Clinical Focus


  • Residency
  • Pediatrics
  • Medical Genetics
  • Neonatology

Honors & Awards


  • 2022 WSPR Abbott Nutrition Pediatric Resident Research Award, Western Society for Pediatric Research (2022)
  • Member of the Genome Training Advisory Committee (GTAC), National Human Genome Research Institute, NIH (2019-2021)
  • National Human Genome Research Institute (NHGRI) Intramural Research Award, National Human Genome Research Institute, NIH (2019)
  • Lorraine Flaherty Award, International Mammalian Genome Society (2018)
  • MD/PhD NIH-Oxford-Cambridge Scholar., National Institutes of Health & University of Oxford (2013-2021)
  • MSTP Fellow, University of Wisconsin-Madison Medical School (2013-2021)

Professional Education


  • Bachelor of Science, Florida International University (2011)
  • Doctor of Medicine, University of Wisconsin Madison (2022)
  • Doctor of Philosophy, University of Oxford (2019)
  • MD, University of Wisconsin School of Medicine and Public Health, Medicine (2021)
  • DPhil, University of Oxford, UK, NIH-Oxford-Cambridge Scholars Program (2019)
  • BS, Florida International University, Biological Sciences (2011)

Patents


  • Jorge Rodriguez-Gil, William J Pavan, Denise M Larson, Forbes D. Porter III. "United States Patent 9,983,200 Compositions and methods for predicting age of onset of a lysosomal storage disease or a disease associated with a lysosomal defect", NHGRI, May 1, 2018

Lab Affiliations


All Publications


  • Polygenic Risk Scores for Prediction of Breast Cancer Risk in Women of African Ancestry: a Cross-Ancestry Approach. Human molecular genetics Gao, G., Zhao, F., Ahearn, T. U., Lunetta, K. L., Troester, M. A., Du, Z., Ogundiran, T. O., Ojengbede, O., Blot, W., Nathanson, K. L., Domchek, S. M., Nemesure, B., Hennis, A., Ambs, S., McClellan, J., Nie, M., Bertrand, K., Zirpoli, G., Yao, S., Olshan, A. F., Bensen, J. T., Bandera, E. V., Nyante, S., Conti, D. V., Press, M. F., Ingles, S. A., John, E. M., Bernstein, L., Hu, J. J., Deming-Halverson, S. L., Chanock, S. J., Ziegler, R. G., Rodriguez-Gil, J. L., Sucheston-Campbell, L. E., Sandler, D. P., Taylor, J. A., Kitahara, C. M., O'Brien, K. M., Bolla, M. K., Dennis, J., Dunning, A. M., Easton, D. F., Michailidou, K., Pharoah, P. D., Wang, Q., Figueroa, J., Biritwum, R., Adjei, E., Wiafe, S., GBHS Study Team, Ambrosone, C. B., Zheng, W., Olopade, O. I., Garcia-Closas, M., Palmer, J. R., Haiman, C. A., Huo, D. 2022

    Abstract

    Polygenic risk scores (PRSs) are useful for predicting breast cancer risk, but the prediction accuracy of existing PRSs in women of African ancestry (AA) remains relatively low. We aim to develop optimal PRSs for prediction of overall and estrogen receptor (ER) subtype-specific breast cancer risk in AA women. The AA dataset comprised 9235 cases and 10184 controls from four genome-wide association study (GWAS) consortia and a GWAS study in Ghana. We randomly divided samples into training and validation sets. We built PRSs using individual level AA data by a forward stepwise logistic regression and then developed joint PRSs that combined 1) the PRSs built in the AA training dataset, and 2) a 313-variant PRS previously developed in women of European ancestry. PRSs were evaluated in the AA validation set. For overall breast cancer, the odd ratio (OR) per standard deviation of the joint PRS in the validation set was 1.34 (95% CI: 1.27-1.42) with area under receiver operating characteristic curve (AUC) of 0.581. Compared to women with average risk (40th-60th PRS percentile), women in the top decile of the PRS had a 1.98-fold increased risk (95% CI: 1.63-2.39). For PRSs of ER-positive and ER-negative breast cancer, the AUCs were 0.608 and 0.576, respectively. Compared to existing methods, the proposed joint PRSs can improve prediction of breast cancer risk in AA women.

    View details for DOI 10.1093/hmg/ddac102

    View details for PubMedID 35554533

  • Correlation of age of onset and clinical severity in Niemann-Pick disease type C1 with lysosomal abnormalities and gene expression. Scientific reports Baxter, L. L., Watkins-Chow, D. E., Johnson, N. L., Farhat, N. Y., Platt, F. M., Dale, R. K., Porter, F. D., Pavan, W. J., Rodriguez-Gil, J. L. 2022; 12 (1): 2162

    Abstract

    Niemann-Pick disease type C1 (NPC1) is a rare, prematurely fatal lysosomal storage disorder which exhibits highly variable severity and disease progression as well as a wide-ranging age of onset, from perinatal stages to adulthood. This heterogeneity has made it difficult to obtain prompt diagnosis and to predict disease course. In addition, small NPC1 patient sample sizes have been a limiting factor in acquiring genome-wide transcriptome data. In this study, primary fibroblasts from an extensive cohort of 41 NPC1 patients were used to validate our previous findings that the lysosomal quantitative probe LysoTracker can be used as a predictor for age of onset and disease severity. We also examined the correlation between these clinical parameters and RNA expression data from primary fibroblasts and identified a set of genes that were significantly associated with lysosomal defects or age of onset, in particular neurological symptom onset. Hierarchical clustering showed that these genes exhibited distinct expression patterns among patient subgroups. This study is the first to collect transcriptomic data on such a large scale in correlation with clinical and cellular phenotypes, providing a rich genomic resource to address NPC1 clinical heterogeneity and discover potential biomarkers, disease modifiers, or therapeutic targets.

    View details for DOI 10.1038/s41598-022-06112-y

    View details for PubMedID 35140266

  • Cross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women. Nature communications Adedokun, B., Du, Z., Gao, G., Ahearn, T. U., Lunetta, K. L., Zirpoli, G., Figueroa, J., John, E. M., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Deming-Halverson, S. L., Rodriguez-Gil, J. L., Yao, S., Ogundiran, T. O., Ojengbede, O., Blot, W., Troester, M. A., Nathanson, K. L., Hennis, A., Nemesure, B., Ambs, S., Fiorica, P. N., Sucheston-Campbell, L. E., Bensen, J. T., Kushi, L. H., Torres-Mejia, G., Hu, D., Fejerman, L., Bolla, M. K., Dennis, J., Dunning, A. M., Easton, D. F., Michailidou, K., Pharoah, P. D., Wang, Q., Sandler, D. P., Taylor, J. A., O'Brien, K. M., Kitahara, C. M., Falusi, A. G., Babalola, C., Yarney, J., Awuah, B., Addai-Wiafe, B., GBHS Study Team, Chanock, S. J., Olshan, A. F., Ambrosone, C. B., Conti, D. V., Ziv, E., Olopade, O. I., Garcia-Closas, M., Palmer, J. R., Haiman, C. A., Huo, D. 2021; 12 (1): 4198

    Abstract

    Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P<0.05 from African ancestry GWAS meta-analysis (9241 cases and 10193 controls), then meta-analyze with European ancestry GWAS data (122977 cases and 105974 controls) from the Breast Cancer Association Consortium. The approach identifies four loci for overall breast cancer risk [1p13.3, 5q31.1, 15q24 (two independent signals), and 15q26.3] and two loci for estrogen receptor-negative disease (1q41 and 7q11.23) at genome-wide significance. Four of the index single nucleotide polymorphisms (SNPs) lie within introns of genes (KCNK2, C5orf56, SCAMP2, and SIN3A) and the other index SNPs are located close to GSTM4, AMPD2, CASTOR2, and RP11-168G16.2. Here we present risk loci with consistent direction of associations in African and European descendants. The study suggests that replication across multiple ancestry populations can help improve the understanding of breast cancer genetics and identify causal variants.

    View details for DOI 10.1038/s41467-021-24327-x

    View details for PubMedID 34234117

  • Hepatocellular carcinoma as a complication of Niemann-Pick disease type C1 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Rodriguez-Gil, J. L., Bianconi, S. E., Farhat, N., Kleiner, D. E., Nelson, M., Porter, F. D. 2021; 185 (10): 3111-3117

    Abstract

    Niemann-Pick disease type C (NPC) is a rare and fatal lysosomal storage disorder characterized by neurodegeneration and hepatic involvement. Mutations in either NPC1 or NPC2, two genes encoding lysosomal proteins, lead to an intracellular accumulation of unesterified cholesterol and sphingolipids in late endosomes/lysosomes. Early cholestatic disease is considered a hallmark of patients with early disease onset. This can potentially result in liver failure shortly after birth or subclinical hepatic inflammation. Previous reports suggest an association between NPC and hepatocellular carcinoma, a cancer that is rare during childhood. We present a 12-year-old male with a known diagnosis of NPC1 disease who was found to have a stage III hepatocellular carcinoma, underwent surgical resection with adjuvant chemotherapy, and subsequently died from metastatic disease. This report provides evidence of an increased risk of hepatocellular carcinoma in NPC patients, suggesting a need for screening in this patient population.

    View details for DOI 10.1002/ajmg.a.62382

    View details for Web of Science ID 000662188600001

    View details for PubMedID 34138521

    View details for PubMedCentralID PMC8446311

  • Evaluating Polygenic Risk Scores for Breast Cancer in Women of African Ancestry. Journal of the National Cancer Institute Du, Z., Gao, G., Adedokun, B., Ahearn, T., Lunetta, K. L., Zirpoli, G., Troester, M. A., Ruiz-Narvaez, E. A., Haddad, S. A., Pal Choudhury, P., Figueroa, J., John, E. M., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Mancuso, N., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Yao, S., Ogundiran, T. O., Ojengbe, O., Bolla, M. K., Dennis, J., Dunning, A. M., Easton, D. F., Michailidou, K., Pharoah, P. D., Sandler, D. P., Taylor, J. A., Wang, Q., Weinberg, C. R., Kitahara, C. M., Blot, W., Nathanson, K. L., Hennis, A., Nemesure, B., Ambs, S., Sucheston-Campbell, L. E., Bensen, J. T., Chanock, S. J., Olshan, A. F., Ambrosone, C. B., Olopade, O. I., Yarney, J., Awuah, B., Addai Wiafe, B., Conti, D. V., GBHS Study Team, Palmer, J. R., Garcia-Closas, M., Huo, D., Haiman, C. A. 2021

    Abstract

    BACKGROUND: Polygenic risk scores (PRS) have been demonstrated to identify women of European, Asian and Latino ancestry at elevated risk of developing breast cancer (BC). We evaluated the performance of existing PRSs trained in European ancestry populations among women of African ancestry.METHODS: We assembled genotype data for women of African ancestry, including 9,241 cases and 10,193 controls. We evaluated associations of 179- and 313-variant PRSs with overall and subtype-specific BC risk. PRS discriminatory accuracy was assessed using area under the receiver operating characteristic curve (AUC). We also evaluated a recalibrated PRS, replacing the index variant with variants in each region that better captured risk in women of African ancestry, and estimated lifetime absolute risk of BC in African Americans by PRS category.RESULTS: For overall BC, the odds ratios per standard deviation of PRS313 was 1.27 (95%CI = 1.23 to 1.31), with an AUC of 0.571 (95%CI = 0.562 to 0.579). Compared to women with average risk (40th-60th PRS percentile), women in the top decile of PRS313 had a 1.54-fold increased risk (95% CI=1.38 to 1.72). By age 85 years, the absolute risk of overall BC was 19.6% for African American women in the top 1% of PRS313 and 6.7% for those in the lowest 1%. The recalibrated PRS did not improve BC risk prediction.CONCLUSION: The PRSs stratify BC risk in women of African ancestry, with attenuated performance compared to that reported in European, Asian and Latina populations. Future work is needed to improve BC risk stratification for women of African ancestry.

    View details for DOI 10.1093/jnci/djab050

    View details for PubMedID 33769540

  • Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry. American journal of human genetics Graff, M., Justice, A. E., Young, K. L., Marouli, E., Zhang, X., Fine, R. S., Lim, E., Buchanan, V., Rand, K., Feitosa, M. F., Wojczynski, M. K., Yanek, L. R., Shao, Y., Rohde, R., Adeyemo, A. A., Aldrich, M. C., Allison, M. A., Ambrosone, C. B., Ambs, S., Amos, C., Arnett, D. K., Atwood, L., Bandera, E. V., Bartz, T., Becker, D. M., Berndt, S. I., Bernstein, L., Bielak, L. F., Blot, W. J., Bottinger, E. P., Bowden, D. W., Bradfield, J. P., Brody, J. A., Broeckel, U., Burke, G., Cade, B. E., Cai, Q., Caporaso, N., Carlson, C., Carpten, J., Casey, G., Chanock, S. J., Chen, G., Chen, M., Chen, Y. I., Chen, W., Chesi, A., Chiang, C. W., Chu, L., Coetzee, G. A., Conti, D. V., Cooper, R. S., Cushman, M., Demerath, E., Deming, S. L., Dimitrov, L., Ding, J., Diver, W. R., Duan, Q., Evans, M. K., Falusi, A. G., Faul, J. D., Fornage, M., Fox, C., Freedman, B. I., Garcia, M., Gillanders, E. M., Goodman, P., Gottesman, O., Grant, S. F., Guo, X., Hakonarson, H., Haritunians, T., Harris, T. B., Harris, C. C., Henderson, B. E., Hennis, A., Hernandez, D. G., Hirschhorn, J. N., McNeill, L. H., Howard, T. D., Howard, B., Hsing, A. W., Hsu, Y. H., Hu, J. J., Huff, C. D., Huo, D., Ingles, S. A., Irvin, M. R., John, E. M., Johnson, K. C., Jordan, J. M., Kabagambe, E. K., Kang, S. J., Kardia, S. L., Keating, B. J., Kittles, R. A., Klein, E. A., Kolb, S., Kolonel, L. N., Kooperberg, C., Kuller, L., Kutlar, A., Lange, L., Langefeld, C. D., Le Marchand, L., Leonard, H., Lettre, G., Levin, A. M., Li, Y., Li, J., Liu, Y., Liu, Y., Liu, S., Lohman, K., Lotay, V., Lu, Y., Maixner, W., Manson, J. E., McKnight, B., Meng, Y., Monda, K. L., Monroe, K., Moore, J. H., Mosley, T. H., Mudgal, P., Murphy, A. B., Nadukuru, R., Nalls, M. A., Nathanson, K. L., Nayak, U., N'Diaye, A., Nemesure, B., Neslund-Dudas, C., Neuhouser, M. L., Nyante, S., Ochs-Balcom, H., Ogundiran, T. O., Ogunniyi, A., Ojengbede, O., Okut, H., Olopade, O. I., Olshan, A., Padhukasahasram, B., Palmer, J., Palmer, C. D., Palmer, N. D., Papanicolaou, G., Patel, S. R., Pettaway, C. A., Peyser, P. A., Press, M. F., Rao, D. C., Rasmussen-Torvik, L. J., Redline, S., Reiner, A. P., Rhie, S. K., Rodriguez-Gil, J. L., Rotimi, C. N., Rotter, J. I., Ruiz-Narvaez, E. A., Rybicki, B. A., Salako, B., Sale, M. M., Sanderson, M., Schadt, E., Schreiner, P. J., Schurmann, C., Schwartz, A. G., Shriner, D. A., Signorello, L. B., Singleton, A. B., Siscovick, D. S., Smith, J. A., Smith, S., Speliotes, E., Spitz, M., Stanford, J. L., Stevens, V. L., Stram, A., Strom, S. S., Sucheston, L., Sun, Y. V., Tajuddin, S. M., Taylor, H., Taylor, K., Tayo, B. O., Thun, M. J., Tucker, M. A., Vaidya, D., Van Den Berg, D. J., Vedantam, S., Vitolins, M., Wang, Z., Ware, E. B., Wassertheil-Smoller, S., Weir, D. R., Wiencke, J. K., Williams, S. M., Williams, L. K., Wilson, J. G., Witte, J. S., Wrensch, M., Wu, X., Yao, J., Zakai, N., Zanetti, K., Zemel, B. S., Zhao, W., Zhao, J. H., Zheng, W., Zhi, D., Zhou, J., Zhu, X., Ziegler, R. G., Zmuda, J., Zonderman, A. B., Psaty, B. M., Borecki, I. B., Cupples, L. A., Liu, C., Haiman, C. A., Loos, R., Ng, M. C., North, K. E. 2021

    Abstract

    Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

    View details for DOI 10.1016/j.ajhg.2021.02.011

    View details for PubMedID 33713608

  • Improved systemic AAV gene therapy with a neurotrophic capsid in Niemann-Pick disease type C1 mice. Life science alliance Davidson, C. D., Gibson, A. L., Gu, T., Baxter, L. L., Deverman, B. E., Beadle, K., Incao, A. A., Rodriguez-Gil, J. L., Fujiwara, H., Jiang, X., Chandler, R. J., Ory, D. S., Gradinaru, V., Venditti, C. P., Pavan, W. J. 2021; 4 (10)

    Abstract

    Niemann-Pick C1 disease (NPC1) is a rare, fatal neurodegenerative disease caused by mutations in NPC1, which encodes the lysosomal cholesterol transport protein NPC1. Disease pathology involves lysosomal accumulation of cholesterol and lipids, leading to neurological and visceral complications. Targeting the central nervous system (CNS) from systemic circulation complicates treatment of neurological diseases with gene transfer techniques. Selected and engineered capsids, for example, adeno-associated virus (AAV)-PHP.B facilitate peripheral-to-CNS transfer and hence greater CNS transduction than parental predecessors. We report that systemic delivery to Npc1 m1N/m1N mice using an AAV-PHP.B vector ubiquitously expressing NPC1 led to greater disease amelioration than an otherwise identical AAV9 vector. In addition, viral copy number and biodistribution of GFP-expressing reporters showed that AAV-PHP.B achieved more efficient, albeit variable, CNS transduction than AAV9 in Npc1 m1N/m1N mice. This variability was associated with segregation of two alleles of the putative AAV-PHP.B receptor Ly6a in Npc1 m1N/m1N mice. Our data suggest that robust improvements in NPC1 disease phenotypes occur even with modest CNS transduction and that improved neurotrophic capsids have the potential for superior NPC1 AAV gene therapy vectors.

    View details for DOI 10.26508/lsa.202101040

    View details for PubMedID 34407999

    View details for PubMedCentralID PMC8380657

  • Transcriptome of HPβCD-treated Niemann-pick disease type C1 cells highlights GPNMB as a biomarker for therapeutics. Human molecular genetics Rodriguez-Gil, J. L., Baxter, L. L., Watkins-Chow, D. E., Johnson, N. L., Davidson, C. D., Carlson, S. R., Incao, A. A., Wallom, K. L., Farhat, N. Y., Platt, F. M., Dale, R. K., Porter, F. D., Pavan, W. J. 2021

    Abstract

    The rare, fatal neurodegenerative disorder Niemann-Pick disease type C1 (NPC1) arises from lysosomal accumulation of unesterified cholesterol and glycosphingolipids. These subcellular pathologies lead to phenotypes of hepatosplenomegaly, neurological degeneration and premature death. The timing and severity of NPC1 clinical presentation is extremely heterogeneous. This study analyzed RNA-Seq data from 42 NPC1 patient-derived, primary fibroblast cell lines to determine transcriptional changes induced by treatment with 2-hydroxypropyl-β-cyclodextrin (HPβCD), a compound currently under investigation in clinical trials. A total of 485 HPβCD-responsive genes were identified. Pathway enrichment analysis of these genes showed significant involvement in cholesterol and lipid biosynthesis. Furthermore, immunohistochemistry of the cerebellum as well as measurements of serum from Npc1m1N null mice treated with HPβCD and adeno-associated virus (AAV) gene therapy suggests that one of the identified genes, GPNMB, may serve as a useful biomarker of treatment response in NPC1 disease. Overall, this large NPC1 patient-derived dataset provides a comprehensive foundation for understanding the genomic response to HPβCD treatment.

    View details for DOI 10.1093/hmg/ddab194

    View details for PubMedID 34296265

  • Cross-ancestry genome-wide association study identifies six new loci for breast cancer in women of African and european ancestry Adedokun, B., Du, Z., Gao, G., Ahearn, T., Lunetta, K. L., Zirpoli, G., Figueroa, J., John, E. M., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Yao, S., Ogundiran, T. O., Ojengbede, O., Blot, W., Troester, M., Nathanson, K. L., Hennis, A., Nemesure, B., Ambs, S., Sucheston-Campbell, L. E., Bensen, J. T., Chanock, S. J., Olshan, A. F., Ambrosone, C. B., Conti, D., Olopade, O., Garcia-Closas, M., Palmer, J. R., Haiman, C. A., Huo, D. AMER ASSOC CANCER RESEARCH. 2020
  • Evaluating a polygenic risk score for breast cancer in women of African ancestry Du, Z., Gao, G., Adedokun, B., Ahearn, T., Lunetta, K. L., Zirpoli, G., Troester, M., Ruiz-Narvaez, E. A., Haddad, S., Figueroa, J., John, E. M., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Yao, S., Ogundiran, T. O., Ojengbede, O. A., Blot, W., Nathanson, K. L., Hennis, A., Nemesure, B., Ambs, S., Sucheston-Campbell, L. E., Bensen, J. T., Chanock, S. J., Olshan, A. F., Ambrosone, C. B., Conti, D. V., Olopade, O. I., Palmer, J. R., Garcia-Closas, M., Huo, D., Haiman, C. A. AMER ASSOC CANCER RESEARCH. 2020
  • Regions of mouse chromosomes 2 and 11 in SJL mice contain critical alleles for resistance to Cryptococcus neoformans Davis, M. J., Rodriguez-Gil, J., Hoke, L., Pinheiro, G., Chang, Y., Khillan, J., Paven, W., Kwon-Chung, J. AMER ASSOC IMMUNOLOGISTS. 2020
  • First person - Jorge Rodriguez-Gil DISEASE MODELS & MECHANISMS Rodriguez-Gil, J. 2020; 13 (3)

    View details for DOI 10.1242/dmm.044222

    View details for Web of Science ID 000522648900011

  • Genetic background modifies phenotypic severity and longevity in a mouse model of Niemann-Pick disease type C1. Disease models & mechanisms Rodriguez-Gil, J. L., Watkins-Chow, D. E., Baxter, L. L., Elliot, G., Harper, U. L., Wincovitch, S. M., Wedel, J. C., Incao, A. A., Huebecker, M., Boehm, F. J., Garver, W. S., Porter, F. D., Broman, K. W., Platt, F. M., Pavan, W. J. 2020; 13 (3)

    Abstract

    Niemann-Pick disease type C1 (NPC1) is a rare, fatal neurodegenerative disorder characterized by lysosomal accumulation of unesterified cholesterol and glycosphingolipids. These subcellular pathologies lead to phenotypes of hepatosplenomegaly, neurological degeneration and premature death. NPC1 is extremely heterogeneous in the timing of clinical presentation and is associated with a wide spectrum of causative NPC1 mutations. To study the genetic architecture of NPC1, we have generated a new NPC1 mouse model, Npc1em1Pav Npc1em1Pav/em1Pav mutants showed notably reduced NPC1 protein compared to controls and displayed the pathological and biochemical hallmarks of NPC1. Interestingly, Npc1em1Pav/em1Pav mutants on a C57BL/6J genetic background showed more severe visceral pathology and a significantly shorter lifespan compared to Npc1em1Pav/em1Pav mutants on a BALB/cJ background, suggesting that strain-specific modifiers contribute to disease severity and survival. QTL analysis for lifespan of 202 backcross N2 mutants on a mixed C57BL/6J and BALB/cJ background detected significant linkage to markers on chromosomes 1 and 7. The discovery of these modifier regions demonstrates that mouse models are powerful tools for analyzing the genetics underlying rare human diseases, which can be used to improve understanding of the variability in NPC1 phenotypes and advance options for patient diagnosis and therapy.This article has an associated First Person interview with the first author of the paper.

    View details for DOI 10.1242/dmm.042614

    View details for PubMedID 31996359

    View details for PubMedCentralID PMC7075069

  • NPC1 Deficiency in Mice is Associated with Fetal Growth Restriction, Neonatal Lethality and Abnormal Lung Pathology. Journal of clinical medicine Rodriguez-Gil, J. L., Watkins-Chow, D. E., Baxter, L. L., Yokoyama, T., Zerfas, P. M., Starost, M. F., Gahl, W. A., Malicdan, M. C., Porter, F. D., Platt, F. M., Pavan, W. J. 2019; 9 (1)

    Abstract

    The rare lysosomal storage disorder Niemann-Pick disease type C1 (NPC1) arises from mutation of NPC1, which encodes a lysosomal transmembrane protein essential for normal transport and trafficking of cholesterol and sphingolipids. NPC1 is highly heterogeneous in both clinical phenotypes and age of onset. Previous studies have reported sub-Mendelian survival rates for mice homozygous for various Npc1 mutant alleles but have not studied the potential mechanisms underlying this phenotype. We performed the first developmental analysis of a Npc1 mouse model, Npc1em1Pav, and discovered significant fetal growth restriction in homozygous mutants beginning at E16.5. Npc1em1Pav/em1Pav mice also exhibited cyanosis, increased respiratory effort, and over 50% lethality at birth. Analysis of neonatal lung tissues revealed lipid accumulation, notable abnormalities in surfactant, and enlarged alveolar macrophages, suggesting that lung abnormalities may be associated with neonatal lethality in Npc1em1Pav/em1Pav mice. The phenotypic severity of the Npc1em1Pav model facilitated this first analysis of perinatal lethality and lung pathology in an NPC1 model organism, and this model may serve as a useful resource for developing treatments for respiratory complications seen in NPC1 patients.

    View details for DOI 10.3390/jcm9010012

    View details for PubMedID 31861571

    View details for PubMedCentralID PMC7019814

  • Characterizing Genetic Susceptibility to Breast Cancer in Women of African Ancestry CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Feng, Y., Rhie, S., Huo, D., Ruiz-Narvaez, E. A., Haddad, S. A., Ambrosone, C. B., John, E. M., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Zheng, Y., Yao, S., Han, Y., Ogundiran, T. O., Rebbeck, T. R., Adebamowo, C., Ojengbede, O., Falusi, A. G., Hennis, A., Nemesure, B., Ambs, S., Blot, W., Cai, Q., Signorello, L., Nathanson, K. L., Lunetta, K. L., Sucheston-Campbell, L. E., Bensen, J. T., Chanock, S. J., Le Marchand, L., Olshan, A. F., Kolonel, L. N., Conti, D. V., Coetzee, G. A., Stram, D. O., Olopade, O. I., Palmer, J. R., Haiman, C. A. 2017; 26 (7): 1016–26

    Abstract

    Background: Genome-wide association studies have identified approximately 100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Because of different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry.Methods: We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER, and ROOT).Results: Fifty-four of the 74 variants (73%) were found to have ORs that were directionally consistent with those previously reported, of which 12 were nominally statistically significant (P < 0.05). Through fine-mapping, in six regions (3p24, 12p11, 14q13, 16q12/FTO, 16q23, 19p13), we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions (11q13, 16q12/TOX3), we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality.Conclusions: Through fine-mapping of known susceptibility regions, we have revealed alleles that better characterize breast cancer risk in women of African ancestry.Impact: The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry. Cancer Epidemiol Biomarkers Prev; 26(7); 1016-26. ©2017 AACR.

    View details for PubMedID 28377418

    View details for PubMedCentralID PMC5500414

  • A functionally significant SNP in TP53 and breast cancer risk in African-American women NPJ BREAST CANCER Murphy, M. E., Liu, S., Yao, S., Huo, D., Liu, Q., Dolfi, S. C., Hirshfield, K. M., Hong, C., Hu, Q., Olshan, A. F., Ogundiran, T. O., Adebamowo, C., Domchek, S. M., Nathanson, K. L., Nemesure, B., Ambs, S., Blot, W. J., Feng, Y., John, E. M., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Nyante, S., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Haiman, C. A., Olopade, O. I., Lunetta, K. L., Palmer, J. R., Ambrosone, C. B. 2017; 3: 5

    Abstract

    A coding region polymorphism exists in the TP53 gene (Pro47Ser; rs1800371) in individuals of African descent, which reduces p53 tumor suppressor function in a mouse model. It has been unclear whether this functionally significant polymorphism alters cancer risk in humans. This analysis included 6907 women with breast cancer and 7644 controls from the AMBER, ROOT, and AABC consortia. We used multivariable logistic regression to estimate associations between the TP53 Pro47Ser allele and overall breast cancer risk. Because polymorphisms in TP53 tend to be associated with cancer risk in pre-menopausal women, we also limited our analyses to this population in the AMBER and ROOT consortia, where menopausal status was known, and conducted a fixed effects meta-analysis. In an analysis of all women in the AMBER, ROOT, and AABC consortia, we found no evidence for association of the Pro47Ser variant with breast cancer risk. However, when we restricted our analysis to only pre-menopausal women from the AMBER and ROOT consortia, there was a per allele odds ratio of 1.72 (95% confidence interval 1.08-2.76; p-value = 0.023). Although the Pro47Ser variant was not associated with overall breast cancer risk, it may increase risk among pre-menopausal women of African ancestry. Following up on more studies in human populations may better elucidate the role of this variant in breast cancer etiology. However, because of the low frequency of the polymorphism in women of African ancestry, its impact at a population level may be minimal.

    View details for PubMedID 28649645

  • Genome-wide association studies in women of African ancestry identified 3q26.21 as a novel susceptibility locus for oestrogen receptor negative breast cancer HUMAN MOLECULAR GENETICS Huo, D., Feng, Y., Haddad, S., Zheng, Y., Yao, S., Han, Y., Ogundiran, T. O., Adebamowo, C., Ojengbede, O., Falusi, A. G., Zheng, W., Blot, W., Cai, Q., Signorello, L., John, E. M., Bernstein, L., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Nathanson, K. L., Domchek, S. M., Rebbeck, T. R., Ruiz-Narvaez, E. A., Sucheston-Campbell, L. E., Bensen, J. T., Simon, M. S., Hennis, A., Nemesure, B., Leske, M., Ambs, S., Chen, L. S., Qian, F., Gamazon, E. R., Lunetta, K. L., Cox, N. J., Chanock, S. J., Kolonel, L. N., Olshan, A. F., Ambrosone, C. B., Olopade, O. I., Palmer, J. R., Haiman, C. A. 2016; 25 (21): 4835–46

    Abstract

    Multiple breast cancer loci have been identified in previous genome-wide association studies, but they were mainly conducted in populations of European ancestry. Women of African ancestry are more likely to have young-onset and oestrogen receptor (ER) negative breast cancer for reasons that are unknown and understudied. To identify genetic risk factors for breast cancer in women of African descent, we conducted a meta-analysis of two genome-wide association studies of breast cancer; one study consists of 1,657 cases and 2,029 controls genotyped with Illumina’s HumanOmni2.5 BeadChip and the other study included 3,016 cases and 2,745 controls genotyped using Illumina Human1M-Duo BeadChip. The top 18,376 single nucleotide polymorphisms (SNP) from the meta-analysis were replicated in the third study that consists of 1,984 African Americans cases and 2,939 controls. We found that SNP rs13074711, 26.5 Kb upstream of TNFSF10 at 3q26.21, was significantly associated with risk of oestrogen receptor (ER)-negative breast cancer (odds ratio [OR]=1.29, 95% CI: 1.18-1.40; P = 1.8 × 10 − 8). Functional annotations suggest that the TNFSF10 gene may be involved in breast cancer aetiology, but further functional experiments are needed. In addition, we confirmed SNP rs10069690 was the best indicator for ER-negative breast cancer at 5p15.33 (OR = 1.30; P = 2.4 × 10 − 10) and identified rs12998806 as the best indicator for ER-positive breast cancer at 2q35 (OR = 1.34; P = 2.2 × 10 − 8) for women of African ancestry. These findings demonstrated additional susceptibility alleles for breast cancer can be revealed in diverse populations and have important public health implications in building race/ethnicity-specific risk prediction model for breast cancer.

    View details for PubMedID 28171663

    View details for PubMedCentralID PMC5975608

  • A new glucocerebrosidase-deficient neuronal cell model provides a tool to probe pathophysiology and therapeutics for Gaucher disease DISEASE MODELS & MECHANISMS Westbroek, W., Nguyen, M., Siebert, M., Lindstrom, T., Burnett, R. A., Aflaki, E., Jung, O., Tamargo, R., Rodriguez-Gil, J. L., Acosta, W., Hendrix, A., Behre, B., Tayebi, N., Fujiwara, H., Sidhu, R., Renvoise, B., Ginns, E. I., Dutra, A., Pak, E., Cramer, C., Ory, D. S., Pavan, W. J., Sidransky, E. 2016; 9 (7): 769-778

    Abstract

    Glucocerebrosidase is a lysosomal hydrolase involved in the breakdown of glucosylceramide. Gaucher disease, a recessive lysosomal storage disorder, is caused by mutations in the gene GBA1 Dysfunctional glucocerebrosidase leads to accumulation of glucosylceramide and glycosylsphingosine in various cell types and organs. Mutations in GBA1 are also a common genetic risk factor for Parkinson disease and related synucleinopathies. In recent years, research on the pathophysiology of Gaucher disease, the molecular link between Gaucher and Parkinson disease, and novel therapeutics, have accelerated the need for relevant cell models with GBA1 mutations. Although induced pluripotent stem cells, primary rodent neurons, and transfected neuroblastoma cell lines have been used to study the effect of glucocerebrosidase deficiency on neuronal function, these models have limitations because of challenges in culturing and propagating the cells, low yield, and the introduction of exogenous mutant GBA1 To address some of these difficulties, we established a high yield, easy-to-culture mouse neuronal cell model with nearly complete glucocerebrosidase deficiency representative of Gaucher disease. We successfully immortalized cortical neurons from embryonic null allele gba(-/-) mice and the control littermate (gba(+/+)) by infecting differentiated primary cortical neurons in culture with an EF1α-SV40T lentivirus. Immortalized gba(-/-) neurons lack glucocerebrosidase protein and enzyme activity, and exhibit a dramatic increase in glucosylceramide and glucosylsphingosine accumulation, enlarged lysosomes, and an impaired ATP-dependent calcium-influx response; these phenotypical characteristics were absent in gba(+/+) neurons. This null allele gba(-/-) mouse neuronal model provides a much-needed tool to study the pathophysiology of Gaucher disease and to evaluate new therapies.

    View details for DOI 10.1242/dmm.024588

    View details for Web of Science ID 000379555800005

    View details for PubMedID 27482815

    View details for PubMedCentralID PMC4958308

  • Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults. PloS one Chen, F., He, J., Zhang, J., Chen, G. K., Thomas, V., Ambrosone, C. B., Bandera, E. V., Berndt, S. I., Bernstein, L., Blot, W. J., Cai, Q., Carpten, J., Casey, G., Chanock, S. J., Cheng, I., Chu, L., Deming, S. L., Driver, W. R., Goodman, P., Hayes, R. B., Hennis, A. J., Hsing, A. W., Hu, J. J., Ingles, S. A., John, E. M., Kittles, R. A., Kolb, S., Leske, M. C., Millikan, R. C., Monroe, K. R., Murphy, A., Nemesure, B., Neslund-Dudas, C., Nyante, S., Ostrander, E. A., Press, M. F., Rodriguez-Gil, J. L., Rybicki, B. A., Schumacher, F., Stanford, J. L., Signorello, L. B., Strom, S. S., Stevens, V., Van Den Berg, D., Wang, Z., Witte, J. S., Wu, S., Yamamura, Y., Zheng, W., Ziegler, R. G., Stram, A. H., Kolonel, L. N., Le Marchand, L., Henderson, B. E., Haiman, C. A., Stram, D. O. 2015; 10 (6)

    Abstract

    Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.

    View details for DOI 10.1371/journal.pone.0131106

    View details for PubMedID 26125186

  • A comprehensive examination of breast cancer risk loci in African American women HUMAN MOLECULAR GENETICS Feng, Y., Stram, D. O., Rhie, S. K., Millikan, R. C., Ambrosone, C. B., John, E. M., Bernstein, L., Zheng, W., Olshan, A. F., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Palmer, J. R., Olopade, O. I., Huo, D., Adebamowo, C. A., Ogundiran, T., Chen, G. K., Stram, A., Park, K., Rand, K. A., Chanock, S. J., Le Marchand, L., Kolonel, L. N., Conti, D. V., Easton, D., Henderson, B. E., Haiman, C. A. 2014; 23 (20): 5518-5526

    Abstract

    Genome-wide association studies have identified 73 breast cancer risk variants mainly in European populations. Given considerable differences in linkage disequilibrium structure between populations of European and African ancestry, the known risk variants may not be informative for risk in African ancestry populations. In a previous fine-mapping investigation of 19 breast cancer loci, we were able to identify SNPs in four regions that better captured risk associations in African American women. In this study of breast cancer in African American women (3016 cases, 2745 controls), we tested an additional 54 novel breast cancer risk variants. Thirty-eight variants (70%) were found to have an association with breast cancer in the same direction as previously reported, with eight (15%) replicating at P < 0.05. Through fine-mapping, in three regions (1q32, 3p24, 10q25), we identified variants that better captured associations with overall breast cancer or estrogen receptor positive disease. We also observed suggestive associations with variants (at P < 5 × 10(-6)) in three separate regions (6q25, 14q13, 22q12) that may represent novel risk variants. Directional consistency of association observed for ∼65-70% of currently known genetic variants for breast cancer in women of African ancestry implies a shared functional common variant at most loci. To validate and enhance the spectrum of alleles that define associations at the known breast cancer risk loci, as well as genome-wide, will require even larger collaborative efforts in women of African ancestry.

    View details for DOI 10.1093/hmg/ddu252

    View details for Web of Science ID 000343202400018

    View details for PubMedCentralID PMC4168823

  • Genome-wide Scan of 29,141 African Americans Finds No Evidence of Directional Selection since Admixture AMERICAN JOURNAL OF HUMAN GENETICS Bhatia, G., Tandon, A., Patterson, N., Aldrich, M. C., Ambrosone, C. B., Amos, C., Bandera, E. V., Berndt, S. I., Bernstein, L., Blot, W. J., Bock, C. H., Caporaso, N., Casey, G., Deming, S. L., Diver, W. R., Gapstur, S. M., Gillanders, E. M., Harris, C. C., Henderson, B. E., Ingles, S. A., Isaacs, W., De Jager, P. L., John, E. M., Kittles, R. A., Larkin, E., McNeill, L. H., Millikan, R. C., Murphy, A., Neslund-Dudas, C., Nyante, S., Press, M. F., Rodriguez-Gil, J. L., Rybicki, B. A., Schwartz, A. G., Signorello, L. B., Spitz, M., Strom, S. S., Tucker, M. A., Wiencke, J. K., Witte, J. S., Wu, X., Yamamura, Y., Zanetti, K. A., Zheng, W., Ziegler, R. G., Chanock, S. J., Haiman, C. A., Reich, D., Price, A. L. 2014; 95 (4): 437-444

    Abstract

    The extent of recent selection in admixed populations is currently an unresolved question. We scanned the genomes of 29,141 African Americans and failed to find any genome-wide-significant deviations in local ancestry, indicating no evidence of selection influencing ancestry after admixture. A recent analysis of data from 1,890 African Americans reported that there was evidence of selection in African Americans after their ancestors left Africa, both before and after admixture. Selection after admixture was reported on the basis of deviations in local ancestry, and selection before admixture was reported on the basis of allele-frequency differences between African Americans and African populations. The local-ancestry deviations reported by the previous study did not replicate in our very large sample, and we show that such deviations were expected purely by chance, given the number of hypotheses tested. We further show that the previous study's conclusion of selection in African Americans before admixture is also subject to doubt. This is because the FST statistics they used were inflated and because true signals of unusual allele-frequency differences between African Americans and African populations would be best explained by selection that occurred in Africa prior to migration to the Americas.

    View details for DOI 10.1016/j.ajhg.2014.08.011

    View details for Web of Science ID 000342654300008

    View details for PubMedCentralID PMC4185117

  • Inflammatory biomarker C-reactive protein and radiotherapy-induced early adverse skin reactions in patients with breast cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Rodriguez-Gil, J. L., Takita, C., Wright, J., Reis, I. M., Zhao, W., Lally, B. E., Hu, J. J. 2014; 23 (9): 1873-83

    Abstract

    Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in American women. Postsurgery adjuvant radiotherapy (RT) significantly reduced the local recurrence rate. However, many patients develop early adverse skin reactions (EASR) that impact quality of life and treatment outcomes.We evaluated an inflammatory biomarker, C-reactive protein (CRP), in predicting RT-induced EASRs in 159 patients with breast cancer undergoing RT. In each patient, we measured pre- and post-RT plasma CRP levels using a highly sensitive ELISA CRP assay. RT-induced EASRs were assessed at weeks 3 and 6 using the National Cancer Institute Common Toxicity Criteria (v3.0). Associations between EASRs and CRP levels were assessed using logistic regression models after adjusting for potential confounders.RT-induced grade 2+ EASRs were observed in 8 (5%) and 80 (50%) patients at weeks 3 and 6 (end of RT), respectively. At the end of RT, a significantly higher proportion of African Americans developed grade 3 EASRs (13.8% vs. 2.3% in others); grade 2+ EASRs were significantly associated with: change of CRP > 1 mg/L [odds ratio (OR), 2.51; 95% confidence interval (CI), 1.06-5.95; P = 0.04], obesity (OR, 2.08; 95% CI, 1.03-4.21; P = 0.04), or combined both factors (OR, 5.21; 95% CI, 1.77-15.38; P = 0.003).This is the first study to demonstrate that an inflammatory biomarker CRP is associated with RT-induced EASRs, particularly combined with obesity.Future larger studies are warranted to validate our findings and facilitate the discovery and development of anti-inflammatory agents to protect normal tissue from RT-induced adverse effects and improve quality of life in patients with breast cancer undergoing RT.

    View details for DOI 10.1158/1055-9965.EPI-14-0263

    View details for PubMedID 24917184

    View details for PubMedCentralID PMC4295640

  • Complementary and alternative medicine in reducing radiation-induced skin toxicity. Radiation and environmental biophysics Hu, J. J., Cui, T., Rodriguez-Gil, J. L., Allen, G. O., Li, J., Takita, C., Lally, B. E. 2014; 53 (3): 621-6

    Abstract

    Radiation therapy-induced acute and late effects, particularly skin toxicities, have significant impact on cancer patients' quality of life and long-term survival. To date, no effective topical agents have been routinely used in the clinical setting to prevent skin toxicity. Using SKH-hr1 hairless mice, we investigated two complementary and alternative medicine in their effects on inflammation and ionizing radiation (IR)-induced skin toxicity: Calendula officinalis (CO) and Ching Wan Hung (CWH). They were applied immediately following each IR dosing of 10 Gy/day for 4 days. Skin toxicity and inflammatory factors were evaluated at multiple time points up to 15 days post-radiation. Serum interleukin (IL)-1α, monocyte chemotactic protein-1 (MCP1), keratinocyte-derived chemokine (KC), and granulocyte colony-stimulating factor (G-CSF) were significantly induced by radiation. Both CO and CWH significantly inhibited IR-induced MCP1 (p < 0.01), KC (p < 0.05), and G-CSF (p < 0.001). IR-induced erythema and blood vessel dilation were significantly reduced by CWH (p < 0.001) but not by CO at day 10 post-IR. Both agents inhibited IR-induced IL-1α (p < 0.01), MCP1 (p < 0.05), and vascular endothelial growth factor (p < 0.05). There were continuous inhibitory effects of CWH on IR-induced skin toxicities and inflammation. In contrast, CO treatment resulted in skin reactions compared to IR alone. Our results suggest that both CO and CWH reduce IR-induced inflammation and CWH reduced IR-induced erythema. In summary, CWH showed promising effects in reducing IR-related inflammation and skin toxicities, and future proof-of-principal testing in humans will be critical in evaluating its potential application in preventing IR-induced skin toxicities.

    View details for DOI 10.1007/s00411-014-0540-y

    View details for PubMedID 24792319

  • Genome-wide association study of age at menarche in African-American women HUMAN MOLECULAR GENETICS Demerath, E. W., Liu, C., Franceschini, N., Chen, G., Palmer, J. R., Smith, E. N., Chen, C. T., Ambrosone, C. B., Arnold, A. M., Bandera, E. V., Berenson, G. S., Bernstein, L., Britton, A., Cappola, A. R., Carlson, C. S., Chanock, S. J., Chen, W., Chen, Z., Deming, S. L., Elks, C. E., Evans, M. K., Gajdos, Z., Henderson, B. E., Hu, J. J., Ingles, S., John, E. M., Kerr, K. F., Kolonel, L. N., Le Marchand, L., Lu, X., Millikan, R. C., Musani, S. K., Nock, N. L., North, K., Nyante, S., Press, M. F., Rodriquez-Gil, J. L., Ruiz-Narvaez, E. A., Schork, N. J., Srinivasan, S. R., Woods, N. F., Zheng, W., Ziegler, R. G., Zonderman, A., Heiss, G., Windham, B. G., Wellons, M., Murray, S. S., Nalls, M., Pastinen, T., Rajkovic, A., Hirschhorn, J., Cupples, L. A., Kooperberg, C., Murabito, J. M., Haiman, C. A. 2013; 22 (16): 3329-3346

    Abstract

    African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single-nucleotide polymorphisms (SNPs) in a total of 18 089 AA women in 15 studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2850 women (Stage 2). First, while no SNP passed the pre-specified P < 5 × 10(-8) threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified in EA women. Secondly, an investigation of SNPs in 42 previously identified menarche loci in EA women demonstrated that 25 (60%) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women.

    View details for DOI 10.1093/hmg/ddt181

    View details for Web of Science ID 000322341300014

  • A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry. Nature genetics Monda, K. L., Chen, G. K., Taylor, K. C., Palmer, C., Edwards, T. L., Lange, L. A., Ng, M. C., Adeyemo, A. A., Allison, M. A., Bielak, L. F., Chen, G., Graff, M., Irvin, M. R., Rhie, S. K., Li, G., Liu, Y., Liu, Y., Lu, Y., Nalls, M. A., Sun, Y. V., Wojczynski, M. K., Yanek, L. R., Aldrich, M. C., Ademola, A., Amos, C. I., Bandera, E. V., Bock, C. H., Britton, A., Broeckel, U., Cai, Q., Caporaso, N. E., Carlson, C. S., Carpten, J., Casey, G., Chen, W., Chen, F., Chen, Y. I., Chiang, C. W., Coetzee, G. A., Demerath, E., Deming-Halverson, S. L., Driver, R. W., Dubbert, P., Feitosa, M. F., Feng, Y., Freedman, B. I., Gillanders, E. M., Gottesman, O., Guo, X., Haritunians, T., Harris, T., Harris, C. C., Hennis, A. J., Hernandez, D. G., McNeill, L. H., Howard, T. D., Howard, B. V., Howard, V. J., Johnson, K. C., Kang, S. J., Keating, B. J., Kolb, S., Kuller, L. H., Kutlar, A., Langefeld, C. D., Lettre, G., Lohman, K., Lotay, V., Lyon, H., Manson, J. E., Maixner, W., Meng, Y. A., Monroe, K. R., Morhason-Bello, I., Murphy, A. B., Mychaleckyj, J. C., Nadukuru, R., Nathanson, K. L., Nayak, U., N'Diaye, A., Nemesure, B., Wu, S., Leske, M. C., Neslund-Dudas, C., Neuhouser, M., Nyante, S., Ochs-Balcom, H., Ogunniyi, A., Ogundiran, T. O., Ojengbede, O., Olopade, O. I., Palmer, J. R., Ruiz-Narvaez, E. A., Palmer, N. D., Press, M. F., Rampersaud, E., Rasmussen-Torvik, L. J., Rodriguez-Gil, J. L., Salako, B., Schadt, E. E., Schwartz, A. G., Shriner, D. A., Siscovick, D., Smith, S. B., Wassertheil-Smoller, S., Speliotes, E. K., Spitz, M. R., Sucheston, L., Taylor, H., Tayo, B. O., Tucker, M. A., Van den Berg, D. J., Edwards, D. R., Wang, Z., Wiencke, J. K., Winkler, T. W., Witte, J. S., Wrensch, M., Wu, X., Yang, J. J., Levin, A. M., Young, T. R., Zakai, N. A., Cushman, M., Zanetti, K. A., Zhao, J. H., Zhao, W., Zheng, Y., Zhou, J., Ziegler, R. G., Zmuda, J. M., Fernandes, J. K., Gilkeson, G. S., Kamen, D. L., Hunt, K. J., Spruill, I. J., Ambrosone, C. B., Ambs, S., Arnett, D. K., Atwood, L., Becker, D. M., Berndt, S. I., Bernstein, L., Blot, W. J., Borecki, I. B., Bottinger, E. P., Bowden, D. W., Burke, G., Chanock, S. J., Cooper, R. S., Ding, J., Duggan, D., Evans, M. K., Fox, C., Garvey, W. T., Bradfield, J. P., Hakonarson, H., Grant, S. F., Hsing, A., Chu, L., Hu, J. J., Huo, D., Ingles, S. A., John, E. M., Jordan, J. M., Kabagambe, E. K., Kardia, S. L., Kittles, R. A., Goodman, P. J., Klein, E. A., Kolonel, L. N., Le Marchand, L., Liu, S., McKnight, B., Millikan, R. C., Mosley, T. H., Padhukasahasram, B., Williams, L. K., Patel, S. R., Peters, U., Pettaway, C. A., Peyser, P. A., Psaty, B. M., Redline, S., Rotimi, C. N., Rybicki, B. A., Sale, M. M., Schreiner, P. J., Signorello, L. B., Singleton, A. B., Stanford, J. L., Strom, S. S., Thun, M. J., Vitolins, M., Zheng, W., Moore, J. H., Williams, S. M., Ketkar, S., Zhu, X., Zonderman, A. B., Kooperberg, C., Papanicolaou, G. J., Henderson, B. E., Reiner, A. P., Hirschhorn, J. N., Loos, R. J., North, K. E., Haiman, C. A. 2013; 45 (6): 690-696

    Abstract

    Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

    View details for DOI 10.1038/ng.2608

    View details for PubMedID 23583978

  • Genome-wide association studies identify four ER negative-specific breast cancer risk loci NATURE GENETICS Garcia-Closas, M., Couch, F. J., Lindstrom, S., Michailidouo, K., Schmidt, M. K., Brook, M. N., Orr, N., Rhie, S. K., Riboli, E., Feigelson, H. S., Le Marchand, L., Buring, J. E., Eccles, D., Miron, P., Fasching, P. A., Brauch, H., Chang-Claude, J., Carpenter, J., Godwin, A. K., Nevanlinna, H., Giles, G. G., Cox, A., Hopper, J. L., Bolla, M. K., Wang, Q., Dennis, J., Dicks, E., Howat, W. J., Schoof, N., Bojesen, S. E., Lambrechts, D., Broeks, A., Andrulis, I. L., Guenel, P., Burwinkel, B., Sawyer, E. J., Hollestelle, A., Fletcher, O., Winqvist, R., Brenner, H., Mannermaa, A., Hamann, U., Meindl, A., Lindblom, A., Zheng, W., Devillee, P., Goldberg, M. S., Lubinski, J., Kristensen, V., Swerdlow, A., Anton-Culver, H., Doerk, T., Muir, K., Matsuo, K., Wu, A. H., Radice, P., Teo, S. H., Shu, X., Blot, W., Kang, D., Hartman, M., Sangrajrang, S., Shen, C., Southey, M. C., Park, D. J., Hammet, F., Stone, J., van't Veer, L. J., Rutgers, E. J., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Peto, J., Schrauder, M. G., Ekici, A. B., Beckmann, M. W., Silva, I. d., Johnson, N., Warren, H., Tomlins, I., Kerin, M. J., Miller, N., Marme, F., Schneeweiss, A., Sohn, C., Therese Truong, T., Laurent-Puig, P., Kerbrat, P., Nordestgaard, B. G., Nielsen, S. F., Flyger, H., Milne, R. L., Arias Perez, J. I., Menendez, P., Mueller, H., Arndt, V., Stegmaier, C., Lichtner, P., Lochmann, M., Justenhoven, C., Ko, Y., Muranen, T. A., Aittomaki, K., Blomqvist, C., Greco, D., Heikkinen, T., Ito, H., Iwata, H., Yatabe, Y., Antonenkova, N. N., Margolin, S., Kataja, V., Kosma, V., Hartikainen, J. M., Balleine, R., Tseng, C., Van Den Berg, D., Stram, D. O., Neven, P., Dieudonne, A., Leunen, K., Rudolph, A., Nickels, S., Flesch-Janys, D., Peterlongo, P., Peissel, B., Bernard, L., Olson, J. E., Wang, X., Stevens, K., Severi, G., Baglietto, L., McLean, C., Coetzee, G. A., Feng, Y., Henderson, B. E., Schumacher, F., Bogdanova, N. V., Labreche, F., Dumont, M., Yip, C. H., Taib, N. A., Cheng, C., Shrubsole, M., Long, J., Pylkas, K., Jukkola-Vuorinen, A., Kauppila, S., Knight, J. A., Glendon, G., Mulligan, A. M., Tollenaar, R. A., Seynaeve, C. M., Kriege, M., Hooning, M. J., van den Ouweland, A. M., van Deurzen, C. H., Lu, W., Gao, Y., Cai, H., Balasubramanian, S. P., Cross, S. S., Reed, M. W., Signorello, L., Cai, Q., Shah, M., Miao, H., Chan, C. W., Chia, K. S., Jakubowska, A., Jaworska, K., Durda, K., Hsiung, C., Wu, P., Yu, J., Ashworth, A., Jones, M., Tessier, D. C., Gonzalez-Neira, A., Pita, G., Alonso, M. R., Vincent, D., Bacot, F., Ambrosone, C. B., Bandera, E. V., John, E. M., Chen, G. K., Hu, J. J., Rodriguez-Gil, J. L., Bernstein, L., Press, M. F., Ziegler, R. G., Millikan, R. M., Deming-Halverson, S. L., Nyante, S., Ingles, S. A., Waisfisz, Q., Tsimiklis, H., Makalic, E., Schmidt, D., Bui, M., Gibson, L., Mueller-Myhsok, B., Schmutzler, R. K., Hein, R., Dahmen, N., Beckmann, L., Aaltonen, K., Czene, K., Irwanto, A., Liu, J., Turnbull, C., Rahman, N., Meijers-Heijboer, H., Uitterlinden, A. G., Rivadeneira, F., Olswold, C., Slager, S., Pilarski, R., Ademuyiwa, F., Konstantopoulou, I., Martin, N. G., Montgomery, G. W., Slamon, D. J., Rauh, C., Lux, M. P., Jud, S. M., Bruning, T., Weaver, J., Harma, P., Pathak, H., Tapper, W., Gerty, S., Durcan, L., Trichopoulos, D., Tumino, R., Peeters, P. H., Kaaks, R., Campa, D., Canzian, F., Weiderpass, E., Johansson, M., Khaw, K., Travis, R., Clavel-Chapelon, F., Kolonel, L. N., Chen, C., Beck, A., Hankinson, S. E., Berg, C. D., Hoover, R. N., Lissowska, J., Figueroa, J. D., Chasman, D. I., Gaudet, M. M., Diver, W. R., Willett, W. C., Hunter, D. J., Simard, J., Benitez, J., Dunning, A. M., Sherman, M. E., Chenevix-Trench, G., Chanock, S. J., Hall, P., Pharoah, P. D., Vachon, C., Easton, D. F., Haiman, C. A., Kraft, P. 2013; 45 (4): 392-398

    Abstract

    Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.

    View details for DOI 10.1038/ng.2561

    View details for Web of Science ID 000316840600009

    View details for PubMedID 23535733

    View details for PubMedCentralID PMC3771695

  • A Genome-Wide Scan for Breast Cancer Risk Haplotypes among African American Women PLOS ONE Song, C., Chen, G. K., Millikan, R. C., Ambrosone, C. B., John, E. M., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Chanock, S. J., Wan, P., Sheng, X., Pooler, L. C., Van den Berg, D. J., Le Marchand, L., Kolonel, L. N., Henderson, B. E., Haiman, C. A., Stram, D. O. 2013; 8 (2)

    Abstract

    Genome-wide association studies (GWAS) simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP) have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls) using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645), thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density.

    View details for DOI 10.1371/journal.pone.0057298

    View details for Web of Science ID 000315524900070

    View details for PubMedID 23468962

    View details for PubMedCentralID PMC3585353

  • Inflammatory biomarker c-reactive protein in radiotherapy-induced skin toxicities of breast cancer patients. Rodriguez-Gil, J. L., Cooley, A., Thomas, V., Takita, C., Wright, J., Poitevien, M., Allen, G. O., Reis, I. M., Zhao, W., Hu, J. J. AMER ASSOC CANCER RESEARCH. 2013
  • A somatic cell defect is associated with the onset of neurological symptoms in a lysosomal storage disease. Molecular genetics and metabolism Rodriguez-Gil, J. L., Larson, D. M., Wassif, C. A., Yanjanin, N. M., Anderson, S. M., Kirby, M. R., Trivedi, N. S., Porter, F. D., Pavan, W. J. 2013; 110 (1-2): 188-90

    Abstract

    Mutations in individuals with the lysosomal storage disorder Niemann-Pick disease, type C1 (NPC1) are heterogeneous, not localized to specific protein domains, and not correlated to time of onset or disease severity. We demonstrate direct correlation of the time of neurological symptom onset with the severity of lysosomal defects in NPC1 patient-derived fibroblasts. This is a novel assay for NPC1 individuals that may be predictive of NPC1 disease progression and broadly applicable to other lysosomal disorders.

    View details for DOI 10.1016/j.ymgme.2013.06.010

    View details for PubMedID 23850077

    View details for PubMedCentralID PMC3775472

  • A genome-wide association study of breast cancer in women of African ancestry HUMAN GENETICS Chen, F., Chen, G. K., Stram, D. O., Millikan, R. C., Ambrosone, C. B., John, E. M., Bernstein, L., Zheng, W., Palmer, J. R., Hu, J. J., Rebbeck, T. R., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Ruiz-Narvaez, E. A., Deming, S. L., Rodriguez-Gil, J. L., DeMichele, A., Chanock, S. J., Blot, W., Signorello, L., Cai, Q., Li, G., Long, J., Huo, D., Zheng, Y., Cox, N. J., Olopade, O. I., Ogundiran, T. O., Adebamowo, C., Nathanson, K. L., Domchek, S. M., Simon, M. S., Hennis, A., Nemesure, B., Wu, S., Leske, M. C., Ambs, S., Hutter, C. M., Young, A., Kooperberg, C., Peters, U., Rhie, S. K., Wan, P., Sheng, X., Pooler, L. C., Van den Berg, D. J., Le Marchand, L., Kolonel, L. N., Henderson, B. E., Haiman, C. A. 2013; 132 (1): 39-48

    Abstract

    Genome-wide association studies (GWAS) in diverse populations are needed to reveal variants that are more common and/or limited to defined populations. We conducted a GWAS of breast cancer in women of African ancestry, with genotyping of >1,000,000 SNPs in 3,153 African American cases and 2,831 controls, and replication testing of the top 66 associations in an additional 3,607 breast cancer cases and 11,330 controls of African ancestry. Two of the 66 SNPs replicated (p < 0.05) in stage 2, which reached statistical significance levels of 10(-6) and 10(-5) in the stage 1 and 2 combined analysis (rs4322600 at chromosome 14q31: OR = 1.18, p = 4.3 × 10(-6); rs10510333 at chromosome 3p26: OR = 1.15, p = 1.5 × 10(-5)). These suggestive risk loci have not been identified in previous GWAS in other populations and will need to be examined in additional samples. Identification of novel risk variants for breast cancer in women of African ancestry will demand testing of a substantially larger set of markers from stage 1 in a larger replication sample.

    View details for DOI 10.1007/s00439-012-1214-y

    View details for Web of Science ID 000313005800005

    View details for PubMedID 22923054

  • A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11 HUMAN MOLECULAR GENETICS Siddiq, A., Couch, F. J., Chen, G. K., Lindstrom, S., Eccles, D., Millikan, R. C., Michailidou, K., Stram, D. O., Beckmann, L., Rhie, S. K., Ambrosone, C. B., Aittomaki, K., Amiano, P., Apicella, C., Baglietto, L., Bandera, E. V., Beckmann, M. W., Berg, C. D., Bernstein, L., Blomqvist, C., Brauch, H., Brinton, L., Bui, Q. M., Buring, J. E., Buys, S. S., Campa, D., Carpenter, J. E., Chasman, D. I., Chang-Claude, J., Chen, C., Clavel-Chapelon, F., Cox, A., Cross, S. S., Czene, K., Deming, S. L., Diasio, R. B., Diver, W. R., Dunning, A. M., Durcan, L., Ekici, A. B., Fasching, P. A., Feigelson, H. S., Fejerman, L., Figueroa, J. D., Fletcher, O., Flesch-Janys, D., Gaudet, M. M., Gerty, S. M., Rodriguez-Gil, J. L., Giles, G. G., van Gils, C. H., Godwin, A. K., Graham, N., Greco, D., Hall, P., Hankinson, S. E., Hartmann, A., Hein, R., Heinz, J., Hoover, R. N., Hopper, J. L., Hu, J. J., Huntsman, S., Ingles, S. A., Irwanto, A., Isaacs, C., Jacobs, K. B., John, E. M., Justenhoven, C., Kaaks, R., Kolonel, L. N., Coetzee, G. A., Lathrop, M., Le Marchand, L., Lee, A. M., Lee, I., Lesnick, T., Lichtner, P., Liu, J., Lund, E., Makalic, E., Martin, N. G., McLean, C. A., Meijers-Heijboer, H., Meindl, A., Miron, P., Monroe, K. R., Montgomery, G. W., Mueller-Myhsok, B., Nickels, S., Nyante, S. J., Olswold, C., Overvad, K., Palli, D., Park, D. J., Palmer, J. R., Pathak, H., Peto, J., Pharoah, P., Rahman, N., Rivadeneira, F., Schmidt, D. F., Schmutzler, R. K., Slager, S., Southey, M. C., Stevens, K. N., Sinn, H., Press, M. F., Ross, E., Riboli, E., Ridker, P. M., Schumacher, F. R., Severi, G., Silva, I. d., Stone, J., Sund, M., Tapper, W. J., Thun, M. J., Travis, R. C., Turnbull, C., Uitterlinden, A. G., Waisfisz, Q., Wang, X., Wang, Z., Weaver, J., Schulz-Wendtland, R., Wilkens, L. R., Van Den Berg, D., Zheng, W., Ziegler, R. G., Ziv, E., Nevanlinna, H., Easton, D. F., Hunter, D. J., Henderson, B. E., Chanock, S. J., Garcia-Closas, M., Kraft, P., Haiman, C. A., Vachon, C. M. 2012; 21 (24): 5373-5384

    Abstract

    Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.

    View details for DOI 10.1093/hmg/dds381

    View details for Web of Science ID 000311965600012

    View details for PubMedID 22976474

    View details for PubMedCentralID PMC3510753

  • Genome-wide meta-analyses of smoking behaviors in African Americans TRANSLATIONAL PSYCHIATRY David, S. P., Hamidovic, A., Chen, G. K., Bergen, A. W., Wessel, J., Kasberger, J. L., BROWN, W. M., Petruzella, S., Thacker, E. L., Kim, Y., Nalls, M. A., Tranah, G. J., Sung, Y. J., Ambrosone, C. B., Arnett, D., Bandera, E. V., Becker, D. M., BECKER, L., Berndt, S. I., Bernstein, L., Blot, W. J., Broeckel, U., Buxbaum, S. G., Caporaso, N., Casey, G., Chanock, S. J., Deming, S. L., Diver, W. R., Eaton, C. B., Evans, D. S., Evans, M. K., Fornage, M., Franceschini, N., Harris, T. B., Henderson, B. E., Hernandez, D. G., Hitsman, B., Hu, J. J., Hunt, S. C., Ingles, S. A., John, E. M., Kittles, R., Kolb, S., Kolonel, L. N., Le Marchand, L., Liu, Y., Lohman, K. K., McKnight, B., Millikan, R. C., Murphy, A., Neslund-Dudas, C., Nyante, S., Press, M., Psaty, B. M., Rao, D. C., Redline, S., Rodriguez-Gil, J. L., Rybicki, B. A., Signorello, L. B., Singleton, A. B., Smoller, J., Snively, B., Spring, B., Stanford, J. L., Strom, S. S., Swan, G. E., Taylor, K. D., Thun, M. J., Wilson, A. F., Witte, J. S., Yamamura, Y., Yanek, L. R., Yu, K., Zheng, W., Ziegler, R. G., Zonderman, A. B., Jorgenson, E., Haiman, C. A., Furberg, H. 2012; 2

    Abstract

    The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

    View details for DOI 10.1038/tp.2012.41

    View details for Web of Science ID 000312895700012

    View details for PubMedID 22832964

    View details for PubMedCentralID PMC3365260

  • A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer NATURE GENETICS Haiman, C. A., Chen, G. K., Vachon, C. M., Canzian, F., Dunning, A., Millikan, R. C., Wang, X., Ademuyiwa, F., Ahmed, S., Ambrosone, C. B., Baglietto, L., Balleine, R., Bandera, E. V., Beckmann, M. W., Berg, C. D., Bernstein, L., Blomqvist, C., Blot, W. J., Brauch, H., Buring, J. E., Carey, L. A., Carpenter, J. E., Chang-Claude, J., Chanock, S. J., Chasman, D. I., Clarke, C. L., Cox, A., Cross, S. S., Deming, S. L., Diasio, R. B., Dimopoulos, A. M., Driver, W. R., Duennebier, T., Durcan, L., Eccles, D., Edlund, C. K., Ekici, A. B., Fasching, P. A., Feigelson, H. S., Flesch-Janys, D., Fostira, F., Foersti, A., Fountzilas, G., Gerty, S. M., Giles, G. G., Godwin, A. K., Goodfellow, P., Graham, N., Greco, D., Hamann, U., Hankinson, S. E., Hartmann, A., Hein, R., Heinz, J., Holbrook, A., Hoover, R. N., Hu, J. J., Hunter, D. J., Ingles, S. A., Irwanto, A., Ivanovich, J., John, E. M., Johnson, N., Jukkola-Vuorinen, A., Kaaks, R., Ko, Y., Kolonel, L. N., Konstantopoulou, I., Kosma, V., Kulkarni, S., Lambrechts, D., Lee, A. M., Le Marchand, L., Lesnick, T., Liu, J., Lindstrom, S., Mannermaa, A., Margolin, S., Martin, N. G., Miron, P., Montgomery, G. W., Nevanlinna, H., Nickels, S., Nyante, S., Olswold, C., Palmer, J., Pathak, H., Pectasides, D., Perou, C. M., Peto, J., Pharoah, P. D., Pooler, L. C., Press, M. F., Pylkas, K., Rebbeck, T. R., Rodriguez-Gil, J. L., Rosenberg, L., Ross, E., Ruediger, T., Silva, I. d., Sawyer, E., Schmidt, M. K., Schulz-Wendtland, R., Schumacher, F., Severi, G., Sheng, X., Signorello, L. B., Sinn, H., Stevens, K. N., Southey, M. C., Tapper, W. J., Tomlinson, I., Hogervorst, F. B., Wauters, E., Weaver, J., Wildiers, H., Winqvist, R., Van Den Berg, D., Wan, P., Xia, L. Y., Yannoukakos, D., Zheng, W., Ziegler, R. G., Siddiq, A., Slager, S. L., Stram, D. O., Easton, D., Kraft, P., Henderson, B. E., Couch, F. J. 2011; 43 (12): 1210-U61

    Abstract

    Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.

    View details for DOI 10.1038/ng.985

    View details for Web of Science ID 000297931400013

    View details for PubMedID 22037553

    View details for PubMedCentralID PMC3279120

  • Fine-mapping of breast cancer susceptibility loci characterizes genetic risk in African Americans HUMAN MOLECULAR GENETICS Chen, F., Chen, G. K., Millikan, R. C., John, E. M., Ambrosone, C. B., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Deming, S. L., Bandera, E. V., Nyante, S., Palmer, J. R., Rebbeck, T. R., Ingles, S. A., Press, M. F., Rodriguez-Gil, J. L., Chanock, S. J., Le Marchand, L., Kolonel, L. N., Henderson, B. E., Stram, D. O., Haiman, C. A. 2011; 20 (22): 4491-4503

    Abstract

    Genome-wide association studies (GWAS) have revealed 19 common genetic variants that are associated with breast cancer risk. Testing of the index signals found through GWAS and fine-mapping of each locus in diverse populations will be necessary for characterizing the role of these risk regions in contributing to inherited susceptibility. In this large study of breast cancer in African-American women (3016 cases and 2745 controls), we tested the 19 known risk variants identified by GWAS and replicated associations (P < 0.05) with only 4 variants. Through fine-mapping, we identified markers in four regions that better capture the association with breast cancer risk in African Americans as defined by the index signal (2q35, 5q11, 10q26 and 19p13). We also identified statistically significant associations with markers in four separate regions (8q24, 10q22, 11q13 and 16q12) that are independent of the index signals and may represent putative novel risk variants. In aggregate, the more informative markers found in the study enhance the association of these risk regions with breast cancer in African Americans [per allele odds ratio (OR) = 1.18, P = 2.8 × 10(-24) versus OR = 1.04, P = 6.1 × 10(-5)]. In this detailed analysis of the known breast cancer risk loci, we have validated and improved upon markers of risk that better characterize their association with breast cancer in women of African ancestry.

    View details for DOI 10.1093/hmg/ddr367

    View details for Web of Science ID 000296103800017

    View details for PubMedID 21852243

    View details for PubMedCentralID PMC3196889

  • Identification, Replication, and Fine-Mapping of Loci Associated with Adult Height in Individuals of African Ancestry PLOS GENETICS N'Diaye, A., Chen, G. K., Palmer, C. D., Ge, B., Tayo, B., Mathias, R. A., Ding, J., Nalls, M. A., Adeyemo, A., Adoue, V., Ambrosone, C. B., Atwood, L., Bandera, E. V., Becker, L. C., Berndt, S. I., Bernstein, L., Blot, W. J., Boerwinkle, E., Britton, A., Casey, G., Chanock, S. J., Demerath, E., Deming, S. L., Diver, W. R., Fox, C., Harris, T. B., Hernandez, D. G., Hu, J. J., Ingles, S. A., John, E. M., Johnson, C., Keating, B., Kittles, R. A., Kolonel, L. N., Kritchevsky, S. B., Le Marchand, L., Lohman, K., Liu, J., Millikan, R. C., Murphy, A., Musani, S., Neslund-Dudas, C., North, K. E., Nyante, S., Ogunniyi, A., Ostrander, E. A., Papanicolaou, G., Patel, S., Pettaway, C. A., Press, M. F., Redline, S., Rodriguez-Gil, J. L., Rotimi, C., Rybicki, B. A., Salako, B., Schreiner, P. J., Signorello, L. B., Singleton, A. B., Stanford, J. L., Stram, A. H., Stram, D. O., Strom, S. S., Suktitipat, B., Thun, M. J., Witte, J. S., Yanek, L. R., Ziegler, R. G., Zheng, W., Zhu, X., Zmuda, J. M., Zonderman, A. B., Evans, M. K., Liu, Y., Becker, D. M., Cooper, R. S., Pastinen, T., Henderson, B. E., Hirschhorn, J. N., Lettre, G., Haiman, C. A. 2011; 7 (10)

    Abstract

    Adult height is a classic polygenic trait of high heritability (h(2) approximately 0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain approximately10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis of genome-wide association (GWA) results for adult height in 20,427 individuals of African ancestry with replication in up to 16,436 African Americans. We found two novel height loci (Xp22-rs12393627, P = 3.4×10(-12) and 2p14-rs4315565, P = 1.2×10(-8)). As a group, height associations discovered in European-ancestry samples replicate in individuals of African ancestry (P = 1.7×10(-4) for overall replication). Fine-mapping of the European height loci in African-ancestry individuals showed an enrichment of SNPs that are associated with expression of nearby genes when compared to the index European height SNPs (P<0.01). Our results highlight the utility of genetic studies in non-European populations to understand the etiology of complex human diseases and traits.

    View details for DOI 10.1371/journal.pgen.1002298

    View details for Web of Science ID 000296665400007

    View details for PubMedID 21998595

    View details for PubMedCentralID PMC3188544

  • The landscape of recombination in African Americans NATURE Hinch, A. G., Tandon, A., Patterson, N., Song, Y., Rohland, N., Palmer, C. D., Chen, G. K., Wang, K., Buxbaum, S. G., Akylbekova, E. L., Aldrich, M. C., Ambrosone, C. B., Amos, C., Bandera, E. V., Berndt, S. I., Bernstein, L., Blot, W. J., Bock, C. H., Boerwinkle, E., Cai, Q., Caporaso, N., Casey, G., Cupples, L. A., Deming, S. L., Diver, W. R., Divers, J., Fornage, M., Gillanders, E. M., Glessner, J., Harris, C. C., Hu, J. J., Ingles, S. A., Isaacs, W., John, E. M., Kao, W. H., Keating, B., Kittles, R. A., Kolonel, L. N., Larkin, E., Le Marchand, L., McNeill, L. H., Millikan, R. C., Murphy, A., Musani, S., Neslund-Dudas, C., Nyante, S., Papanicolaou, G. J., Press, M. F., Psaty, B. M., Reiner, A. P., Rich, S. S., Rodriguez-Gil, J. L., Rotter, J. I., Rybicki, B. A., Schwartz, A. G., Signorello, L. B., Spitz, M., Strom, S. S., Thun, M. J., Tucker, M. A., Wang, Z., Wiencke, J. K., Witte, J. S., Wrensch, M., Wu, X., Yamamura, Y., Zanetti, K. A., Zheng, W., Ziegler, R. G., Zhu, X., Redline, S., Hirschhorn, J. N., Henderson, B. E., Taylor, H. A., Price, A. L., Hakonarson, H., Chanock, S. J., Haiman, C. A., Wilson, J. G., Reich, D., Myers, S. R. 2011; 476 (7359): 170-U67

    Abstract

    Recombination, together with mutation, gives rise to genetic variation in populations. Here we leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P value < 10(-245)). We identify a 17-base-pair DNA sequence motif that is enriched in these hotspots, and is an excellent match to the predicted binding target of PRDM9 alleles common in West Africans and rare in Europeans. Sites of this motif are predicted to be risk loci for disease-causing genomic rearrangements in individuals carrying these alleles. More generally, this map provides a resource for research in human genetic variation and evolution.

    View details for DOI 10.1038/nature10336

    View details for Web of Science ID 000293731900028

    View details for PubMedID 21775986

    View details for PubMedCentralID PMC3154982

  • Association between oxidative damage and early adverse skin reactions following postoperative adjuvant radiotherapy in breast cancer patients Thomas, V., Poitevien, M., Allen, G. O., Rodriguez-Gil, J., Tillotson, J., Vargas, N., Takita, C., Wright, J., Hu, J. J. AMER ASSOC CANCER RESEARCH. 2011
  • Enhanced Statistical Tests for GWAS in Admixed Populations: Assessment using African Americans from CARe and a Breast Cancer Consortium PLOS GENETICS Pasaniuc, B., Zaitlen, N., Lettre, G., Chen, G. K., Tandon, A., Kao, W. H., Ruczinski, I., Fornage, M., Siscovick, D. S., Zhu, X., Larkin, E., Lange, L. A., Cupples, L. A., Yang, Q., Akylbekova, E. L., Musani, S. K., Divers, J., Mychaleckyj, J., Li, M., Papanicolaou, G. J., Millikan, R. C., Ambrosone, C. B., John, E. M., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Nyante, S. J., Bandera, E. V., Ingles, S. A., Press, M. F., Chanock, S. J., Deming, S. L., Rodriguez-Gil, J. L., Palmer, C. D., Buxbaum, S., Ekunwe, L., Hirschhorn, J. N., Henderson, B. E., Myers, S., Haiman, C. A., Reich, D., Patterson, N., Wilson, J. G., Price, A. L. 2011; 7 (4)

    Abstract

    While genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations.

    View details for DOI 10.1371/journal.pgen.1001371

    View details for Web of Science ID 000289977000015

    View details for PubMedID 21541012

    View details for PubMedCentralID PMC3080860

  • Pre-treatment Oxidative Damage Associated with Early Adverse Skin Reactions from Adjuvant Radiotherapy in Breast Cancer Patients Thomas, V., Poitevien, M., Allen, G. O., Rodriguez-Gil, J., Tillotson, J., Vargas, N., Takita, C., Wright, J., Hu, J. J. ELSEVIER SCIENCE INC. 2011: S713-S714