1027 cases of congenital/infantile cataract were identified. Of the children in those cases, 629 were born in Denmark and had ICI. Bilateral isolated cataract cases were male dominated (62%; 95% confidence interval [CI], 56%-69%) but not unilateral isolated cases (40%; 95% CI, 34%-47%). Older age (> or =40 years) of mothers at delivery and caesarean section increased the risk of ICI cataract. Low birth weight (< 2000 g) was associated with a 10.6-fold (95% CI, 6.99-16.10) increased risk of bilateral, but not unilateral, ICI cataract. No significant associations were found with birth order, month/place of birth, or cigarette smoking during pregnancy.Variables indicative of environmental influence were not associated with ICI cataract. Low-birth-weight children (< 2000 g) had a significantly increased risk of bilateral ICI, whereas no strong risk factors were found for unilateral cataract. Together with the sex difference, this suggests that the etiologies of bilateral and unilateral cataract are different.

    View details for DOI 10.1167/iovs.04-0979

    View details for Web of Science ID 000231488800009

    View details for PubMedID 16123403

  • A comparison of risk factors for wheeze and recurrent cough in preschool children AMERICAN JOURNAL OF EPIDEMIOLOGY Hermann, C., Westergaard, T., Pedersen, B. V., Wohlfahrt, J., Host, A., Melbye, M. 2005; 162 (4): 345-350

    Abstract

    In a study of 2,978 Danish children aged 5 years from two suburban counties of Copenhagen, carried out in 1998, the authors compared risk factor profiles for wheeze and recurrent cough without wheeze by using polytomous logistic regression to clarify whether the two conditions are likely to have the same etiology. Data were obtained 1) by a mailed parental questionnaire (International Study of Asthma and Allergies in Childhood questions and supplementary questions on cough, sociodemography, perinatal factors, and environmental exposure); 2) through general practitioners (familial allergic disease); and 3) from the National Medical Birth Register (birth weight). Wheeze (WH) was defined as more than one episode of wheeze within the last 12 months (irrespective of cough status) and recurrent cough without WH (RC) as cough occurring outside colds and usually lasting for periods of more than 1 week in children with no more than one attack of wheeze within the last 12 months. Risk factors for comparison were selected as those that, after repeated stepwise logistic regression, remained significant for children with WH or RC. Significant differences were found for gender (p = 0.003), gestational age (p = 0.0002), maternal history of asthma (p = 0.0008), and standard of housing condition (p = 0.04)-all risk factors for WH but not RC. Results may suggest that the two conditions have different etiologies.

    View details for DOI 10.1093/aje/kwi212

    View details for Web of Science ID 000231150600007

    View details for PubMedID 16014783

  • Childhood vaccination and nontargeted infectious disease hospitalization JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Hviid, A., Wohlfahrt, J., Stellfeld, M., Melbye, M. 2005; 294 (6): 699-705

    Abstract

    It has been hypothesized that multiple-antigen vaccines, such as measles-mumps-rubella vaccine, or aggregated vaccine exposure could lead to immune dysfunction, resulting in nontargeted infectious diseases as a result of an "overload" mechanism.To evaluate the relationship between routinely administered childhood vaccines (Haemophilus influenzae type b; diphtheria-tetanus-inactivated poliovirus; diphtheria-tetanus-acellular pertussis-inactivated poliovirus; whole-cell pertussis; measles-mumps-rubella; oral poliovirus) and hospitalization for nontargeted infectious diseases.Population-based cohort comprising all children born in Denmark from 1990 through 2001 (N = 805 206). Longitudinal information was collected on type and number of vaccine doses received and hospitalization with infectious diseases, specifically acute upper respiratory tract infection, viral and bacterial pneumonia, septicemia, viral central nervous system infection, bacterial meningitis, and diarrhea.Rate ratios for each type of infectious disease according to vaccination status.During 2,900,463 person-years of follow-up, 84,317 cases of infectious disease hospitalization were identified. Out of 42 possible associations (6 vaccines and 7 infectious disease categories), the only adverse association was for Haemophilus influenzae type b vaccine and acute upper respiratory tract infection (rate ratio, 1.05; 95% confidence interval, 1.01-1.08 comparing vaccinated participants with unvaccinated participants). This one adverse association of 42 possible outcomes was within the limits of what would be expected by chance alone and the effect was not temporal or dose-response. When considering aggregated vaccine exposure, we found no adverse associations between an increasing number of vaccinations and infectious diseases.These results do not support the hypotheses that multiple-antigen vaccines or aggregated vaccine exposure increase the risk of nontargeted infectious disease hospitalization.

    View details for Web of Science ID 000231068600023

    View details for PubMedID 16091572

  • Sibship characteristics and risk of allergic rhinitis and asthma AMERICAN JOURNAL OF EPIDEMIOLOGY Westergaard, T., Rostgaard, K., Wohlfahrt, J., Andersen, P. K., Aaby, P., Melbye, M. 2005; 162 (2): 125-132

    Abstract

    Studying associations between sibship characteristics and allergic diseases in detail may contribute clues to their etiology. The authors studied associations between sibship characteristics and risk of self-reported allergic rhinitis and asthma among 31,145 pregnant women participating in a nationwide study in Denmark during 1997-2000. Increasing sibship size was associated with a decreased risk of allergic rhinitis and asthma with allergic rhinitis but not with asthma without allergic rhinitis. The protective effect of having older siblings was stronger than the protective effect of having younger siblings for both allergic rhinitis and asthma with allergic rhinitis. There was no association between interval to closest older or younger sibling and risk of allergic rhinitis or asthma with allergic rhinitis, while the risk of asthma without allergic rhinitis increased with intervals of 2 or more years compared with less than 2 years to the nearest older sibling. The protective effect of having siblings on the risk of asthma with allergic rhinitis could be explained by a protective effect of siblings on the risk of allergic rhinitis alone. In conclusion, our findings suggest that different etiologic mechanisms are involved for allergic rhinitis and asthma with respect to the effect of sibship characteristics. Furthermore, the findings that allergic rhinitis was associated with the number of younger siblings but not with the age interval to younger siblings support the hypothesis of an influence of postnatal mechanisms and suggest that these mechanisms may not necessarily be operating only in early life.

    View details for DOI 10.1093/aje/kwi169

    View details for Web of Science ID 000230204200003

    View details for PubMedID 15972945

  • Cigarette smoking and risk of non-hodgkin's lymphoma - A population-based case-control study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Schollkopf, C., Smedby, K. E., Hjalgrim, H., Rostgaard, K., Gadeberg, O., Roos, G., Porwit-MacDonald, A., Glimelius, B., Adami, H. O., Melbye, M. 2005; 14 (7): 1791-1796

    Abstract

    Epidemiologic evidence of an association between tobacco smoking and non-Hodgkin's lymphoma has been conflicting. This may reflect that non-Hodgkin's lymphoma comprises several distinct disease entities with different etiologies, as some studies have indicated an association between smoking and follicular lymphoma.To investigate the association between cigarette smoking and non-Hodgkin's lymphoma risk, overall and by subtype.As part of a nationwide Danish-Swedish population-based case-control study, we interviewed 3,055 incident non-Hodgkin's lymphoma patients and 3,187 population controls. All lymphomas were uniformly classified according to the WHO classification. We used unconditional logistic regression to estimate adjusted odds ratios (OR) and 95% confidence intervals (95% CI) for the association between cigarette smoking and risk of non-Hodgkin's lymphoma.Cigarette smoking was not associated with the risk of non-Hodgkin's lymphoma overall (OR, 0.97; 95% CI, 0.87-1.08) nor with the major subgroups such as diffuse large B-cell lymphoma (OR, 0.94; 95% CI, 0.79-1.10), chronic lymphocytic leukemia (OR, 0.86; 95% CI, 0.72-1.02), or follicular lymphoma (OR, 1.03; 95% CI, 0.85-1.24). Female smokers were at a marginally increased risk of follicular lymphoma (OR, 1.41; 95% CI, 1.04-1.92). Men who had ever smoked had a significantly increased risk of T-cell lymphoma (OR, 1.67; 95% CI, 1.11-2.51). No dose-response association with cigarette smoking could be established for any lymphoma subgroup.We found little evidence of an association between cigarette smoking and non-Hodgkin's lymphoma risk overall. Although increased risks of follicular lymphoma in female smokers and of T-cell lymphoma in male smokers were suggested, no dose-response relationship was observed, leaving limited support for causality.

    View details for Web of Science ID 000230525700032

    View details for PubMedID 16030118

  • [Cohort study of sibling effect and infectious diseases on the development of atopic dermatitis--secondary publication]. Ugeskrift for laeger Benn, C. S., Melbye, M., Wohlfahrt, J., Björkstén, B., Aaby, P. 2005; 167 (16): 1754-1757

    View details for PubMedID 15898607

  • Lung function in Greenlandic and Danish children and adolescents RESPIRATORY MEDICINE Krause, T. G., Pedersen, B. V., Thomsen, S. F., Koch, A., Wohlfahrt, J., Backer, V., Melbye, M. 2005; 99 (3): 363-371

    Abstract

    Respiratory morbidity in Inuit children is high. However, little is know regarding lung function measures in this population. The forced expiratory volumes in one second (FEV(1)) and forced vital capacity (FVC) in 888 Greenlandic Inuits (N=888) and Danes (N=477) aged 6-18 years were compared. Furthermore, associations between level of lung function and atopy and lifestyle factors were estimated in Greenlanders. The effect of height on FEV(1) and FVC was significantly different in Greenlanders and Danes, this difference in lung function increased with increasing height, and could not be explained by differences in age weight and BMI. Thus, Greenlanders taller than 130 cm had up to 300-400 ml higher FEV(1) and FVC compared with Danes of the same height. Among Greenlanders, those living in settlements had the highest levels of both FEV(1) and FVC. Greenlanders had elevated levels of FEV(1) and FVC compared with Danes. The Inuit having a shorter limb length in relation to trunk height may account for these differences. However, our finding that Greenlanders living in settlements had the highest lung function level also suggests a possible role of factors in the traditional Greenlandic lifestyle.

    View details for DOI 10.1016/j.rmed.2004.07.016

    View details for Web of Science ID 000227296600016

    View details for PubMedID 15733513

  • Ultraviolet radiation exposure and risk of malignant lymphomas JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Smedby, K. E., Hjalgrim, H., Melbye, M., Torrang, A., Rostgaard, K., Munksgaard, L., Adami, J., Hansen, M., Porwit-MacDonald, A., JENSEN, B. A., Roos, G., Pedersen, B. B., SUNDSTROM, C., Glimelius, B., Adami, H. O. 2005; 97 (3): 199-209

    Abstract

    The incidence of malignant lymphomas has been increasing rapidly, but the causes of these malignancies remain poorly understood. One hypothesis holds that exposure to ultraviolet (UV) radiation increases lymphoma risk. We tested this hypothesis in a population-based case-control study in Denmark and Sweden.A total of 3740 patients diagnosed between October 1, 1999, and August 30, 2002, with incident malignant lymphomas, including non-Hodgkin lymphoma, chronic lymphocytic leukemia, and Hodgkin lymphoma, and 3187 population controls provided detailed information on history of UV exposure and skin cancer and information on other possible risk factors for lymphomas. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by logistic regression. Statistical tests were two-sided.Multivariable-adjusted analyses revealed consistent, statistically significant negative associations between various measures of UV light exposure and risk of non-Hodgkin lymphoma. A high frequency of sun bathing and sunburns at age 20 years and 5-10 years before the interview and sun vacations abroad were associated with 30%-40% reduced risks of non-Hodgkin lymphoma (e.g., for sunbathing four times a week or more at age 20 versus never sunbathing, OR = 0.7, 95% CI = 0.6 to 0.9; for two or more sunburns a year at age 20 versus no sunburns, OR = 0.6, 95% CI = 0.5 to 0.8). These inverse associations increased in strength with increasing levels of exposure (all P(trend)< or =.01). Similar, albeit weaker, associations were observed for Hodgkin lymphoma. There were no clear differences among non-Hodgkin lymphoma subtypes, although associations were stronger for B-cell than for T-cell lymphomas. A history of skin cancer was associated with a doubling in risks of both non-Hodgkin and Hodgkin lymphoma.A history of high UV exposure was associated with reduced risk of non-Hodgkin lymphoma. The positive association between skin cancer and malignant lymphomas is, therefore, unlikely to be mediated by UV exposure.

    View details for DOI 10.1093/jnci/dji022

    View details for Web of Science ID 000226748200011

    View details for PubMedID 15687363

  • Body mass index and risk of malignant lymphoma in Scandinavian men and women JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Chang, E. T., Hjalgrim, H., Smedby, K. E., Akerman, M., Tani, E., Johnsen, H. E., Glimelius, B., Adami, H. O., Melbye, M. 2005; 97 (3): 210-218

    Abstract

    The incidence of non-Hodgkin lymphoma and prevalence of obesity are increasing globally. A suggested positive association between obesity and risk of non-Hodgkin lymphoma has prompted us to investigate the relationship between body mass index (BMI) and risk of malignant lymphoma subtypes in a population-based case-control study.Telephone interviews were conducted with 3055 case patients with non-Hodgkin lymphoma and 618 case patients with Hodgkin lymphoma diagnosed between October 1, 1999, and August 30, 2002, and 3187 population-based control subjects. The interviews assessed current height, normal adult weight, and other possible risk factors. Multivariable odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for risk of lymphoma were estimated by unconditional logistic regression. All statistical tests were two-sided.BMI was not associated with risk of overall non-Hodgkin lymphoma or of Hodgkin lymphoma (for example, comparing the highly obese group [BMI > or =35.0 kg/m2] with the normal-weight group [BMI = 18.5-24.9 kg/m2], OR for risk of non-Hodgkin lymphoma = 0.9, 95% CI = 0.6 to 1.3; P(trend) across all categories of BMI = .27). BMI was also not associated with risk of any non-Hodgkin lymphoma subtype evaluated, although there was some evidence of a positive association with risk of diffuse large B-cell lymphoma (for example, comparing the highly obese group with the normal-weight group, OR for diffuse large B-cell lymphoma = 1.5, 95% CI = 0.9 to 2.4; P(trend) =.05).Excess weight does not appear to be associated with an increased risk of malignant lymphoma in general, or with a risk of most major lymphoma subtypes. Hence, the growing incidence of obesity is unlikely to be an important contributor to the increasing incidence of non-Hodgkin lymphoma worldwide.

    View details for DOI 10.1093/jnci/dji012

    View details for Web of Science ID 000226748200012

    View details for PubMedID 15687364

  • Dietary factors and risk of non-Hodgkin lymphoma in men and women CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Chang, E. T., Smedby, K. E., Zhang, S. M., Hjalgrim, H., Melbye, M., Ost, A., Glimelius, B., Wolk, A., Adami, H. O. 2005; 14 (2): 512-520

    Abstract

    The incidence of non-Hodgkin lymphoma (NHL) has increased worldwide in recent decades. Diet could influence NHL risk by modulating the immune system, although evidence is limited. We did a population-based case-control study to determine whether differences in diet were associated with NHL risk.A total of 597 NHL cases and 467 population controls in Sweden completed a semiquantitative food frequency questionnaire evaluating their dietary habits 2 years before the interview. Unconditional logistic regression was used to estimate the odds ratios (OR) and corresponding 95% confidence intervals (95% CI) for associations between food intake and risk of NHL.High consumption of dairy products and fried red meat was associated with increased risk of NHL. The OR of NHL for individuals in the highest quartile compared with the lowest quartile of dairy intake was 1.5 (95% CI, 1.1-2.2; P(trend) = 0.003). The OR for the highest versus lowest quartile of fried red meat intake was 1.5 (95% CI, 1.0-2.1; P(trend) = 0.02). In contrast, high consumption of fruits and vegetables was associated with reduced risk of NHL, particularly follicular lymphoma, among women but not men. Compared with the lowest quartile of vegetable intake, the OR of follicular lymphoma among women in the highest quartile of vegetable intake was 0.3 (95% CI, 0.1-0.7; P(trend) = 0.002).The positive associations of NHL risk with dairy products and fried red meat and the inverse association with fruits and vegetables suggest that diet affects NHL risk and could explain the increase of some histopathogic subtypes.

    View details for Web of Science ID 000227113800033

    View details for PubMedID 15734980

  • Familial risk and clustering of nasopharyngeal carcinoma in Guangdong, China CANCER Friborg, J., Wohlfahrt, J., Melbye, M. 2005; 103 (1): 211-211

    View details for DOI 10.1002/cncr.20759

    View details for Web of Science ID 000226237000028

    View details for PubMedID 15540234

  • Pattern of drug prescription for children under the age of four years in a population in Greenland ACTA PAEDIATRICA Hahn, G. H., Koch, A., Melbye, M., Molbak, K. 2005; 94 (1): 99-106

    Abstract

    To provide knowledge of drug prescription patterns in general and of antibiotics in particular, and number of consultations and diagnoses leading to prescriptions among children aged 0-4 y in the Arctic.A population-based cohort of children aged 0-4 y, living in Sisimiut, the second largest town in Greenland, was followed from August 1996 to December 1998. Information on consultations, diagnoses and drug prescriptions was obtained from medical files at the local health centre.Among 280 participating children, the mean number of consultations per child was 5.64 per year at risk (range 0-17), of prescriptions 4.02 per year at risk (range 0-17.2), and of prescribed systemic antibiotics per child 1.47 per year at risk (range 0-7.25). Systemic antibiotics formed the therapeutic subgroup most often issued for children, constituting 33.5% of all prescriptions. Of the systemic antibiotics, 50% were broad-spectrum penicillins, 34% penicillin V, 14% macrolides and 2% other antibiotics. The most frequent diagnoses leading to drug prescription in general as well as to prescription of systemic antibiotics were respiratory tract infections, accounting for 59% of all prescriptions and 81% of prescriptions of systemic antibiotics. Children aged 1/2-1 y of age had the highest prescription rates of drugs in general and of systemic antibiotics.Compared to other countries, prescription rates of drugs in general and of systemic antibiotics in particular were high. The use of broad-spectrum penicillins was higher than recommended in Greenlandic national guidelines, and might be reduced.

    View details for DOI 10.1080/08035250410022189

    View details for Web of Science ID 000226520100017

    View details for PubMedID 15858968

  • Alcohol intake and risk of non-Hodgkin lymphoma in men and women CANCER CAUSES & CONTROL Chang, E. T., Smedby, K. E., Zhang, S. M., Hjalgrim, H., Melbye, M., Ost, A., Wolk, A., Adami, H. O., Glimelius, B. 2004; 15 (10): 1067-1076

    Abstract

    The effect of alcohol intake on risk of NHL is unclear. We therefore conducted a population-based case-control study to examine the association between alcohol and NHL risk.613 NHL cases and 480 population controls in Sweden reported their average consumption of beer, wine, and liquor 2 years before the study. Unconditional logistic regression was used to estimate the odds ratios (OR) and corresponding 95% confidence intervals (CI) for associations between alcohol intake and NHL risk.Intake of total alcohol, beer, wine, or liquor was not associated with risk of overall NHL. There was no difference in risk of NHL among those who habitually consumed above 19.1 g of ethanol per day, compared to those who consumed on average 0-2.2 g of ethanol per day (OR = 1.2 (95% CI: 0.8, 1.7); Ptrend = 0.29). However, the association was significantly positive among males (OR = 1.8 (95% CI: 1.1, 2.9); Ptrend = 0.06). Total alcohol, beer, wine, or liquor intake was not associated with any major histopathologic subtype of NHL examined, apart from an association between high wine consumption and increased risk of chronic lymphocytic leukemia.Alcohol does not appear to be a major etiologic factor for overall NHL, nor its common subtypes.

    View details for Web of Science ID 000226583100009

    View details for PubMedID 15801490

  • A nationwide Danish study of 1027 cases of congenital/infantile cataracts - Etiological and clinical classifications 11th Pediatric Ophthamology Conference Haargaard, B., Wohlfahrt, J., FLEDELIUS, H. C., Rosenberg, T., Melbye, M. ELSEVIER SCIENCE INC. 2004: 2292–98

    Abstract

    To study the distribution of congenital/infantile cataract in the entire population of Denmark according to etiological and clinical classifications.Population-based cohort study with retrospective chart review.All children (0 to 17 years old) who were born between 1959 and 2001 and registered with congenital/infantile cataract in Denmark during the period 1977 to 2001. Cases were ascertained from the mandatory Danish National Register of Patients, and all medical records were reviewed.Etiological and clinical classifications of the cataract cases were based on information from the medical records.Classification of congenital/infantile cataract according to presumed etiology; gender; clinical appearance, including laterality and morphology; and the time trends according to etiology and laterality.A total of 1027 children with congenital/infantile cataract, 529 boys and 498 girls, were included, of whom 64% were bilateral. Males predominated with bilateral cataract, whereas females predominated with unilateral cases. Isolated cataract was the most frequent clinical presentation (71% of all cases), followed by an even proportion of cataract associated with additional ocular dysmorphology and cataract associated with systemic anomalies. Almost two thirds of all cases had an unknown etiology (idiopathic). Idiopathic cases showed a higher proportion of unilateral cataract and of additional ocular dysmorphology compared with cases of known etiology. The etiology was unknown in 87% of unilateral cases and in 50% of bilateral cases. The distribution by presumed etiology was stable during the study period, except for cataract caused by maternal infections, which decreased mainly due to the elimination of congenital rubella.With the exception of the decline of congenital rubella, the proportion of congenital/infantile cataract cases of unknown, genetic, and infectious origins has been stable since the late 1970s. The causes of 87% of unilateral cataracts and 50% of bilateral congenital/infantile cataracts remain unknown, making the prevention of the disease a continuing challenge.

    View details for DOI 10.1016/j.ophtha.2004.06.024

    View details for Web of Science ID 000225512300024

    View details for PubMedID 15582089

  • Reproductive factors and extreme levels of maternal serum alpha-fetoprotein: a population-based study ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA Lei, U., Wohlfahrt, J., Christens, P., Westergaard, T., Lambe, M., Norgaard-Pedersen, B., Melbye, M. 2004; 83 (12): 1147-1151

    Abstract

    Levels of maternal alpha-fetoprotein (AFP) are increased during multiple gestations and preeclampsia but little is known regarding AFP levels in relation to other reproductive factors. Consequently, the objective of this work was to describe the possible relationship between AFP levels during pregnancy and maternal age at birth, maternal age at first birth, parity, time since previous birth and gender of the offspring.Based on national registries we obtained the reproductive history on a population-based cohort of 44 227 women who had serum AFP levels determined in gestational weeks 14-21 and whose present and previous pregnancies resulted in live-born singletons.Many previous births and an interval of less than 2 years since last birth were significantly associated with extremely low levels of AFP in the mother. However, age at first birth and age at present pregnancy did not influence the AFP level. Women who gave birth to a girl had AFP levels that were 5%[95% confidence interval (CI) 4-6%] lower than those of women who had a boy. Adjustment for birthweight did not significantly affect the estimate.Low serum AFP levels in pregnancy are significantly correlated with high parity and with a short interval between births. The significantly lower levels of AFP in women who gave birth to girls could indicate a possible gender-specific regulatory mechanism.

    View details for Web of Science ID 000225576200010

    View details for PubMedID 15548147

  • Childhood infections and risk of multiple sclerosis BRAIN Bager, P., Nielsen, N. M., Bihrmann, K., Frisch, M., Hjalgrim, H., Wohlfart, J., Koch-Henriksen, N., Melbye, M., Westergaard, T. 2004; 127: 2491-2497

    Abstract

    Multiple sclerosis has been hypothesized to be the result from an aberrant immune response possibly triggered by delayed exposure to a common childhood infection. Because the vast majority of previous studies testing this hypothesis have been based on a history of childhood infections recalled years to decades later in adulthood, we investigated whether age at six common childhood infections was associated with risk of multiple sclerosis, using information recalled in the childhood of a historical cohort of school children in Denmark. Cases included all individuals with multiple sclerosis in the country born between 1940 and 1975, who had attended school in the capital, Copenhagen. Controls were age- and sex-matched peers. School health records were obtained for all subjects. The records contained information on measles, pertussis, scarlet fever, birth order, sibship size, social class of the father, school years, and name of school and attended school classes for children born since 1940 (n(cases) = 455, n(controls) = 1801). For children born since 1950, the records also contained information on rubella, varicella and mumps (n(cases) = 182, n(controls) = 690). Neither age at infection with measles, rubella, varicella, mumps, pertussis and scarlet fever (upper age limit, 14 years) nor the cumulative number of these infections between the ages of 10 and 14 years was associated with the risk of multiple sclerosis. In addition, the risk of multiple sclerosis was not associated with birth order or social class. No clustering of multiple sclerosis in school classes was observed. Our findings suggest that measles, rubella, mumps, varicella, pertussis and scarlet fever, even if acquired late in childhood, are not associated with increased risk of multiple sclerosis later in life.

    View details for DOI 10.1093/brain/awh283

    View details for Web of Science ID 000224703700012

    View details for PubMedID 15371288

  • Birth weight and risk for childhood leukemia in Denmark, Sweden, Norway, and Iceland JOURNAL OF THE NATIONAL CANCER INSTITUTE Hjalgrim, L. L., Rostgaard, K., Hjalgrim, H., Westergaard, T., Thomassen, H., Forestier, E., Gustafsson, G., Kristinsson, J., Melbye, M., Schmiegelow, K. 2004; 96 (20): 1549-1556

    Abstract

    Compelling evidence suggests that chi