Joshua W. Knowles

All Publications

• Hymecromone Promotes Longevity and Insulin Sensitivity in Mice. Cells Nagy, N., Czepiel, K. S., Kaber, G., Stefanovski, D., Hargil, A., Pennetzdorfer, N., Targ, R., Reghupaty, S. C., Wight, T. N., Vernon, R. B., Hull-Meichle, R. L., Marshall, P., Medina, C. O., Martinez, H., Kalinowski, A., Paladini, R. D., Garantziotis, S., Knowles, J. W., Bollyky, P. L. 2024; 13 (20)

  Abstract

  Given that the extracellular matrix polymer hyaluronan (HA) has been implicated in longevity, we asked whether 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, impacts lifespan in mice. We designed a prospective study of long-term administration of 4-MU with conventional C57BL/6J mice. We find that 4-MU extends median survival from 122 weeks (control) to 154 weeks (4-MU), an increase of 32 weeks (p < 0.0001 by Log-rank Mantel Cox test). The maximum lifespan of 4-MU treated mice increased from 159 to 194 weeks. In tandem with these effects, 4-MU enhances insulin sensitivity, a metabolic parameter known to regulate lifespan, as measured by insulin tolerance testing (ITT) as well as frequent sampling intra venous glucose tolerance tests (FSIVGTTs). We further observed that 4-MU treated mice weigh less while consuming the same amount of food, indicating that 4-MU treatment alters energy expenditure. However, we do not observe changes in tissue HA content in this model. We conclude that 4-MU promotes insulin sensitivity and longevity but that the underlying mechanism, and the contribution of HA is unclear. 4-MU, already approved in various countries for hepatobiliary conditions, is currently under investigation and clinical development as a therapy for several chronic inflammatory conditions. These data suggest that the beneficial effects of 4-MU on tissue metabolism may include effects on longevity.

  View details for DOI 10.3390/cells13201727

  View details for PubMedID 39451245

• One-year real-world experience with mavacamten and its physiologic effects on obstructive hypertrophic cardiomyopathy FRONTIERS IN CARDIOVASCULAR MEDICINE Kim, D., Chu, E. L., Keamy-Minor, E. E., Paranjpe, I., Tang, W. L., O'Sullivan, J. W., Desai, Y. B., Liu, M. B., Munsey, E., Hecker, K., Cuenco, I., Kao, B., Bacolor, E., Bonnett, C., Linder, A., Lacar, K., Robles, N., Lamendola, C., Smith, A., Knowles, J. W., Perez, M. V., Kawana, M., Sallam, K. I., Weldy, C. S., Wheeler, M. T., Parikh, V. N., Salisbury, H., Ashley, E. A., Stanford Ctr Inherited Cardiovasc Dis 2024; 11

  View details for DOI 10.3389/fcvm.2024.1429230

  View details for Web of Science ID 001312496500001

• One-year real-world experience with mavacamten and its physiologic effects on obstructive hypertrophic cardiomyopathy. Frontiers in cardiovascular medicine Kim, D. S., Chu, E. L., Keamy-Minor, E. E., Paranjpe, I. D., Tang, W. L., O'Sullivan, J. W., Desai, Y. B., Liu, M. B., Munsey, E., Hecker, K., Cuenco, I., Kao, B., Bacolor, E., Bonnett, C., Linder, A., Lacar, K., Robles, N., Lamendola, C., Smith, A., Knowles, J. W., Perez, M. V., Kawana, M., Sallam, K. I., Weldy, C. S., Wheeler, M. T., Parikh, V. N., Salisbury, H., Ashley, E. A. 2024; 11: 1429230

  Abstract

  Mavacamten is a first-in-class cardiac myosin ATPase inhibitor, approved by the United States Food and Drug Administration for the treatment of hypertrophic cardiomyopathy with obstructive physiology (oHCM). Here, we present the real-world use of mavacamten in 50 patients with oHCM at a tertiary care referral center. In both our highlighted case and in our aggregate data, we report significant improvement in wall thickness, mitral regurgitation, left ventricular outflow tract obstruction and New York Heart Association symptom class. Moreover, in our center's experience, neither arrhythmia burden, nor contractility have worsened in the vast majority of patients: we note a clinically insignificant mean decrease in left ventricular ejection fraction (LVEF), with only two patients requiring temporary mavacamten discontinuance for LVEF < 50%. Adverse events were rare, unrelated to mavacamten itself, and seen solely in patients with disease too advanced to have been represented in clinical trials. Moreover, our multidisciplinary pathway enabled us to provide a large number of patients with a novel closely-monitored therapeutic within just a few months of commercial availability. These data lead us to conclude that mavacamten, as a first-in-class cardiac myosin inhibitor, is safe and efficacious in real-world settings.

  View details for DOI 10.3389/fcvm.2024.1429230

  View details for PubMedID 39314763

  View details for PubMedCentralID PMC11417615

• A functional genomic framework to elucidate novel causal metabolic dysfunction-associated fatty liver disease genes. Hepatology (Baltimore, Md.) Saliba-Gustafsson, P., Justesen, J. M., Ranta, A., Sharma, D., Bielczyk-Maczynska, E., Li, J., Najmi, L. A., Apodaka, M., Aspichueta, P., Björck, H. M., Eriksson, P., Schurr, T. M., Franco-Cereceda, A., Gloudemans, M., Mujica, E., den Hoed, M., Assimes, T. L., Quertermous, T., Carcamo-Orive, I., Park, C. Y., Knowles, J. W. 2024

  Abstract

  Metabolic dysfunction-associated fatty liver disease (MASLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for MASLD have been hampered by the relative paucity of human data from gold-standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using MASLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined GWAS of MASLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for MASLD.We used the UK Biobank to explore the associations of our novel MASLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study MASLD genes in vitro using CRISPRi. Our data identify VKORC1, TNKS, LYPLAL1 and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of MASLD.Complementary genetic and genomic approaches are useful for the identification of MASLD genes. Our data supports VKORC1 as a bona fide MASLD gene. We have established a functional genomic framework to study at scale putative novel MASLD genes from human genetic association studies.

  View details for DOI 10.1097/HEP.0000000000001066

  View details for PubMedID 39190705

• Loss of RREB1 reduces adipogenesis and improves insulin sensitivity in mouse and human adipocytes. bioRxiv : the preprint server for biology Yu, G. Z., Krentz, N. A., Bentley, L., Zhao, M., Paphiti, K., Sun, H., Honecker, J., Nygård, M., Dashti, H., Bai, Y., Reid, M., Thaman, S., Wabitsch, M., Rajesh, V., Yang, J., Mattis, K. K., Abaitua, F., Casero, R., Hauner, H., Knowles, J. W., Wu, J. Y., Mandrup, S., Claussnitzer, M., Svensson, K. J., Cox, R. D., Gloyn, A. L. 2024

  Abstract

  There are multiple independent genetic signals at the Ras-responsive element binding protein 1 (RREB1) locus associated with type 2 diabetes risk, fasting glucose, ectopic fat, height, and bone mineral density. We have previously shown that loss of RREB1 in pancreatic beta cells reduces insulin content and impairs islet cell development and function. However, RREB1 is a widely expressed transcription factor and the metabolic impact of RREB1 loss in vivo remains unknown. Here, we show that male and female global heterozygous knockout (Rreb1 +/-) mice have reduced body length, weight, and fat mass on high-fat diet. Rreb1+/- mice have sex- and diet-specific decreases in adipose tissue and adipocyte size; male mice on high-fat diet had larger gonadal adipocytes, while males on standard chow and females on high-fat diet had smaller, more insulin sensitive subcutaneous adipocytes. Mouse and human precursor cells lacking RREB1 have decreased adipogenic gene expression and activated transcription of genes associated with osteoblast differentiation, which was associated with Rreb1 +/- mice having increased bone mineral density in vivo. Finally, human carriers of RREB1 T2D protective alleles have smaller adipocytes, consistent with RREB1 loss-of-function reducing diabetes risk.

  View details for DOI 10.1101/2024.07.30.605923

  View details for PubMedID 39131393

  View details for PubMedCentralID PMC11312556

• X chromosome dosage drives statin-induced dysglycemia and mitochondrial dysfunction. Nature communications Zhang, P., Munier, J. J., Wiese, C. B., Vergnes, L., Link, J. C., Abbasi, F., Ronquillo, E., Scheker, K., Muñoz, A., Kuang, Y. L., Theusch, E., Lu, M., Sanchez, G., Oni-Orisan, A., Iribarren, C., McPhaul, M. J., Nomura, D. K., Knowles, J. W., Krauss, R. M., Medina, M. W., Reue, K. 2024; 15 (1): 5571

  Abstract

  Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy.

  View details for DOI 10.1038/s41467-024-49764-2

  View details for PubMedID 38956041

  View details for PubMedCentralID 6047411

• Generation of two familial hypercholesterolemia patient-specific induced pluripotent stem cell lines harboring heterozygous mutations in the LDLR gene. Stem cell research Gao, J., Li, J., Xu, L., Yan, C. D., Knowles, J. W., Wu, J. C. 2024; 78: 103463

  Abstract

  Familial hypercholesterolemia (FH) is a genetic disorder affecting the metabolism of lipoprotein, characterized by elevated levels of plasma concentrations of low-density lipoprotein cholesterol (LDLC). The most common FH cause is mutations within the gene that encodes for the LDL receptor (LDLR) protein. Two induced pluripotent stem cell (iPSC) lines were generated from patients with FH, each carrying a single heterozygous mutation in the LDLR gene, one is a missense mutation, c.631C > T, and the other is a splice-site mutation, c.313 + 1G > A. Both iPSC lines exhibited strong expression of pluripotency markers, demonstrated the ability to differentiate into derivatives of the three germ layers, and maintained normal karyotypes. These derived iPSC lines represent powerful tools for in vitro modeling FH and offer a promising platform for therapeutic development.

  View details for DOI 10.1016/j.scr.2024.103463

  View details for PubMedID 38852422

• Design and Pilot Results from Million Veteran Program Return Of Actionable Genetic Results (MVP-ROAR) Study. American heart journal Vassy, J. L., Brunette, C. A., Yi, T., Harrison, A., Cardellino, M. P., Assimes, T. L., Christensen, K. D., Devineni, P., Gaziano, J. M., Gong, X., Hui, Q., Knowles, J. W., Muralidhar, S., Natarajan, P., Pyarajan, S., Sears, M. G., Shi, Y., Sturm, A. C., Whitbourne, S. B., Sun, Y. V., Danowski, M. E. 2024

  Abstract

  As a mega-biobank linked to a national healthcare system, the Million Veteran Program (MVP) can directly improve the health care of participants. To determine the feasibility and outcomes of returning medically actionable genetic results to MVP participants, the program launched the MVP Return Of Actionable Results (MVP-ROAR) Study, with familial hypercholesterolemia (FH) as an exemplar actionable condition.The MVP-ROAR Study consists of a completed single-arm pilot phase and an ongoing randomized clinical trial (RCT), in which MVP participants are recontacted and invited to receive clinical confirmatory gene sequencing testing and a telegenetic counseling intervention. The primary outcome of the RCT is 6-month change in low-density lipoprotein cholesterol (LDL-C) between participants receiving results at baseline and those receiving results after 6 months.The pilot developed processes to identify and recontact participants nationally with probable pathogenic variants in low-density lipoprotein receptor (LDLR) on the MVP genotype array, invite them to clinical confirmatory gene sequencing, and deliver a telegenetic counseling intervention. Among participants in the pilot phase, 8 (100%) had active statin prescriptions after 6 months. Results were shared with 16 first-degree family members. Six-month ΔLDL-C (low-density lipoprotein cholesterol) after the genetic counseling intervention was -37 mg/dL (95% CI: -12 to -61; p=0.03). The ongoing RCT will determine between-arm differences in this primary outcome.While underscoring the importance of clinical confirmation of research results, the pilot phase of the MVP-ROAR Study marks a turning point in MVP and demonstrates the feasibility of returning genetic results to participants and their providers. The ongoing RCT will contribute to understanding how such a program might improve patient health care and outcomes.

  View details for DOI 10.1016/j.ahj.2024.04.021

  View details for PubMedID 38762090

• Chemerin in Participants with or without Insulin Resistance and Diabetes. Biomedicines Zhao, L., Zhou, J., Abbasi, F., Fathzadeh, M., Knowles, J. W., Leung, L. L., Morser, J. 2024; 12 (4)

  Abstract

  Chemerin is a chemokine/adipokine, regulating inflammation, adipogenesis and energy metabolism whose activity depends on successive proteolytic cleavages at its C-terminus. Chemerin levels and processing are correlated with insulin resistance. We hypothesized that chemerin processing would be higher in individuals with type 2 diabetes (T2D) and in those who are insulin resistant (IR). This hypothesis was tested by characterizing different chemerin forms by specific ELISA in the plasma of 18 participants with T2D and 116 without T2D who also had their insulin resistance measured by steady-state plasma glucose (SSPG) concentration during an insulin suppression test. This approach enabled us to analyze the association of chemerin levels with a direct measure of insulin resistance (SSPG concentration). Participants were divided into groups based on their degree of insulin resistance using SSPG concentration tertiles: insulin sensitive (IS, SSPG ≤ 91 mg/dL), intermediate IR (IM, SSPG 92-199 mg/dL), and IR (SSPG ≥ 200 mg/dL). Levels of different chemerin forms were highest in patients with T2D, second highest in individuals without T2D who were IR, and lowest in persons without T2D who were IM or IS. In the whole group, chemerin levels positively correlated with both degree of insulin resistance (SSPG concentration) and adiposity (BMI). Participants with T2D and those without T2D who were IR had the most proteolytic processing of chemerin, resulting in higher levels of both cleaved and degraded chemerin. This suggests that increased inflammation in individuals who have T2D or are IR causes more chemerin processing.

  View details for DOI 10.3390/biomedicines12040924

  View details for PubMedID 38672278

  View details for PubMedCentralID PMC11048116

• Development and utility of a clinical research informatics application for participant recruitment and workflow management for a return of results pilot trial in familial hypercholesterolemia in the Million Veteran Program. JAMIA open Brunette, C. A., Yi, T., Danowski, M. E., Cardellino, M., Harrison, A., Assimes, T. L., Knowles, J. W., Christensen, K. D., Sturm, A. C., Sun, Y. V., Hui, Q., Pyarajan, S., Shi, Y., Whitbourne, S. B., Gaziano, J. M., Muralidhar, S., Vassy, J. L. 2024; 7 (1): ooae020

  Abstract

  Objective: The development of clinical research informatics tools and workflow processes associated with re-engaging biobank participants has become necessary as genomic repositories increasingly consider the return of actionable research results.Materials and Methods: Here we describe the development and utility of an informatics application for participant recruitment and enrollment management for the Veterans Affairs Million Veteran Program Return Of Actionable Results Study, a randomized controlled pilot trial returning individual genetic results associated with familial hypercholesterolemia.Results: The application is developed in Python-Flask and was placed into production in November 2021. The application includes modules for chart review, medication reconciliation, participant contact and biospecimen logging, survey recording, randomization, and documentation of genetic counseling and result disclosure. Three primary users, a genetic counselor and two research coordinators, and 326 Veteran participants have been integrated into the system as of February 23, 2023. The application has successfully handled 3367 task requests involving greater than 95000 structured data points. Specifically, application users have recorded 326 chart reviews, 867 recruitment telephone calls, 158 telephone-based surveys, and 61 return of results genetic counseling sessions, among other available study tasks.Conclusion: The development of usable, customizable, and secure informatics tools will become increasingly important as large genomic repositories begin to return research results at scale. Our work provides a proof-of-concept for developing and using such tools to aid in managing the return of results process within a national biobank.

  View details for DOI 10.1093/jamiaopen/ooae020

  View details for PubMedID 38464744

• Is it time for a paradigm shift? Inclusion of APOE on genetic dyslipidemia panels. Journal of genetic counseling Ison, H. E., Mowaswes, M., Durst, R., Leucker, T., Knowles, J. W., Brown, E. E. 2024

  Abstract

  APOE codes for apolipoprotein E (ApoE), which plays an important role in lipid and lipoprotein metabolism and homeostasis of tissue lipid content. Several variants in APOE have been associated with inherited dyslipidemias, and a subsequent increased risk of developing premature coronary artery disease (CAD). However, these variants and their impact on risk can be thought of on a spectrum, with some being more monogenic in nature, and others contributing in a polygenic/multifactorial manner. Despite these known associations, there is often hesitancy around ordering APOE genetic testing due to the association with Alzheimer's disease. This paper aims to catalyze discussion around APOE testing and counseling strategies, highlight the nuances around this topic, and advocate for inclusion of APOE testing on dyslipidemia panels when an inherited dyslipidemia is suspected.

  View details for DOI 10.1002/jgc4.1889

  View details for PubMedID 38549201

• Lac-Phe mediates the effects of metformin on food intake and body weight. Nature metabolism Xiao, S., Li, V. L., Lyu, X., Chen, X., Wei, W., Abbasi, F., Knowles, J. W., Tung, A. S., Deng, S., Tiwari, G., Shi, X., Zheng, S., Farrell, L., Chen, Z. Z., Taylor, K. D., Guo, X., Goodarzi, M. O., Wood, A. C., Chen, Y. I., Lange, L. A., Rich, S. S., Rotter, J. I., Clish, C. B., Tahir, U. A., Gerszten, R. E., Benson, M. D., Long, J. Z. 2024

  Abstract

  Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. There is ongoing debate about the mechanisms that mediate metformin's effects on energy balance. Here, we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite N-lactoyl-phenylalanine (Lac-Phe) in cells, in mice and two independent human cohorts. Metformin drives Lac-Phe biosynthesis through the inhibition of complex I, increased glycolytic flux and intracellular lactate mass action. Intestinal epithelial CNDP2+ cells, not macrophages, are the principal in vivo source of basal and metformin-inducible Lac-Phe. Genetic ablation of Lac-Phe biosynthesis in male mice renders animals resistant to the effects of metformin on food intake and body weight. Lastly, mediation analyses support a role for Lac-Phe as a downstream effector of metformin's effects on body mass index in participants of a large population-based observational cohort, the Multi-Ethnic Study of Atherosclerosis. Together, these data establish Lac-Phe as a critical mediator of the body weight-lowering effects of metformin.

  View details for DOI 10.1038/s42255-024-00999-9

  View details for PubMedID 38499766

  View details for PubMedCentralID 6829283

• Generation of two induced pluripotent stem cell lines from healthy patients of African American ancestry. Stem cell research Mullen, M., Kojic, A., Alamana, C., Canel, G., Lai, C., Knowles, J. W., Wu, J. C. 2024; 76: 103322

  Abstract

  Stem cells are a resourceful tool for investigating cardiovascular disease in the context of race and gender. Once derived from blood or skin cells, the reprogrammed induced pluripotent stem cells (iPSCs) adopt an embryonic-like pluripotent state, enabling researchers to develop drug screening or disease modeling platforms. Here, we generated two iPSC lines from peripheral blood mononuclear cells (PBMCs) of two healthy African American patients. Both lines display the usual morphology of pluripotent stem cells, demonstrate elevated expression of pluripotent markers, show normal karyotype, and differentiate into all three germ layers in vitro.

  View details for DOI 10.1016/j.scr.2024.103322

  View details for PubMedID 38359472

• A functional genomic framework to elucidate novel causal non-alcoholic fatty liver disease genes. medRxiv : the preprint server for health sciences Saliba-Gustafsson, P., Justesen, J. M., Ranta, A., Sharma, D., Bielczyk-Maczynska, E., Li, J., Najmi, L. A., Apodaka, M., Aspichueta, P., Björck, H. M., Eriksson, P., Franco-Cereceda, A., Gloudemans, M., Mujica, E., den Hoed, M., Assimes, T. L., Quertermous, T., Carcamo-Orive, I., Park, C. Y., Knowles, J. W. 2024

  Abstract

  Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for NAFLD have been hampered by the relative paucity of human data from gold-standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using NAFLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined GWAS of NAFLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for NAFLD.We used the UK Biobank to explore the associations of our novel NAFLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study NAFLD genes in vitro using CRISPRi. Our data identify VKORC1, TNKS, LYPLAL1 and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of NAFLD.Complementary genetic and genomic approaches are useful for the identification of NAFLD genes. Our data supports VKORC1 as a bona fide NAFLD gene. We have established a functional genomic framework to study at scale putative novel NAFLD genes from human genetic association studies.

  View details for DOI 10.1101/2024.02.03.24302258

  View details for PubMedID 38352379

  View details for PubMedCentralID PMC10863038

• Trends of Lipid Concentrations, Awareness, Evaluation, and Treatment in Severe Dyslipidemia in US Adults. Mayo Clinic proceedings Shetty, N. S., Gaonkar, M., Patel, N., Knowles, J. W., Natarajan, P., Arora, G., Arora, P. 2024

  Abstract

  To evaluate the contemporary trends of lipid concentrations, cholesterol evaluation, hypercholesterolemia awareness, and statin use among individuals with severe dyslipidemia (low-density lipoprotein cholesterol [LDL-C] level ≥190 mg/dL) between 2011 and 2020.This serial cross-sectional analysis included nonpregnant adults ≥20 years of age from the National Health and Nutrition Examination Survey between 2011 and 2020. Age-adjusted weighted trends of LDL-C, triglycerides, cholesterol evaluation in the past 5 years, hypercholesterolemia awareness, and documented statin use among individuals with severe dyslipidemia were estimated.Among 24,722 participants included, the prevalence of severe dyslipidemia was 5.4% (SE: 0.2%) which was stable across the study period (Ptrend=.78). Among individuals with severe dyslipidemia (mean age: 55.3 [SE: 0.7] years; 52.2% females; 68.8% non-Hispanic White), LDL-C (224.3 [SE: 4.2] mg/dL in 2011-2012 to 224.2 [SE: 4.6] mg/dL in 2017-2020; Ptrend =.83), and triglyceride (123.3 [SE: 1.1] mg/dL in 2011-2012 to 101.8 [SE: 1.1] mg/dL in 2017-2020; Ptrend=.13), levels remained stable from 2011 to 2020. The rates of cholesterol evaluation in the past 5 years (72.0% [SE: 5.7%] in 2011-2012 to 78.0% [SE: 4.8%] in 2017-2020; Ptrend=.91), hypercholesterolemia awareness (48.1% [SE: 5.5%] in 2011-2012 to 51.9% [SE: 5.8%] in 2017- 2020; Ptrend=.77), and documented statin use (34.7% [SE: 4.5%] in 2011-2012 to 33.4% [SE: 4.0%] in 2017-2020; Ptrend=.28) remained stagnant in individuals with severe dyslipidemia between 2011 and 2020.Among individuals with severe dyslipidemia, cholesterol evaluation and hypercholesterolemia awareness rates were stable at ∼75% and ∼50% in the past decade. Only ∼34% of individuals with severe dyslipidemia took statins between 2011 and 2020, which likely contributed to the stable LDL-C levels noted across the study period. Further investigations into the determinants of statin use and adherence to statins are needed.

  View details for DOI 10.1016/j.mayocp.2023.09.016

  View details for PubMedID 38189687

• Impact of Virtual Interviewing on Cardiovascular Fellowship Applicant Diversity: Insights From 2 Academic Programs. Journal of the American Heart Association Witting, C., Knowles, J. W., DeFaria Yeh, D., Beyene, T. J., Gummipundi, S. E., Heidenreich, P. A., Yong, C. M. 2023: e030255

  View details for DOI 10.1161/JAHA.123.030255

  View details for PubMedID 38156448

• RNA Interference Therapy Targeting Apolipoprotein C-III in Hypertriglyceridemia. NEJM evidence Gaudet, D., Clifton, P., Sullivan, D., Baker, J., Schwabe, C., Thackwray, S., Scott, R., Hamilton, J., Given, B., Melquist, S., Zhou, R., Chang, T., San Martin, J., Watts, G. F., Goldberg, I. J., Knowles, J. W., Hegele, R. A., Ballantyne, C. M. 2023; 2 (12): EVIDoa2200325

  Abstract

  APOC3-Targeting RNAi for HypertriglyceridemiaThis randomized controlled trial examined the safety and side effects of the small interfering RNA ARO-APOC3 in healthy volunteers and patients with hypertriglyceridemia and chylomicronemia. ARO-APOC3 was associated with few adverse events and no dose-limiting toxicities.

  View details for DOI 10.1056/EVIDoa2200325

  View details for PubMedID 38320498

• USPSTF Recommendation on Screening for Lipid Disorders in Children and Adolescents. JAMA Wilemon, K., Knowles, J. W., Baum, S. J. 2023; 330 (20): 2024

  View details for DOI 10.1001/jama.2023.20446

  View details for PubMedID 38015224

• Lac-Phe mediates the anti-obesity effect of metformin. bioRxiv : the preprint server for biology Xiao, S., Li, V. L., Lyu, X., Chen, X., Wei, W., Abbasi, F., Knowles, J. W., Deng, S., Tiwari, G., Shi, X., Zheng, S., Farrell, L., Chen, Z. Z., Taylor, K. D., Guo, X., Goodarzi, M. O., Wood, A. C., Ida Chen, Y. D., Lange, L. A., Rich, S. S., Rotter, J. I., Clish, C. B., Tahir, U. A., Gerszten, R. E., Benson, M. D., Long, J. Z. 2023

  Abstract

  Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. The mechanisms that mediate metformin's effects on energy balance remain incompletely defined. Here we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite Lac-Phe in mice as well as in two independent human cohorts. In cell culture, metformin drives Lac-Phe biosynthesis via inhibition of complex I, increased glycolytic flux, and intracellular lactate mass action. Other biguanides and structurally distinct inhibitors of oxidative phosphorylation also increase Lac-Phe levels in vitro. Genetic ablation of CNDP2, the principal biosynthetic enzyme for Lac-Phe, in mice renders animals resistant to metformin's anorexigenic and anti-obesity effects. Mediation analyses also support a role for Lac-Phe in metformin's effect on body mass index in humans. These data establish the CNDP2/Lac-Phe pathway as a critical mediator of the effects of metformin on energy balance.

  View details for DOI 10.1101/2023.11.02.565321

  View details for PubMedID 37961394

  View details for PubMedCentralID PMC10635077

• Another Use for Polygenic Risk Scores: Improving Risk Prediction for Heterozygous Familial Hypercholesterolemia. JACC. Advances Palmisano, B. T., Knowles, J. W. 2023; 2 (9): 100663

  View details for DOI 10.1016/j.jacadv.2023.100663

  View details for PubMedID 38938727

  View details for PubMedCentralID PMC11198439

• Principles for Health Information Collection, Sharing, and Use: A Policy Statement From the American Heart Association CIRCULATION Spector-Bagdady, K., Armoundas, A. A., Arnaout, R., Hall, J. L., McSwain, B., Knowles, J. W., Price, W., Rawat, D. B., Riegel, B., Wang, T. Y., Wiley, K., Chung, M. K., Amer Heart Assoc Advocacy Coor 2023; 148 (13): 1061-1069

  Abstract

  The evolution of the electronic health record, combined with advances in data curation and analytic technologies, increasingly enables data sharing and harmonization. Advances in the analysis of health-related and health-proxy information have already accelerated research discoveries and improved patient care. This American Heart Association policy statement discusses how broad data sharing can be an enabling driver of progress by providing data to develop, test, and benchmark innovative methods, scalable insights, and potential new paradigms for data storage and workflow. Along with these advances come concerns about the sensitive nature of some health data, equity considerations about the involvement of historically excluded communities, and the complex intersection of laws attempting to govern behavior. Data-sharing principles are therefore necessary across a wide swath of entities, including parties who collect health information, funders, researchers, patients, legislatures, commercial companies, and regulatory departments and agencies. This policy statement outlines some of the key equity and legal background relevant to health data sharing and responsible management. It then articulates principles that will guide the American Heart Association's engagement in public policy related to data collection, sharing, and use to continue to inform its work across the research enterprise, as well as specific examples of how these principles might be applied in the policy landscape. The goal of these principles is to improve policy to support the use or reuse of health information in ways that are respectful of patients and research participants, equitable in impact in terms of both risks and potential benefits, and beneficial across broad and demographically diverse communities in the United States.

  View details for DOI 10.1161/CIR.0000000000001173

  View details for Web of Science ID 001072138200013

  View details for PubMedID 37646159

• RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts. Nature medicine Watts, G. F., Schwabe, C., Scott, R., Gladding, P. A., Sullivan, D., Baker, J., Clifton, P., Hamilton, J., Given, B., Melquist, S., Zhou, R., Chang, T., San Martin, J., Gaudet, D., Goldberg, I. J., Knowles, J. W., Hegele, R. A., Ballantyne, C. M. 2023

  Abstract

  Elevated triglycerides and non-high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an RNA interference therapy that targets angiopoietin-like protein 3 (ANGPTL3), a regulator of lipoprotein metabolism. This first-in-human, phase 1, randomized, placebo-controlled, open-label trial investigated single and repeat ARO-ANG3 doses in four cohorts of fifty-two healthy participants and one cohort of nine participants with hepatic steatosis, part of a basket trial. Safety (primary objective) and pharmacokinetics (in healthy participants) and pharmacodynamics (secondary objectives) of ARO-ANG3 were evaluated. ARO-ANG3 was generally well tolerated, with similar frequencies of treatment-emergent adverse events in active and placebo groups. Systemic absorption of ARO-ANG3 in healthy participants was rapid and sustained, with a mean Tmax of 6.0-10.5h and clearance from plasma within 24-48h after dosing with a mean t of 3.9-6.6h. In healthy participants, ARO-ANG3 treatment reduced ANGPTL3 (mean -45% to -78%) 85days after dose. Reductions in triglyceride (median -34% to -54%) and non-HDL-C (mean -18% to -29%) (exploratory endpoints) concentrations occurred with the three highest doses. These early-phase data support ANGPTL3 as a potential therapeutic target for ASCVD treatment. ClinicalTrials.gov identifier: NCT03747224.

  View details for DOI 10.1038/s41591-023-02494-2

  View details for PubMedID 37626170

• ARO-ANG3, AN INVESTIGATIONAL RNAI THERAPEUTIC, DECREASES SERUM LDL-CHOLESTEROL, APOLIPOPROTEIN B, AND ANGIOPOIETIN-LIKE PROTEIN 3 IN PATIENTS WITH HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLAEMIA Raal, F., Bergeron, J., Watts, G., Gaudet, D., Sullivan, D., Turner, T., Hegele, R., Ballantyne, C., Knowles, J., Goldberg, I., Fu, R., Alagarsamy, S., Hamilton, J., Rosenson, R. ELSEVIER IRELAND LTD. 2023

  View details for Web of Science ID 001060595800210

• A single-cell CRISPRi platform for characterizing candidate genes relevant to metabolic disorders in human adipocytes. American journal of physiology. Cell physiology Bielczyk-Maczynska, E., Sharma, D., Blencowe, M., Saliba Gustafsson, P., Gloudemans, M. J., Yang, X., Carcamo-Orive, I., Wabitsch, M., Svensson, K. J., Park, C. Y., Quertermous, T., Knowles, J. W., Li, J. 2023

  Abstract

  CROP-Seq combines gene silencing using CRISPR interference with single-cell RNA sequencing. Here, we applied CROP-Seq to study adipogenesis and adipocyte biology. Human preadipocyte SGBS cell line expressing KRAB-dCas9 was transduced with a sgRNA library. Following selection, individual cells were captured using microfluidics at different timepoints during adipogenesis. Bioinformatic analysis of transcriptomic data was used to determine the knock-down effects, the dysregulated pathways, and to predict cellular phenotypes. Single-cell transcriptomes recapitulated adipogenesis states. For all targets, over 400 differentially expressed genes were identified at least at one timepoint. As a validation of our approach, the knock-down of PPARG and CEBPB (which encode key proadipogenic transcription factors) resulted in the inhibition of adipogenesis. Gene set enrichment analysis generated hypotheses regarding the molecular function of novel genes. MAFF knock-down led to downregulation of transcriptional response to proinflammatory cytokine TNF-α in preadipocytes and to decreased CXCL-16 and IL-6 secretion. TIPARP knock-down resulted in increased expression of adipogenesis markers. In summary, this powerful, hypothesis-free tool can identify novel regulators of adipogenesis, preadipocyte and adipocyte function associated with metabolic disease.

  View details for DOI 10.1152/ajpcell.00148.2023

  View details for PubMedID 37486064

• Plasma proteomic signatures of a direct measure of insulin sensitivity in two population cohorts. Diabetologia Zanetti, D., Stell, L., Gustafsson, S., Abbasi, F., Tsao, P. S., Knowles, J. W., Zethelius, B., Ärnlöv, J., Balkau, B., Walker, M., Lazzeroni, L. C., Lind, L., Petrie, J. R., Assimes, T. L. 2023

  Abstract

  The euglycaemic-hyperinsulinaemic clamp (EIC) is the reference standard for the measurement of whole-body insulin sensitivity but is laborious and expensive to perform. We aimed to assess the incremental value of high-throughput plasma proteomic profiling in developing signatures correlating with the M value derived from the EIC.We measured 828 proteins in the fasting plasma of 966 participants from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study and 745 participants from the Uppsala Longitudinal Study of Adult Men (ULSAM) using a high-throughput proximity extension assay. We used the least absolute shrinkage and selection operator (LASSO) approach using clinical variables and protein measures as features. Models were tested within and across cohorts. Our primary model performance metric was the proportion of the M value variance explained (R2).A standard LASSO model incorporating 53 proteins in addition to routinely available clinical variables increased the M value R2 from 0.237 (95% CI 0.178, 0.303) to 0.456 (0.372, 0.536) in RISC. A similar pattern was observed in ULSAM, in which the M value R2 increased from 0.443 (0.360, 0.530) to 0.632 (0.569, 0.698) with the addition of 61 proteins. Models trained in one cohort and tested in the other also demonstrated significant improvements in R2 despite differences in baseline cohort characteristics and clamp methodology (RISC to ULSAM: 0.491 [0.433, 0.539] for 51 proteins; ULSAM to RISC: 0.369 [0.331, 0.416] for 67 proteins). A randomised LASSO and stability selection algorithm selected only two proteins per cohort (three unique proteins), which improved R2 but to a lesser degree than in standard LASSO models: 0.352 (0.266, 0.439) in RISC and 0.495 (0.404, 0.585) in ULSAM. Reductions in improvements of R2 with randomised LASSO and stability selection were less marked in cross-cohort analyses (RISC to ULSAM R2 0.444 [0.391, 0.497]; ULSAM to RISC R2 0.348 [0.300, 0.396]). Models of proteins alone were as effective as models that included both clinical variables and proteins using either standard or randomised LASSO. The single most consistently selected protein across all analyses and models was IGF-binding protein 2.A plasma proteomic signature identified using a standard LASSO approach improves the cross-sectional estimation of the M value over routine clinical variables. However, a small subset of these proteins identified using a stability selection algorithm affords much of this improvement, especially when considering cross-cohort analyses. Our approach provides opportunities to improve the identification of insulin-resistant individuals at risk of insulin resistance-related adverse health consequences.

  View details for DOI 10.1007/s00125-023-05946-z

  View details for PubMedID 37329449

  View details for PubMedCentralID 5866840

• Single-cell transcriptome dataset of human and mouse in vitro adipogenesis models. Scientific data Li, J., Jin, C., Gustafsson, S., Rao, A., Wabitsch, M., Park, C. Y., Quertermous, T., Knowles, J. W., Bielczyk-Maczynska, E. 2023; 10 (1): 387

  Abstract

  Adipogenesis is a process in which fat-specific progenitor cells (preadipocytes) differentiate into adipocytes that carry out the key metabolic functions of the adipose tissue, including glucose uptake, energy storage, and adipokine secretion. Several cell lines are routinely used to study the molecular regulation of adipogenesis, in particular the immortalized mouse 3T3-L1 line and the primary human Simpson-Golabi-Behmel syndrome (SGBS) line. However, the cell-to-cell variability of transcriptional changes prior to and during adipogenesis in these models is not well understood. Here, we present a single-cell RNA-Sequencing (scRNA-Seq) dataset collected before and during adipogenic differentiation of 3T3-L1 and SGBS cells. To minimize the effects of experimental variation, we mixed 3T3-L1 and SGBS cells and used computational analysis to demultiplex transcriptomes of mouse and human cells. In both models, adipogenesis results in the appearance of three cell clusters, corresponding to preadipocytes, early and mature adipocytes. These data provide a groundwork for comparative studies on these widely used in vitro models of human and mouse adipogenesis, and on cell-to-cell variability during this process.

  View details for DOI 10.1038/s41597-023-02293-x

  View details for PubMedID 37328521

  View details for PubMedCentralID 2597101

• Contemporary Homozygous Familial Hypercholesterolemia in the United States: Insights From the CASCADE FH Registry. Journal of the American Heart Association Cuchel, M., Lee, P. C., Hudgins, L. C., Duell, P. B., Ahmad, Z., Baum, S. J., Linton, M. F., de Ferranti, S. D., Ballantyne, C. M., Larry, J. A., Hemphill, L. C., Kindt, I., Gidding, S. S., Martin, S. S., Moriarty, P. M., Thompson, P. P., Underberg, J. A., Guyton, J. R., Andersen, R. L., Whellan, D. J., Benuck, I., Kane, J. P., Myers, K., Howard, W., Staszak, D., Jamison, A., Card, M. C., Bourbon, M., Chora, J. R., Rader, D. J., Knowles, J. W., Wilemon, K., McGowan, M. P. 2023: e029175

  Abstract

  Background Homozygous familial hypercholesterolemia (HoFH) is a rare, treatment-resistant disorder characterized by early-onset atherosclerotic and aortic valvular cardiovascular disease if left untreated. Contemporary information on HoFH in the United States is lacking, and the extent of underdiagnosis and undertreatment is uncertain. Methods and Results Data were analyzed from 67 children and adults with clinically diagnosed HoFH from the CASCADE (Cascade Screening for Awareness and Detection) FH Registry. Genetic diagnosis was confirmed in 43 patients. We used the clinical characteristics of genetically confirmed patients with HoFH to query the Family Heart Database, a US anonymized payer health database, to estimate the number of patients with similar lipid profiles in a "real-world" setting. Untreated low-density lipoprotein cholesterol levels were lower in adults than children (533 versus 776mg/dL; P=0.001). At enrollment, atherosclerotic cardiovascular disease and supravalvular and aortic valve stenosis were present in 78.4% and 43.8% and 25.5% and 18.8% of adults and children, respectively. At most recent follow-up, despite multiple lipid-lowering treatment, low-density lipoprotein cholesterol goals were achieved in only a minority of adults and children. Query of the Family Heart Database identified 277 individuals with profiles similar to patients with genetically confirmed HoFH. Advanced lipid-lowering treatments were prescribed for 18%; 40% were on no lipid-lowering treatment; atherosclerotic cardiovascular disease was reported in 20%; familial hypercholesterolemia diagnosis was uncommon. Conclusions Only patients with the most severe HoFH phenotypes are diagnosed early. HoFH remains challenging to treat. Results from the Family Heart Database indicate HoFH is systemically underdiagnosed and undertreated. Earlier screening, aggressive lipid-lowering treatments, and guideline implementation are required to reduce disease burden in HoFH.

  View details for DOI 10.1161/JAHA.122.029175

  View details for PubMedID 37119068

• Single-cell transcriptome dataset of human and mouse in vitro adipogenesis models. bioRxiv : the preprint server for biology Li, J., Jin, C., Gustafsson, S., Rao, A., Wabitsch, M., Park, C. Y., Quertermous, T., Bielczyk-Maczynska, E., Knowles, J. W. 2023

  Abstract

  Adipogenesis is a process in which fat-specific progenitor cells (preadipocytes) differentiate into adipocytes that carry out the key metabolic functions of the adipose tissue, including glucose uptake, energy storage, and adipokine secretion. Several cell lines are routinely used to study the molecular regulation of adipogenesis, in particular the immortalized mouse 3T3-L1 line and the primary human Simpson-Golabi-Behmel syndrome (SGBS) line. However, the cell-to-cell variability of transcriptional changes prior to and during adipogenesis in these models is not well understood. Here, we present a single-cell RNA-Sequencing (scRNA-Seq) dataset collected before and during adipogenic differentiation of 3T3-L1 and SGBS cells. To minimize the effects of experimental variation, we mixed 3T3-L1 and SGBS cells and used computational analysis to demultiplex transcriptomes of mouse and human cells. In both models, adipogenesis results in the appearance of three cell clusters, corresponding to preadipocytes, early and mature adipocytes. These data provide a groundwork for comparative studies on human and mouse adipogenesis, as well as on cell-to-cell variability in gene expression during this process.

  View details for DOI 10.1101/2023.03.27.534456

  View details for PubMedID 37034809

  View details for PubMedCentralID PMC10081256

• The relationship between insulin resistance and ion mobility lipoprotein fractions. American journal of preventive cardiology Rowland, C. M., Abbasi, F., Shiffman, D., Knowles, J. W., McPhaul, M. J. 2023; 13: 100457

  Abstract

  Objective: Insulin resistance (IR) increases risk of type 2 diabetes and atherosclerotic cardiovascular disease and is associated with lipid and lipoprotein abnormalities including high triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C). Lipoprotein size and lipoprotein subfractions (LS) have also been used to assist in identifying persons with IR. Associations of LS and IR have not been validated using both direct measures of IR and direct measures of LS. We assessed the usefulness of fasting lipoprotein subfractions (LS) by ion mobility to identify individuals with IR.Methods: Lipid panel, LS by ion mobility (LS-IM), and IR by steady-state plasma glucose (SSPG) concentration were assessed in 526 adult volunteers without diabetes. IR was defined as being in the highest tertile of SSPG concentration. LS-IM score was calculated by linear combination of regression coefficients from a stepwise regression analysis with SSPG concentration as the dependent variable. Improvement in prediction of IR was evaluated after combining LS-IM score with TG/HDL-C, TG/HDL-C and BMI as well as with TG/HDL-C, BMI, sex, race and ethnicity. IR prediction was evaluated by area under the receiver operating characteristic curve (AUC) and positive predictive value (PPV) considering the highest 5% of scores as positive test.Results: Prediction of IR was similar by LS-IM score and TG/HDL-C (AUC=0.68; PPV=0.59 and AUC=0.70; PPV=0.59, respectively) and prediction was improved when LS-IM was combined with TG/HDL-C (AUC=0.73; PPV=0.70), TG/HDL-C and BMI (AUC=0.82; PPV=0.81) and with TG/HDL-C, BMI, sex, race and ethnicity (AUC=0.84; PPV=0.89).Conclusion: For identifying individuals with IR, LS-IM score and TG/HDL-C are comparable and their combination further improves IR prediction by TG/HDL-C alone. Among patients who have undergone IM testing, the LS-IM score may assist prioritization of subjects for further evaluation and interventions to reduce IR.

  View details for DOI 10.1016/j.ajpc.2022.100457

  View details for PubMedID 36619297

• G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis. Nature communications Bielczyk-Maczynska, E., Zhao, M., Zushin, P. H., Schnurr, T. M., Kim, H. J., Li, J., Nallagatla, P., Sangwung, P., Park, C. Y., Cornn, C., Stahl, A., Svensson, K. J., Knowles, J. W. 2022; 13 (1): 7408

  Abstract

  Human genetics has been instrumental in identification of genetic variants linked to type 2 diabetes. Recently a rare, putative loss-of-function mutation in the orphan G-protein coupled receptor 151 (GPR151) was found to be associated with lower odds ratio for type 2 diabetes, but the mechanism behind this association has remained elusive. Here we show that Gpr151 is a fasting- and glucagon-responsive hepatic gene which regulates hepatic gluconeogenesis. Gpr151 ablation in mice leads to suppression of hepatic gluconeogenesis genes and reduced hepatic glucose production in response to pyruvate. Importantly, the restoration of hepatic Gpr151 levels in the Gpr151 knockout mice reverses the reduced hepatic glucose production. In this work, we establish a previously unknown role of Gpr151 in the liver that provides an explanation to the lowered type 2 diabetes risk in individuals with nonsynonymous mutations in GPR151.

  View details for DOI 10.1038/s41467-022-35069-9

  View details for PubMedID 36456565

  View details for PubMedCentralID 508922

• Analysis of Transcriptional Variability in a Large Human iPSC Library Reveals Genetic and Non-genetic Determinants of Heterogeneity (vol 20, pg 518, 2017) CELL STEM CELL Carcamo-Orive, I., Hoffman, G. E., Cundiff, P., Beckmann, N. D., D'Souza, S. L., Knowles, J. W., Patel, A., Hendry, C., Papatsenko, D., Abbasi, F., Reaven, G. M., Whalen, S., Lee, P., Shahbazi, M., Henrion, M. R., Zhu Kuixi, Wang, S., Roussos, P., Schadt, E. E., Pandey, G., Chang Rui, Quertermous, T., Lemischka, I. 2022; 29 (10): 1505

  View details for DOI 10.1016/j.stem.2022.08.011

  View details for Web of Science ID 000880132100009

  View details for PubMedID 36206733

• Chronic liver disease-related mortality in diabetes before and during the COVID-19 in the United States. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver Kim, D., Alshuwaykh, O., Dennis, B. B., Cholankeril, G., Knowles, J. W., Ahmed, A. 2022

  Abstract

  BACKGROUND: Global pandemic of COVID-19 represents an unprecedented challenge. COVID-19 has predominantly targeted vulnerable populations with pre-existing chronic medical diseases, such as diabetes and chronic liver disease.AIMS: We estimated chronic liver disease-related mortality trends among individuals with diabetes before and during the COVID-19 pandemic.METHODS: Utilizing the US national mortality database and Census, we determined the quarterly age-standardized chronic liver disease-related mortality and quarterly percentage change (QPC) among individuals with diabetes.RESULTS: The quarterly age-standardized mortality for chronic liver disease and/or cirrhosis among individuals with diabetes remained stable before the COVID-19 pandemic and sharply increased during the COIVD-19 pandemic at a QPC of 8.5%. The quarterly mortality from nonalcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD) increased markedly during the COVID-19 pandemic. Mortality for hepatitis C virus (HCV) infection declined with a quarterly rate of -3.3% before the COVID-19 pandemic and remained stable during the COVID-19 pandemic. While ALD- and HCV-related mortality was higher in men than in women, NAFLD-related mortality in women was higher than in men.CONCLUSIONS: The sharp increase in mortality for chronic liver disease and/or cirrhosis among individuals with diabetes during the COVID-19 pandemic was associated with increased mortality from NAFLD and ALD.

  View details for DOI 10.1016/j.dld.2022.09.006

  View details for PubMedID 36182570

• Analysis of Insulin Resistance Among Children and Adolescents in Slovenia With Hypercholesterolemia After Treatment With Statins. JAMA network open Groselj, U., Sikonja, J., Mlinaric, M., Kotnik, P., Battelino, T., Knowles, J. W. 2022; 5 (9): e2231097

  View details for DOI 10.1001/jamanetworkopen.2022.31097

  View details for PubMedID 36094507

• STATIN THERAPY IS NOT ASSOCIATED WITH INSULIN RESISTANCE IN CHILDREN AND ADOLESCENTS WITH FAMILIAL HYPERCHOLESTEROLAEMIA Groselj, U., Sikonja, J., Mlinaric, M., Kotnik, P., Battelino, T., Knowles, J. W. ELSEVIER IRELAND LTD. 2022: E173

  View details for Web of Science ID 000853696400488

• Creation of the American Heart Association Journals' Equity, Diversity, and Inclusion Editorial Board: The Next Step to Achieving the 2024 Impact Goal. Circulation Lewis, E. F., Beaty, C., Boltze, J., Breathett, K., Clair, W. K., de Las Fuentes, L., Essien, U. R., Goodell, H., Hinson, H. E., Kershaw, K. N., Knowles, J. W., Mazimba, S., Mujahid, M., Okafor, H. E., Woo Park, K., Schultz, J. 2022: 101161CIRCULATIONAHA122061450

  View details for DOI 10.1161/CIRCULATIONAHA.122.061450

  View details for PubMedID 35862071

• Apolipoprotein B, Residual Cardiovascular Risk After Acute Coronary Syndrome, and Effects of Alirocumab. Circulation Hagström, E., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Danchin, N., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J. W., Liberopoulos, E., Marx, N., McGinniss, J., Manvelian, G., Pordy, R., Scemama, M., White, H. D., Zeiher, A. M., Schwartz, G. G. 2022: 101161CIRCULATIONAHA121057807

  Abstract

  Apolipoprotein B (apoB) provides an integrated measure of atherogenic risk. Whether apoB levels and apoB lowering hold incremental predictive information on residual risk after acute coronary syndrome beyond that provided by low-density lipoprotein cholesterol is uncertain.The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin therapy. Primary outcome was major adverse cardiovascular events (MACEs; coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, hospitalization for unstable angina). Associations between baseline apoB or apoB at 4 months and MACEs were assessed in adjusted Cox proportional hazards and propensity score-matched models.Median follow-up was 2.8 years. In proportional hazards analysis in the placebo group, MACE incidence increased across increasing baseline apoB strata (3.2 [95% CI, 2.9-3.6], 4.0 [95% CI, 3.6-4.5], and 5.5 [95% CI, 5.0-6.1] events per 100 patient-years in strata <75, 75-<90, ≥90 mg/dL, respectively; Ptrend<0.0001) and after adjustment for low-density lipoprotein cholesterol (Ptrend=0.035). Higher baseline apoB stratum was associated with greater relative (Ptrend<0.0001) and absolute reduction in MACEs with alirocumab versus placebo. In the alirocumab group, the incidence of MACEs after month 4 decreased monotonically across decreasing achieved apoB strata (4.26 [95% CI, 3.78-4.79], 3.09 [95% CI, 2.69-3.54], and 2.41 [95% CI, 2.11-2.76] events per 100 patient-years in strata ≥50, >35-<50, and ≤35 mg/dL, respectively). Compared with propensity score-matched patients from the placebo group, treatment hazard ratios for alirocumab also decreased monotonically across achieved apoB strata. Achieved apoB was predictive of MACEs after adjustment for achieved low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol but not vice versa.In patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, MACEs increased across baseline apoB strata. Alirocumab reduced MACEs across all strata of baseline apoB, with larger absolute reductions in patients with higher baseline levels. Lower achieved apoB was associated with lower risk of MACEs, even after accounting for achieved low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol, indicating that apoB provides incremental information. Achievement of an apoB level ≤35 mg/dL may reduce lipoprotein-attributable residual risk after acute coronary syndrome.URL: https://www.gov. Unique identifier: NCT01663402.

  View details for DOI 10.1161/CIRCULATIONAHA.121.057807

  View details for PubMedID 35770629

• Generation of two iPSC lines from hypertrophic cardiomyopathy patients carrying MYBPC3 and PRKAG2 variants. Stem cell research Manhas, A., Jahng, J. W., Vera, C. D., Shenoy, S. P., Knowles, J. W., Wu, J. C. 2022; 61: 102774

  Abstract

  Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder characterized by a thick left ventricular wall and an increased risk of arrhythmias, heart failure, and sudden cardiac death. The MYBPC3 and PRAKG2 are known causal genes for HCM. Here we generated two human-induced pluripotent stem cell lines from two HCM patients carrying two heterozygous mutations in MYBPC3 (c.459delC) and PRKAG2 (c.1703C > T). Both iPSC lines expressed pluripotent markers, had a normal karyotype, and were able to differentiate into three germ layers, making them potentially valuable tools for modeling HCM in vitro and investigating the pathological mechanisms related to these two variants.

  View details for DOI 10.1016/j.scr.2022.102774

  View details for PubMedID 35413566

• Integration of genetic colocalizations with physiological and pharmacological perturbations identifies cardiometabolic disease genes. Genome medicine Gloudemans, M. J., Balliu, B., Nachun, D., Schnurr, T. M., Durrant, M. G., Ingelsson, E., Wabitsch, M., Quertermous, T., Montgomery, S. B., Knowles, J. W., Carcamo-Orive, I. 2022; 14 (1): 31

  Abstract

  BACKGROUND: Identification of causal genes for polygenic human diseases has been extremely challenging, and our understanding of how physiological and pharmacological stimuli modulate genetic risk at disease-associated loci is limited. Specifically, insulin resistance (IR), a common feature of cardiometabolic disease, including type 2 diabetes, obesity, and dyslipidemia, lacks well-powered genome-wide association studies (GWAS), and therefore, few associated loci and causal genes have been identified.METHODS: Here, we perform and integrate linkage disequilibrium (LD)-adjusted colocalization analyses across nine cardiometabolic traits (fasting insulin, fasting glucose, insulin sensitivity, insulin sensitivity index, type 2 diabetes, triglycerides, high-density lipoprotein, body mass index, and waist-hip ratio) combined with expression and splicing quantitative trait loci (eQTLs and sQTLs) from five metabolically relevant human tissues (subcutaneous and visceral adipose, skeletal muscle, liver, and pancreas). To elucidate the upstream regulators and functional mechanisms for these genes, we integrate their transcriptional responses to 21 relevant physiological and pharmacological perturbations in human adipocytes, hepatocytes, and skeletal muscle cells and map their protein-protein interactions.RESULTS: We identify 470 colocalized loci and prioritize 207 loci with a single colocalized gene. Patterns of shared colocalizations across traits and tissues highlight different potential roles for colocalized genes in cardiometabolic disease and distinguish several genes involved in pancreatic beta-cell function from others with a more direct role in skeletal muscle, liver, and adipose tissues. At the loci with a single colocalized gene, 42 of these genes were regulated by insulin and 35 by glucose in perturbation experiments, including 17 regulated by both. Other metabolic perturbations regulated the expression of 30 more genes not regulated by glucose or insulin, pointing to other potential upstream regulators of candidate causal genes.CONCLUSIONS: Our use of transcriptional responses under metabolic perturbations to contextualize genetic associations from our custom colocalization approach provides a list of likely causal genes and their upstream regulators in the context of IR-associated cardiometabolic risk.

  View details for DOI 10.1186/s13073-022-01036-8

  View details for PubMedID 35292083

• Integration of genetic colocalizations with physiological and pharmacological perturbations identifies cardiometabolic disease genes Gloudemans, M. J., Balliu, B., Nachun, D., Durrant, M. G., Ingelsson, E., Wabitsch, M., Quertermous, T., Montgomery, S. B., Knowles, J., Carcamo-Orive, I. W B SAUNDERS CO-ELSEVIER INC. 2022: S24-S25

  View details for DOI 10.1016/j.metabol.2021.155025

  View details for Web of Science ID 000778891500062

• A guide for the diagnosis of rare and undiagnosed disease: beyond the exome. Genome medicine Marwaha, S., Knowles, J. W., Ashley, E. A. 2022; 14 (1): 23

  Abstract

  Rare diseases affect 30 million people in the USA and more than 300-400 million worldwide, often causing chronic illness, disability, and premature death. Traditional diagnostic techniques rely heavily on heuristic approaches, coupling clinical experience from prior rare disease presentations with the medical literature. A large number of rare disease patients remain undiagnosed for years and many even die without an accurate diagnosis. In recent years, gene panels, microarrays, and exome sequencing have helped to identify the molecular cause of such rare and undiagnosed diseases. These technologies have allowed diagnoses for a sizable proportion (25-35%) of undiagnosed patients, often with actionable findings. However, a large proportion of these patients remain undiagnosed. In this review, we focus on technologies that can be adopted if exome sequencing is unrevealing. We discuss the benefits of sequencing the whole genome and the additional benefit that may be offered by long-read technology, pan-genome reference, transcriptomics, metabolomics, proteomics, and methyl profiling. We highlight computational methods to help identify regionally distant patients with similar phenotypes or similar genetic mutations. Finally, we describe approaches to automate and accelerate genomic analysis. The strategies discussed here are intended to serve as a guide for clinicians and researchers in the next steps when encountering patients with non-diagnostic exomes.

  View details for DOI 10.1186/s13073-022-01026-w

  View details for PubMedID 35220969

• Online Patient Education Materials Related to Lipoprotein(a): Readability Assessment. Journal of medical Internet research Pearson, K., Ngo, S., Ekpo, E., Sarraju, A., Baird, G., Knowles, J., Rodriguez, F. 1800; 24 (1): e31284

  Abstract

  BACKGROUND: Lipoprotein(a) (Lp(a)) is a highly proatherogenic lipid fraction that is a clinically significant risk modifier. Patients wanting to learn more about Lp(a) are likely to use online patient educational materials (OPEMs). However, the readability of OPEMs may exceed the health literacy of the public.OBJECTIVE: This study aims to assess the readability of OPEMs related to Lp(a). We hypothesized that the readability of these online materials would exceed the sixth grade level recommended by the American Medical Association.METHODS: Using an online search engine, we queried the top 20 search results from 10 commonly used Lp(a)-related search terms to identify a total of 200 websites. We excluded duplicate websites, advertised results, research journal articles, or non-patient-directed materials, such as those intended only for health professionals or researchers. Grade level readability was calculated using 5 standard readability metrics (automated readability index, SMOG index, Coleman-Liau index, Gunning Fog score, Flesch-Kincaid score) to produce robust point (mean) and interval (CI) estimates of readability. Generalized estimating equations were used to model grade level readability by each search term, with the 5 readability scores nested within each OPEM.RESULTS: A total of 27 unique websites were identified for analysis. The average readability score for the aggregated results was a 12.2 (95% CI 10.9798-13.3978) grade level. OPEMs were grouped into 6 categories by primary source: industry, lay press, research foundation and nonprofit organizations, university or government, clinic, and other. The most readable category was OPEMs published by universities or government agencies (9.0, 95% CI 6.8-11.3). The least readable OPEMs on average were the ones published by the lay press (13.0, 95% CI 11.2-14.8). All categories exceeded the sixth grade reading level recommended by the American Medical Association.CONCLUSIONS: Lack of access to readable OPEMs may disproportionately affect patients with low health literacy. Ensuring that online content is understandable by broad audiences is a necessary component of increasing the impact of novel therapeutics and recommendations regarding Lp(a).

  View details for DOI 10.2196/31284

  View details for PubMedID 35014955

• G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis Nature Communications Bielczyk-Maczynska, E., Zhao, M., Zushin, P. H., Schnurr, T. M., Kim, H., Li, J., Sangwung, P., Nallagatla, P., Park, C., Cornn, C., Stahl, A., Svensson, K. J., Knowles, J. W. 2022

  View details for DOI 10.1038/s41467-022-35069-9

• Interactions of physical activity, muscular fitness, adiposity, and genetic risk for NAFLD. Hepatology communications Schnurr, T. M., Katz, S. F., Justesen, J. M., O'Sullivan, J. W., Saliba-Gustafsson, P., Assimes, T. L., Carcamo-Orive, I., Ahmed, A., Ashley, E. A., Hansen, T., Knowles, J. W. 2022

  Abstract

  Genetic predisposition and unhealthy lifestyle are risk factors for nonalcoholic fatty liver disease (NAFLD). We investigated whether the genetic risk of NAFLD is modified by physical activity, muscular fitness, and/or adiposity. In up to 242,524 UK Biobank participants without excessive alcohol intake or known liver disease, we examined cross-sectional interactions and joint associations of physical activity, muscular fitness, body mass index (BMI), and a genetic risk score (GRS) with alanine aminotransferase (ALT) levels and the proxy definition for suspected NAFLD of ALT levels > 30 U/L in women and >40 U/L in men. Genetic predisposition to NAFLD was quantified using a GRS consisting of 68 loci known to be associated with chronically elevated ALT. Physical activity was assessed using accelerometry, and muscular fitness was estimated by measuring handgrip strength. We found that increased physical activity and grip strength modestly attenuate genetic predisposition to elevation in ALT levels, whereas higher BMI markedly amplifies it (all p values < 0.001). Among those with normal weight and high level of physical activity, the odds of suspected NAFLD were 1.6-fold higher in those with high versus low genetic risk (reference group). In those with high genetic risk, the odds of suspected NAFLD were 12-fold higher in obese participants with low physical activity versus those with normal weight and high physical activity (odds ratio for NAFLD = 19.2 and 1.6, respectively, vs. reference group). Conclusion: In individuals with high genetic predisposition for NAFLD, maintaining a normal body weight and increased physical activity may reduce the risk of NAFLD.

  View details for DOI 10.1002/hep4.1932

  View details for PubMedID 35293152

• Ultrarapid Nanopore Genome Sequencing in a Critical Care Setting. The New England journal of medicine Gorzynski, J. E., Goenka, S. D., Shafin, K., Jensen, T. D., Fisk, D. G., Grove, M. E., Spiteri, E., Pesout, T., Monlong, J., Baid, G., Bernstein, J. A., Ceresnak, S., Chang, P. C., Christle, J. W., Chubb, H., Dalton, K. P., Dunn, K., Garalde, D. R., Guillory, J., Knowles, J. W., Kolesnikov, A., Ma, M., Moscarello, T., Nattestad, M., Perez, M., Ruzhnikov, M. R., Samadi, M., Setia, A., Wright, C., Wusthoff, C. J., Xiong, K., Zhu, T., Jain, M., Sedlazeck, F. J., Carroll, A., Paten, B., Ashley, E. A. 2022

  View details for DOI 10.1056/NEJMc2112090

  View details for PubMedID 35020984

• Coronary Artery Disease Risk of Familial Hypercholesterolemia Genetic Variants Independent of Clinically Observed Longitudinal Cholesterol Exposure. Circulation. Genomic and precision medicine Clarke, S. L., Tcheandjieu, C., Hilliard, A. T., Lee, M., Lynch, J., Chang, K. M., Miller, D., Knowles, J. W., O'Donnell, C., Tsao, P., Rader, D. J., Wilson, P. W., Sun, Y. V., Gaziano, M., Assimes, T. L. 2022: CIRCGEN121003501

  Abstract

  Familial hypercholesterolemia (FH) genetic variants confer risk for coronary artery disease independent of LDL-C (low-density lipoprotein cholesterol) when considering a single measurement. In real clinical settings, longitudinal LDL-C data are often available through the electronic health record. It is unknown whether genetic testing for FH variants provides additional risk-stratifying information once longitudinal LDL-C is considered.We used the extensive electronic health record data available through the Million Veteran Program to conduct a nested case-control study. The primary outcome was coronary artery disease, derived from electronic health record codes for acute myocardial infarction and coronary revascularization. Incidence density sampling was used to match case/control exposure windows, defined by the date of the first LDL-C measurement to the date of the first coronary artery disease code of the index case. Adjustments for the first, maximum, or mean LDL-C were analyzed. FH variants in LDLR, APOB, and PCSK9 were assessed by custom genotype array.In a cohort of 23 091 predominantly prevalent cases at enrollment and 230 910 matched controls, FH variant carriers had an increased risk for coronary artery disease (odds ratio [OR], 1.53 [95% CI, 1.24-1.89]). Adjusting for mean LDL-C led to the greatest attenuation of the risk estimate, but significant risk remained (odds ratio, 1.33 [95% CI, 1.08-1.64]). The degree of attenuation was not affected by the number and the spread of LDL-C measures available.The risk associated with carrying an FH variant cannot be fully captured by the LDL-C data available in the electronic health record, even when considering multiple LDL-C measurements spanning more than a decade.

  View details for DOI 10.1161/CIRCGEN.121.003501

  View details for PubMedID 35143253

• The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification. Genetics in medicine : official journal of the American College of Medical Genetics Chora, J. R., Iacocca, M. A., Tichy, L., Wand, H., Kurtz, C. L., Zimmermann, H., Leon, A., Williams, M., Humphries, S. E., Hooper, A. J., Trinder, M., Brunham, L. R., Costa Pereira, A., Jannes, C. E., Chen, M., Chonis, J., Wang, J., Kim, S., Johnston, T., Soucek, P., Kramarek, M., Leigh, S. E., Carrie, A., Sijbrands, E. J., Hegele, R. A., Freiberger, T., Knowles, J. W., Bourbon, M., ClinGen Familial Hypercholesterolemia Expert Panel 1800

  Abstract

  PURPOSE: In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published consensus standardized guidelines for sequence-level variant classification in Mendelian disorders. To increase accuracy and consistency, the Clinical Genome Resource Familial Hypercholesterolemia (FH) Variant Curation Expert Panel was tasked with optimizing the existing ACMG/AMP framework for disease-specific classification in FH. In this study, we provide consensus recommendations for the most common FH-associated gene, LDLR, where >2300 unique FH-associated variants have been identified.METHODS: The multidisciplinary FH Variant Curation Expert Panel met in person and through frequent emails and conference calls to develop LDLR-specific modifications of ACMG/AMP guidelines. Through iteration, pilot testing, debate, and commentary, consensus among experts was reached.RESULTS: The consensus LDLR variant modifications to existing ACMG/AMP guidelines include (1) alteration of population frequency thresholds, (2) delineation of loss-of-function variant types, (3) functional study criteria specifications, (4) cosegregation criteria specifications, and (5) specific use and thresholds for in silico prediction tools, among others.CONCLUSION: Establishment of these guidelines as the new standard in the clinical laboratory setting will result in a more evidence-based, harmonized method for LDLR variant classification worldwide, thereby improving the care of patients with FH.

  View details for DOI 10.1016/j.gim.2021.09.012

  View details for PubMedID 34906454

• Signaling defects associated with insulin resistance in non-diabetic and diabetic individuals and modification by sex. The Journal of clinical investigation Haider, N., Lebastchi, J., Jayavelu, A. K., Batista, T. M., Pan, H., Dreyfuss, J. M., Carcamo-Orive, I., Knowles, J. W., Mann, M., Kahn, C. R. 2021

  Abstract

  Insulin resistance is present in one-quarter of the general population, predisposing to a wide-range of diseases. Our aim was to identify cell-intrinsic determinants of insulin resistance in this population using IPS cell-derived myoblasts (iMyos). We found that these cells exhibited a large network of altered protein phosphorylation in vitro. Integrating these data with data from type-2-diabetic iMyos revealed critical sites of conserved altered phosphorylation in IRS-1, AKT, mTOR and TBC1D1, in addition to changes in protein phosphorylation involved in Rho/Rac signaling, chromatin organization and RNA processing. There were also striking differences in the phosphoproteome in cells from males versus females. These sex-specific and insulin resistance defects were linked to functional differences in downstream actions. Thus, there are cell-autonomous signaling alterations associated with insulin resistance within the general population and important differences in males and females, many of which are shared with diabetes, and contribute to differences in physiology and disease.

  View details for DOI 10.1172/JCI151818

  View details for PubMedID 34506305

• Statins Are Associated With Increased Insulin Resistance and Secretion. Arteriosclerosis, thrombosis, and vascular biology Abbasi, F., Lamendola, C., Harris, C. S., Harris, V., Tsai, M., Tripathi, P., Abbas, F., Reaven, G., Reaven, P., Snyder, M. P., Kim, S. H., Knowles, J. W. 2021: ATVBAHA121316159

  Abstract

  OBJECTIVE: Statin treatment reduces the risk of atherosclerotic cardiovascular disease but is associated with a modest increased risk of type 2 diabetes, especially in those with insulin resistance or prediabetes. Our objective was to determine the physiological mechanism for the increased type 2 diabetes risk. Approach and Results: We conducted an open-label clinical trial of atorvastatin 40 mg daily in adults without known atherosclerotic cardiovascular disease or type 2 diabetes at baseline. The co-primary outcomes were changes at 10 weeks versus baseline in insulin resistance as assessed by steady-state plasma glucose during the insulin suppression test and insulin secretion as assessed by insulin secretion rate area under the curve (ISRAUC) during the graded-glucose infusion test. Secondary outcomes included glucose and insulin, both fasting and during oral glucose tolerance test. Of 75 participants who enrolled, 71 completed the study (median age 61 years, 37% women, 65% non-Hispanic White, median body mass index, 27.8 kg/m2). Atorvastatin reduced LDL (low-density lipoprotein)-cholesterol (median decrease 53%, P<0.001) but did not change body weight. Compared with baseline, atorvastatin increased insulin resistance (steady-state plasma glucose) by a median of 8% (P=0.01) and insulin secretion (ISRAUC) by a median of 9% (P<0.001). There were small increases in oral glucose tolerance test glucoseAUC (median increase, 0.05%; P=0.03) and fasting insulin (median increase, 7%; P=0.01).CONCLUSIONS: In individuals without type 2 diabetes, high-intensity atorvastatin for 10 weeks increases insulin resistance and insulin secretion. Over time, the risk of new-onset diabetes with statin use may increase in individuals who become more insulin resistant but are unable to maintain compensatory increases in insulin secretion.REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02437084.

  View details for DOI 10.1161/ATVBAHA.121.316159

  View details for PubMedID 34433298

• Genetics of Type 2 Diabetes: Opportunities for Precision Medicine: JACC Focus Seminar. Journal of the American College of Cardiology Kim, D. S., Gloyn, A. L., Knowles, J. W. 2021; 78 (5): 496-512

  Abstract

  Type 2 diabetes (T2D) is highly prevalent and is a strong contributor for cardiovascular disease. However, there is significant heterogeneity in disease pathogenesis and the risk of complications. Enormous progress has been made in our ability to catalog genetic variation associated with T2D risk and variation in disease-relevant quantitative traits. These discoveries hold the potential to shed light on tractable targets and pathways for safe and effective therapeutic development, but the promise of precision medicine has been slow to be realized. Recent studies have identified subgroups of individuals with differential risk for intermediate phenotypes (eg, lipid levels, fasting insulin, body mass index) that contribute to T2D risk, helping to account for the observed clinical heterogeneity. These "partitioned genetic risk scores" not only have the potential to identify patients at greatest risk of cardiovascular disease and rapid disease progression, but also could aid patient stratification bridging the gap toward precision medicine for T2D.

  View details for DOI 10.1016/j.jacc.2021.03.346

  View details for PubMedID 34325839

• Lipoprotein(a) and Benefit of PCSK9 Inhibition in Patients With Nominally Controlled LDL Cholesterol JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Schwartz, G. G., Szarek, M., Bittner, V. A., Diaz, R., Goodman, S. G., Jukema, J., Landmesser, U., Lopez-Jaramillo, P., Manvelian, G., Pordy, R., Scemama, M., Sinnaeve, P. R., White, H. D., Steg, P., Odyssey Outcomes Committ Invest 2021; 78 (5): 421-433

  Abstract

  Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk.In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels.ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was <70 mg/dL (median 69.4 mg/dL; interquartile range: 64.3-74.0 mg/dL); in 14,573 patients (77.0%), both determinations were ≥70 mg/dL (median 94.0 mg/dL; interquartile range: 83.2-111.0 mg/dL).In the lower LDL-C subgroup, MACE rates were 4.2 and 3.1 per 100 patient-years among placebo-treated patients with baseline lipoprotein(a) greater than or less than or equal to the median (13.7 mg/dL). Corresponding adjusted treatment hazard ratios were 0.68 (95% confidence interval [CI]: 0.52-0.90) and 1.11 (95% CI: 0.83-1.49), with treatment-lipoprotein(a) interaction on MACE (Pinteraction = 0.017). In the higher LDL-C subgroup, MACE rates were 4.7 and 3.8 per 100 patient-years among placebo-treated patients with lipoprotein(a) >13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with Pinteraction = 0.43.In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

  View details for DOI 10.1016/j.jacc.2021.04.102

  View details for Web of Science ID 000679372200001

  View details for PubMedID 34325831

  View details for PubMedCentralID PMC8822604

• Diverse Racial/Ethnic Group Underreporting and Underrepresentation in High-Impact Cholesterol Treatment Trials. Circulation Sarraju, A., Valencia, A., Knowles, J. W., Maron, D. J., Rodriguez, F. 2021; 143 (24): 2409-2411

  View details for DOI 10.1161/CIRCULATIONAHA.120.050034

  View details for PubMedID 34125567

• Health disparities in cardiometabolic risk among Black and Hispanic youth in the United States. American journal of preventive cardiology Katz, S. F., Rodriguez, F., Knowles, J. W. 2021; 6: 100175

  Abstract

  Cardiometabolic risk factors in children and adolescents track into adulthood and are associated with increased risk of atherosclerotic cardiovascular disease. The purpose of this review is to examine the pervasive race and ethnic disparities in cardiometabolic risk factors among Black and Hispanic youth in the United States. We focus on three traditional cardiometabolic risk factors (obesity, type 2 diabetes mellitus, and dyslipidemia) as well as on the emerging cardiometabolic risk factor of non-alcoholic fatty liver disease. Additionally, we highlight interventions aimed at improving cardiometabolic health among these minority pediatric populations. Finally, we advocate for continued research on effective prevention strategies to reduce cardiometabolic risk and avert further disparities in cardiovascular morbidity and mortality.

  View details for DOI 10.1016/j.ajpc.2021.100175

  View details for PubMedID 34327498

• Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment DIABETES CARE Schwartz, G. G., Szarek, M., Bittner, V. A., Bhatt, D. L., Diaz, R., Goodman, S. G., Jukema, J., Loy, M., Manvelian, G., Pordy, R., White, H. D., Steg, P., ODYSSEY OUTCOMES Comm Investigator 2021; 44 (5): 1219-1227

  Abstract

  In observational data, lower levels of lipoprotein(a) have been associated with greater prevalence of type 2 diabetes. Whether pharmacologic lowering of lipoprotein(a) influences incident type 2 diabetes is unknown. We determined the relationship of lipoprotein(a) concentration with incident type 2 diabetes and effects of treatment with alirocumab, a PCSK9 inhibitor.In the ODYSSEY OUTCOMES trial alirocumab was compared with placebo in patients with acute coronary syndrome. Incident diabetes was determined from laboratory, medication, and adverse event data.Among 13,480 patients without diabetes at baseline, 1,324 developed type 2 diabetes over a median 2.7 years. Median baseline lipoprotein(a) was 21.9 mg/dL. With placebo, 10 mg/dL lower baseline lipoprotein(a) was associated with hazard ratio 1.04 (95% CI 1.02-1.06, P < 0.001) for incident type 2 diabetes. Alirocumab reduced lipoprotein(a) by a median 23.2% with greater absolute reductions from higher baseline levels and no overall effect on incident type 2 diabetes (hazard ratio 0.95, 95% CI 0.85-1.05). At low baseline lipoprotein(a) levels, alirocumab tended to reduce incident type 2 diabetes, while at high baseline lipoprotein(a) alirocumab tended to increase incident type 2 diabetes compared with placebo (treatment-baseline lipoprotein(a) interaction P = 0.006). In the alirocumab group, a 10 mg/dL decrease in lipoprotein(a) from baseline was associated with hazard ratio 1.07 (95% CI 1.03-1.12; P = 0.0002) for incident type 2 diabetes.In patients with acute coronary syndrome, baseline lipoprotein(a) concentration associated inversely with incident type 2 diabetes. Alirocumab had neutral overall effect on incident type 2 diabetes. However, treatment-related reductions in lipoprotein(a), more pronounced from high baseline levels, were associated with increased risk of incident type 2 diabetes. Whether these findings pertain to other therapies that reduce lipoprotein(a) is undetermined.

  View details for DOI 10.2337/dc20-2842

  View details for Web of Science ID 000651122400036

  View details for PubMedID 33722880

  View details for PubMedCentralID PMC8132323

• Generation of two heterozygous MYBPC3 mutation-carrying human iPSC lines, SCVIi001-A and SCVIi002-A, for modeling hypertrophic cardiomyopathy. Stem cell research Liu, L., Shenoy, S. P., Jahng, J. W., Liu, Y., Knowles, J. W., Zhuge, Y., Wu, J. C. 2021; 53: 102279

  Abstract

  Hypertrophic cardiomyopathy (HCM) is an inherited heart disease that can cause sudden cardiac death and heart failure. HCM often arises from mutations in sarcomeric genes, among which the MYBPC3 is the most frequently mutated. Here we generated two human induced pluripotent stem cell (iPSC) lines from a HCM patient who has a familial history of HCM and his daughter who carries the pathogenic non-coding mutation. All lines show the typical morphology of pluripotent cells, a high expression of pluripotency markers, normal karyotype, and in vitro capacity to differentiate into all three germ layers. These lines provide a valuable resource for studying the molecular basis of HCM and drug screening for HCM.

  View details for DOI 10.1016/j.scr.2021.102279

  View details for PubMedID 33743363

• Identification of rare and common regulatory variants in pluripotent cells using population-scale transcriptomics. Nature genetics Bonder, M. J., Smail, C., Gloudemans, M. J., Fresard, L., Jakubosky, D., D'Antonio, M., Li, X., Ferraro, N. M., Carcamo-Orive, I., Mirauta, B., Seaton, D. D., Cai, N., Vakili, D., Horta, D., Zhao, C., Zastrow, D. B., Bonner, D. E., HipSci Consortium, iPSCORE consortium, Undiagnosed Diseases Network, PhLiPS consortium, Wheeler, M. T., Kilpinen, H., Knowles, J. W., Smith, E. N., Frazer, K. A., Montgomery, S. B., Stegle, O., Jan Bonder, M., Seaton, D., Jakubosky, D. A., Brown, C. D., Park, Y. 2021

  Abstract

  Induced pluripotent stem cells (iPSCs) are an established cellular system to study the impact of genetic variants in derived cell types and developmental contexts. However, in their pluripotent state, the disease impact of genetic variants is less well known. Here, we integrate data from 1,367 human iPSC lines to comprehensively map common and rare regulatory variants in human pluripotent cells. Using this population-scale resource, we report hundreds of new colocalization events for human traits specific to iPSCs, and find increased power to identify rare regulatory variants compared with somatic tissues. Finally, we demonstrate how iPSCs enable the identification of causal genes for rare diseases.

  View details for DOI 10.1038/s41588-021-00800-7

  View details for PubMedID 33664507

• Validation of an Integrated Risk Tool, Including Polygenic Risk Score, for Atherosclerotic Cardiovascular Disease in Multiple Ethnicities and Ancestries. The American journal of cardiology Weale, M. E., Riveros-Mckay, F., Selzam, S., Seth, P., Moore, R., Tarran, W. A., Gradovich, E., Giner-Delgado, C., Palmer, D., Wells, D., Saffari, A., Sivley, R. M., Lachapelle, A. S., Wand, H., Clarke, S. L., Knowles, J. W., O'Sullivan, J. W., Ashley, E. A., McVean, G., Plagnol, V., Donnelly, P. 2021

  Abstract

  The American College of Cardiology / American Heart Association pooled cohort equations tool (ASCVD-PCE) is currently recommended to assess 10-year risk for atherosclerotic cardiovascular disease (ASCVD). ASCVD-PCE does not currently include genetic risk factors. Polygenic risk scores (PRSs) have been shown to offer a powerful new approach to measuring genetic risk for common diseases, including ASCVD, and to enhance risk prediction when combined with ASCVD-PCE. Most work to date, including the assessment of tools, has focused on performance in individuals of European ancestries. Here we present evidence for the clinical validation of a new integrated risk tool (IRT), ASCVD-IRT, which combines ASCVD-PCE with PRS to predict 10-year risk of ASCVD across diverse ethnicity and ancestry groups. We demonstrate improved predictive performance of ASCVD-IRT over ASCVD-PCE, not only in individuals of self-reported White ethnicities (net reclassification improvement (NRI) (with 95% confidence interval) = 2.7% (1.1 - 4.2)) but also Black / African American / Black Caribbean / Black African (NRI = 2.5% (0.6 - 4.3)) and South Asian (Indian, Bangladeshi or Pakistani) ethnicities (NRI = 8.7% (3.1 - 14.4)). NRI confidence intervals were wider and included zero for ethnicities with smaller sample sizes, including Hispanic (NRI = 7.5% (-1.4 - 16.5)), but PRS effect sizes in these ethnicities were significant and of comparable size to those seen in individuals of White ethnicities. Comparable results were obtained when individuals were analysed by genetically inferred ancestry. Together, these results validate the performance of ASCVD-IRT in multiple ethnicities and ancestries, and favour their generalisation to all ethnicities and ancestries.

  View details for DOI 10.1016/j.amjcard.2021.02.032

  View details for PubMedID 33675770

• RECOMMENDATIONS FOR LDLR VARIANT INTERPRETATION BY THE CLINGEN'S FAMILIAL HYPERCHOLESTEROLEMIA EXPERT PANEL Chora, J., Iacocca, M., Tichy, L., Wand, H., Kurtz, L. C., Zimmermann, H., Meredith, A., Williams, M., Humphries, S. E., Hooper, A. J., Brunham, L., Pereira, A., Chen, M., Wang, J., Trinder, M., Jannes, C., Chonis, J., Kim, S., Pesaran, T., Johnston, T., Carrie, A., Leigh, S., Hegele, R. A., Sijbrands, E., Freiberger, T., Knowles, J. W., Bourbon, M. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for Web of Science ID 000612833500180

• Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis. Cell metabolism Jiang, Z., Zhao, M., Voilquin, L., Jung, Y., Aikio, M. A., Sahai, T., Dou, F. Y., Roche, A. M., Carcamo-Orive, I., Knowles, J. W., Wabitsch, M., Appel, E. A., Maikawa, C. L., Camporez, J. P., Shulman, G. I., Tsai, L., Rosen, E. D., Gardner, C. D., Spiegelman, B. M., Svensson, K. J. 2021

  Abstract

  With the increasing prevalence of type 2 diabetes and fatty liver disease, there is still an unmet need to better treat hyperglycemia and hyperlipidemia. Here, we identify isthmin-1 (Ism1) as an adipokine and one that has a dual role in increasing adipose glucose uptake while suppressing hepatic lipid synthesis. Ism1 ablation results in impaired glucose tolerance, reduced adipose glucose uptake, and reduced insulin sensitivity, demonstrating an endogenous function for Ism1 in glucose regulation. Mechanistically, Ism1 activates a PI3K-AKT signaling pathway independently of the insulin and insulin-like growth factor receptors. Notably, while the glucoregulatory function is shared with insulin, Ism1 counteracts lipid accumulation in the liver by switching hepatocytes from a lipogenic to a protein synthesis state. Furthermore, therapeutic dosing of recombinant Ism1 improves diabetes in diet-induced obese mice and ameliorates hepatic steatosis in a diet-induced fatty liver mouse model. These findings uncover an unexpected, bioactive protein hormone that might have simultaneous therapeutic potential for diabetes and fatty liver disease.

  View details for DOI 10.1016/j.cmet.2021.07.010

  View details for PubMedID 34348115

• The need for polygenic score reporting standards in evidence-based practice: lipid genetics use case. Current opinion in lipidology Wand, H. n., Knowles, J. W., Clarke, S. L. 2021

  Abstract

  Polygenic scores (PGS) are used to quantify the genetic predisposition for heritable traits, with hypothesized utility for personalized risk assessments. Lipid PGS are primed for clinical translation, but evidence-based practice changes will require rigorous PGS standards to ensure reproducibility and generalizability. Here we review applicable reporting and technical standards for dyslipidemia PGS translation along phases of the ACCE (Analytical validity, Clinical validity, Clinical utility, Ethical considerations) framework for evaluating genetic tests.New guidance suggests existing standards for study designs incorporating the ACCE framework are applicable to PGS and should be adopted. One recent example is the Clinical Genomics Resource (ClinGen) and Polygenic Score Catalog's PRS reporting standards, which define minimal requirements for describing rationale for score development, study population definitions and data parameters, risk model development and application, risk model evaluation, and translational considerations, such as generalizability beyond the target population studied.Lipid PGS are likely to be integrated into clinical practice in the future. Clinicians will need to be prepared to determine if and when lipid PGS is useful and valid. This decision-making will depend on the quality of evidence for the clinical use of PGS. Establishing reporting standards for PGS will help facilitate data sharing and transparency for critical evaluation, ultimately benefiting the efficiency of evidence-based practice.

  View details for DOI 10.1097/MOL.0000000000000733

  View details for PubMedID 33538426

• An integrated approach to identify environmental modulators of genetic risk factors for complex traits. American journal of human genetics Balliu, B., Carcamo-Orive, I., Gloudemans, M. J., Nachun, D. C., Durrant, M. G., Gazal, S., Park, C. Y., Knowles, D. A., Wabitsch, M., Quertermous, T., Knowles, J. W., Montgomery, S. B. 2021

  Abstract

  Complex traits and diseases can be influenced by both genetics and environment. However, given the large number of environmental stimuli and power challenges for gene-by-environment testing, it remains a critical challenge to identify and prioritize specific disease-relevant environmental exposures. We propose a framework for leveraging signals from transcriptional responses to environmental perturbations to identify disease-relevant perturbations that can modulate genetic risk for complex traits and inform the functions of genetic variants associated with complex traits. We perturbed human skeletal-muscle-, fat-, and liver-relevant cell lines with 21 perturbations affecting insulin resistance, glucose homeostasis, and metabolic regulation in humans and identified thousands of environmentally responsive genes. By combining these data with GWASs from 31 distinct polygenic traits, we show that the heritability of multiple traits is enriched in regions surrounding genes responsive to specific perturbations and, further, that environmentally responsive genes are enriched for associations with specific diseases and phenotypes from the GWAS Catalog. Overall, we demonstrate the advantages of large-scale characterization of transcriptional changes in diversely stimulated and pathologically relevant cells to identify disease-relevant perturbations.

  View details for DOI 10.1016/j.ajhg.2021.08.014

  View details for PubMedID 34582792

• Predictive network modeling in human induced pluripotent stem cells identifies key driver genes for insulin responsiveness. PLoS computational biology Carcamo-Orive, I., Henrion, M. Y., Zhu, K., Beckmann, N. D., Cundiff, P., Moein, S., Zhang, Z., Alamprese, M., D'Souza, S. L., Wabitsch, M., Schadt, E. E., Quertermous, T., Knowles, J. W., Chang, R. 2020; 16 (12): e1008491

  Abstract

  Insulin resistance (IR) precedes the development of type 2 diabetes (T2D) and increases cardiovascular disease risk. Although genome wide association studies (GWAS) have uncovered new loci associated with T2D, their contribution to explain the mechanisms leading to decreased insulin sensitivity has been very limited. Thus, new approaches are necessary to explore the genetic architecture of insulin resistance. To that end, we generated an iPSC library across the spectrum of insulin sensitivity in humans. RNA-seq based analysis of 310 induced pluripotent stem cell (iPSC) clones derived from 100 individuals allowed us to identify differentially expressed genes between insulin resistant and sensitive iPSC lines. Analysis of the co-expression architecture uncovered several insulin sensitivity-relevant gene sub-networks, and predictive network modeling identified a set of key driver genes that regulate these co-expression modules. Functional validation in human adipocytes and skeletal muscle cells (SKMCs) confirmed the relevance of the key driver candidate genes for insulin responsiveness.

  View details for DOI 10.1371/journal.pcbi.1008491

  View details for PubMedID 33362275

• SPECIFICATION OF ACMG/AMP GUIDELINES FOR STANDARDIZED VARIANT INTERPRETATION IN FAMILIAL HYPERCHOLESTEROLEMIA: ON BEHALF OF THE CLINGEN FH VARIANT CURATION EXPERT PANEL Iacocca, M. A., Chora, J. R., Freiberger, T., Carrie, A., Sijbrands, E. J., Wand, H., Williams, M., Zimmermann, H., Leon, A., Kurtz, C. L., Tichy, L., Alves, A. C., Wang, J., Cuchel, M., Humphries, S. E., Defesche, J. C., Mata, P., Santos, R. D., Kullo, I. J., Brunham, L. R., Hegele, R. A., Knowles, J. W., Bourbon, M. ELSEVIER IRELAND LTD. 2020: E5

  View details for Web of Science ID 000748958900013

• RNAi inhibition of angiopoietin-like protein 3 (ANGPTL3) with ARO-ANG3 mimics the lipid and lipoprotein profile of familial combined hypolipidemia Watts, G. F., Schwabe, C., Scott, R., Gladding, P., Sullivan, D., Baker, J., Clifton, P., Hamilton, J., Given, B., San Martin, J., Melquist, S., Knowles, J. W., Goldberg, Hegele, R., Ballantyne, C. OXFORD UNIV PRESS. 2020: 3331

  View details for Web of Science ID 000606106303338

• RNA interference targeting apolipoprotein C-III with ARO-APOC3 in healthy volunteers mimics lipid and lipoprotein findings seen in subjects with inherited apolipoprotein C-III deficiency Schwabe, C., Scott, R., Sullivan, D., Baker, J., Clifton, P., Hamilton, J., Given, B., San Martin, J., Melquist, S., Watts, G. F., Goldberg, Knowles, J. W., Hegele, R., Ballantyne, C. OXFORD UNIV PRESS. 2020: 3330

  View details for Web of Science ID 000606106303337

• Children with Heterozygous Familial Hypercholesterolemia in the United States: Data from the CASCADE FH Registry. The Journal of pediatrics de Ferranti, S. D., Shrader, P., Linton, M. F., Knowles, J. W., Hudgins, L. C., Benuck, I., Kindt, I., O'Brien, E. C., Peterson, A. L., Ahmad, Z. S., Clauss, S., Duell, P. B., Shapiro, M. D., Wilemon, K., Gidding, S. S., Neal, W. 2020

  Abstract

  OBJECTIVE: To describe enrollment characteristics of youth in the CAscade SCreening for Awareness and DEtection (CASCADE) Familial Hypercholesterolemia Registry.STUDY DESIGN: Cross-sectional analysis of 493 participants <18 years old with heterozygous FH recruited from US lipid clinics (n=20), between April 1, 2014 and January 12, 2018. At enrollment, some were new patients and some were in care. Clinical characteristics are described, including lipid levels and lipid lowering treatments (LLTs).RESULTS: Mean age at diagnosis was 9.4 (4.0) years; 47% female, 68% white and 12% Hispanic. Average (SD) highest LDL-C was 238 (61) mg/dL prior to treatment. Lipid lowering therapy (LLT) was used by 64% of participants; 56% were treated with statin. LDL-C declined 84 mg/dL (33%) among those treated with LLT; statins produced the greatest decline, 100 mg/dL (39% reduction). At enrollment, 39% had reached an LDL-C goal, either <130 mg/dL or ≥50% decrease from pre-treatment; 20% of those on LLT reached both goals.CONCLUSIONS: Among youth enrolled in CASCADE FH, diagnosis occurred relatively late, only 77% of children eligible for LLT were on treatment and 39% of those treated met LDL-C goals. Opportunities exist for earlier diagnosis, broader use of LLT, and greater LDL-C lowering.

  View details for DOI 10.1016/j.jpeds.2020.09.042

  View details for PubMedID 32976895

• Expression of Glycolytic Enzymes in Induced Pluripotent Stem Cells, Derived Megakaryocytes, and Endothelial Cells Chandra, A., Vaidya, D., Chang, R., Knowles, J., Carcamo-Oribe, I., Kammers, K., Martin, J., Taub, M., Hoyle, D., Gao, Y., Yanek, L., Kral, B., Faraday, N., Becker, D., Mathias, R., Cheng, L., Leek, J., Wang, Z., Becker, L. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for DOI 10.1161/res.127.suppl_1.330

  View details for Web of Science ID 000606541500099

• Discovery and quality analysis of a comprehensive set of structural variants and short tandem repeats. Nature communications Jakubosky, D., Smith, E. N., D'Antonio, M., Jan Bonder, M., Young Greenwald, W. W., D'Antonio-Chronowska, A., Matsui, H., i2QTL Consortium, Stegle, O., Montgomery, S. B., DeBoever, C., Frazer, K. A., Bonder, M. J., Cai, N., Carcamo-Orive, I., D'Antonio, M., Frazer, K. A., Young Greenwald, W. W., Jakubosky, D., Knowles, J. W., Matsui, H., McCarthy, D. J., Mirauta, B. A., Montgomery, S. B., Quertermous, T., Seaton, D. D., Smail, C., Smith, E. N., Stegle, O. 2020; 11 (1): 2928

  Abstract

  Structural variants (SVs) and short tandem repeats (STRs) are important sources of genetic diversity but are not routinely analyzed in genetic studies because they are difficult to accurately identify and genotype. Because SVs and STRs range in size and type, it is necessary to apply multiple algorithms that incorporate different types of evidence from sequencing data and employ complex filtering strategies to discover a comprehensive set of high-quality and reproducible variants. Here we assemble a set of 719 deep whole genome sequencing (WGS) samples (mean 42*) from 477 distinct individuals which we use to discover and genotype a wide spectrum of SV and STR variants using five algorithms. We use 177 unique pairs of genetic replicates to identify factors that affect variant call reproducibility and develop a systematic filtering strategy to create of one of the most complete and well characterized maps of SVs and STRs to date.

  View details for DOI 10.1038/s41467-020-16481-5

  View details for PubMedID 32522985

• Properties of structural variants and short tandem repeats associated with gene expression and complex traits. Nature communications Jakubosky, D., D'Antonio, M., Bonder, M. J., Smail, C., Donovan, M. K., Young Greenwald, W. W., Matsui, H., i2QTL Consortium, D'Antonio-Chronowska, A., Stegle, O., Smith, E. N., Montgomery, S. B., DeBoever, C., Frazer, K. A., Bonder, M. J., Cai, N., Carcamo-Orive, I., D'Antonio, M., Frazer, K. A., Young Greenwald, W. W., Jakubosky, D., Knowles, J. W., Matsui, H., McCarthy, D. J., Mirauta, B. A., Montgomery, S. B., Quertermous, T., Seaton, D. D., Smail, C., Smith, E. N., Stegle, O. 2020; 11 (1): 2927

  Abstract

  Structural variants (SVs) and short tandem repeats (STRs) comprise a broad group of diverse DNA variants which vastly differ in their sizes and distributions across the genome. Here, we identify genomic features of SV classes and STRs that are associated with gene expression and complex traits, including their locations relative to eGenes, likelihood of being associated with multiple eGenes, associated eGene types (e.g., coding, noncoding, level of evolutionary constraint), effect sizes, linkage disequilibrium with tagging single nucleotide variants used in GWAS, and likelihood of being associated with GWAS traits. We identify a set of high-impact SVs/STRs associated with the expression of three or more eGenes via chromatin loops and show that they are highly enriched for being associated with GWAS traits. Our study provides insights into the genomic properties of structural variant classes and short tandem repeats that are associated with gene expression and human traits.

  View details for DOI 10.1038/s41467-020-16482-4

  View details for PubMedID 32522982

• Insulin Resistance and Mitochondrial Dysfunction Mediated by Nat1 Deficiency Sangwung, P., Fathzadeh, M., Knowles, J. AMER DIABETES ASSOC. 2020

  View details for DOI 10.2337/db20-1736-P

  View details for Web of Science ID 000554509804004

• Gaps in Dyslipidemia Care Among Working-Aged Individuals With Employer-Sponsored Health Care. Journal of the American Heart Association Shiffman, D., Louie, J. Z., Devlin, J. J., Knowles, J. W., McPhaul, M. J. 2020: e015807

  Abstract

  Background The American Heart Association and American College of Cardiology guidelines defined patient-management groups that would benefit from lowering of low-density lipoprotein cholesterol (LDL-C). We assessed gaps in dyslipidemia care among employees and spouses with health benefits. Methods and Results We studied 17889 employees and spouses who were covered by an employer-sponsored health plan and participated in an annual health assessment. Using medical claims, laboratory tests, and risk assessment questionnaires, we found that 43% of participants were in one of 4 patient-management groups: secondary prevention, severe hypercholesterolemia (LDL-C ≥190mg/dL at least once in the preceding 5years), diabetes mellitus, or elevated 10-year risk of cardiovascular disease. To assess gaps in dyslipidemia care, we used LDL-C ≤70mg/dL as the goal for both the secondary prevention group and those in the elevated 10-year risk group with >20% risk; LDL-C ≤100mg/dL was used for the other groups. Among those in patient-management groups, 27.3% were in the secondary prevention group, 7.4% were in the severe hypercholesterolemia group, 29.9% were in the diabetes mellitus group, and 35.4% were in the elevated 10-year risk group. About 74% of those in patient-management groups had above-goal LDL-C levels, whereas only 31% had evidence of a lipid-lowering therapy in the past 6months: 45% in the secondary prevention group, 31% in the severe hypercholesterolemia group, 36% in the diabetes mellitus group, and 17% in the elevated 10-year risk group. Conclusions The substantial gaps in LDL-C treatment and goal attainment among members of an employer-sponsored medical plan who were mostly aware of their LDL-C levels indicate the need for gap-closure initiatives.

  View details for DOI 10.1161/JAHA.119.015807

  View details for PubMedID 32319337

• Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia NEW ENGLAND JOURNAL OF MEDICINE Raal, F. J., Kallend, D., Ray, K. K., Turner, T., Koenig, W., Wright, R., Wijngaard, P. J., Curcio, D., Jaros, M. J., Leiter, L. A., Kastelein, J. P., ORION-9 Investigators 2020; 382 (16): 1520-1530

  Abstract

  Familial hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. Monoclonal antibodies directed against proprotein convertase subtilisin-kexin type 9 (PCSK9) have been shown to reduce LDL cholesterol levels by more than 50% but require administration every 2 to 4 weeks. In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia.In this phase 3, double-blind trial, we randomly assigned, in a 1:1 ratio, 482 adults who had heterozygous familial hypercholesterolemia to receive subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The two primary end points were the percent change from baseline in the LDL cholesterol level on day 510 and the time-adjusted percent change from baseline in the LDL cholesterol level between day 90 and day 540.The median age of the patients was 56 years, and 47% were men; the mean baseline level of LDL cholesterol was 153 mg per deciliter. At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% confidence interval [CI], -43.7 to -35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of -47.9 percentage points (95% CI, -53.5 to -42.3; P<0.001). The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% (95% CI, -41.1 to -35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3 to 9.2) in the placebo group, for a between-group difference of -44.3 percentage points (95% CI, -48.5 to -40.1; P<0.001). There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia. Adverse events and serious adverse events were similar in the two groups.Among adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile. (Funded by the Medicines Company; ORION-9 ClinicalTrials.gov number, NCT03397121.).

  View details for DOI 10.1056/NEJMoa1913805

  View details for Web of Science ID 000527733300010

  View details for PubMedID 32197277

• Delisting STAP1: The Rise and Fall of a Putative Hypercholesterolemia Gene. Arteriosclerosis, thrombosis, and vascular biology Hegele, R. A., Knowles, J. W., Horton, J. D. 2020; 40 (4): 847–49

  View details for DOI 10.1161/ATVBAHA.120.314006

  View details for PubMedID 32208993

• Association of insulin resistance, from mid-life to late-life, with aortic stiffness in late-life: the Atherosclerosis Risk in Communities Study. Cardiovascular diabetology Poon, A. K., Meyer, M. L., Tanaka, H., Selvin, E., Pankow, J., Zeng, D., Loehr, L., Knowles, J. W., Rosamond, W., Heiss, G. 2020; 19 (1): 11

  Abstract

  BACKGROUND: Insulin resistance may contribute to aortic stiffening that leads to end-organ damage. We examined the cross-sectional association and prospective association of insulin resistance and aortic stiffness in older adults without diabetes.METHODS: We analyzed 2571 men and women at Visit 5 (in 2011-2013), and 2350 men and women at repeat examinations from baseline at Visit 1 (in 1987-1989) to Visit 5 (in 2011-2013). Linear regression was used to estimate the difference in aortic stiffness per standard unit of HOMA-IR, TG/HDL-C, and TyG at Visit 5. Linear mixed effects were used to assess if high, as opposed to non-high, aortic stiffness (>75th percentile) was preceded by a faster annual rate of change in log-HOMA-IR, log-TG/HDL-C, and log-TyG from Visit 1 to Visit 5.RESULTS: The mean age of participants was 75years, 37% (n=957) were men, and 17% (n=433) were African American. At Visit 5, higher HOMA-IR, higher TG/HDL-C, and higher TyG were associated with higher aortic stiffness (16cm/s per SD (95% CI 6, 27), 29cm/s per SD (95% CI 18, 40), and 32cm/s per SD (95% CI 22, 42), respectively). From Visit 1 to Visit 5, high aortic stiffness, compared to non-high aortic stiffness, was not preceded by a faster annual rate of change in log-HOMA-IR from baseline to 9years (0.030 (95% CI 0.024, 0.035) vs. 0.025 (95% CI 0.021, 0.028); p=0.15) or 9years onward (0.011 (95% CI 0.007, 0.015) vs. 0.011 (95% CI 0.009, 0.013); p=0.31); in log-TG/HDL-C from baseline to 9years (0.019 (95% CI 0.015, 0.024) vs. 0.024 (95% CI 0.022, 0.026); p=0.06) or 9years onward (-0.007 (95% CI -0.010, -0.005) vs. -0.009 (95% CI -0.010, -0.007); p=0.08); or in log-TyG from baseline to 9years (0.002 (95% CI 0.002, 0.003) vs. 0.003 (95% CI 0.003, 0.003); p=0.03) or 9years onward (0 (95% CI 0, 0) vs. 0 (95% CI 0, 0); p=0.08).CONCLUSIONS: Among older adults without diabetes, insulin resistance was associated with aortic stiffness, but the putative role of insulin resistance in aortic stiffness over the life course requires further study.

  View details for DOI 10.1186/s12933-020-0986-y

  View details for PubMedID 31992297

• Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After AcuteCoronary Syndrome. Journal of the American College of Cardiology Bittner, V. A., Szarek, M., Aylward, P. E., Bhatt, D. L., Diaz, R., Edelberg, J. M., Fras, Z., Goodman, S. G., Halvorsen, S., Hanotin, C., Harrington, R. A., Jukema, J. W., Loizeau, V., Moriarty, P. M., Moryusef, A., Pordy, R., Roe, M. T., Sinnaeve, P., Tsimikas, S., Vogel, R., White, H. D., Zahger, D., Zeiher, A. M., Steg, P. G., Schwartz, G. G., ODYSSEY OUTCOMES Committees and Investigators 2020; 75 (2): 133–44

  Abstract

  BACKGROUND: Lipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C).OBJECTIVES: A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE).METHODS: One to 12months after ACS, 18,924 patients on high-intensity statin therapy were randomized to alirocumab or placebo and followed for 2.8 years (median). Lipoprotein(a) was measured at randomization and 4 and 12months thereafter. The primary MACE outcome was coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina.RESULTS: Baseline lipoprotein(a) levels (median: 21.2mg/dl; interquartile range [IQR]: 6.7 to 59.6mg/dl) and LDL-C [corrected for cholesterol content in lipoprotein(a)] predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0mg/dl (IQR: 0 to 13.5mg/dl), corrected LDL-C by 51.1mg/dl (IQR: 33.7 to 67.2mg/dl), and reduced the risk of MACE (hazardratio [HR]: 0.85; 95% confidence interval [CI]: 0.78 to 0.93). Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95%CI: 0.990 to 0.999; p=0.0081).CONCLUSIONS: Baseline lipoprotein(a) and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS. Lipoprotein(a) lowering by alirocumab is an independent contributor to MACE reduction, which suggests that lipoprotein(a) should be an independent treatment target after ACS. (ODYSSEY Outcomes: Evaluationof Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

  View details for DOI 10.1016/j.jacc.2019.10.057

  View details for PubMedID 31948641

• Cardiorespiratory Fitness, Body-Mass Index, and Markers of Insulin Resistance in Apparently Healthy Women and Men. The American journal of medicine Clarke, S. L., Reaven, G. M., Leonard, D., Barlow, C. E., Haskell, W. L., Willis, B. L., DeFina, L., Knowles, J. W., Maron, D. J. 2020

  Abstract

  BACKGROUND: Insulin resistance may be present in healthy adults and is associated poor health outcomes. Obesity is a risk factor for insulin resistance, but most obese adults do not have insulin resistance. Fitness may be protective, but the association between fitness, weight, and insulin resistance has not been studied in a large population of healthy adults.METHODS: A cross-sectional analysis of cardiorespiratory fitness, body-mass index, and markers of insulin resistance was performed. Study participants were enrolled at the Cooper Clinic (Dallas, Texas). The analysis included 19,263 women and 48,433 men with no history of diabetes or cardiovascular disease. Cardiorespiratory fitness was measured using exercise treadmill testing. Impaired fasting glucose (100-125 mg/dL) and elevated fasting triglycerides (≥150 mg/dL) were used as a markers of insulin resistance.RESULTS: Among normal weight individuals, poor fitness was associated with a 2.2 (1.4-3.6; p=0.001) fold higher odds of insulin resistance in women and a 2.8 (2.1-3.6; p<0.001) fold higher odds in men. The impact of fitness remained significant for overweight and obese individuals, with the highest risk group being the unfit obese. Among obese women, the odds ratio for insulin resistance was 11.0 (8.7-13.9; p<0.001) for fit and 20.3 (15.5-26.5; p<0.001) for unfit women. Among obese men, the odds ratio for insulin resistance was 7.4 (6.7-8.2; p<0.001) for fit and 12.9 (11.4-14.6; p<0.001) for unfit men.CONCLUSION: Independent of weight, poor fitness is associated with risk of insulin resistance. Obese individuals, particularly women, may benefit from the greatest absolute risk reduction by achieving moderate fitness.

  View details for DOI 10.1016/j.amjmed.2019.11.031

  View details for PubMedID 31926863

• FAM13A affects body fat distribution and adipocyte function. Nature communications Fathzadeh, M. n., Li, J. n., Rao, A. n., Cook, N. n., Chennamsetty, I. n., Seldin, M. n., Zhou, X. n., Sangwung, P. n., Gloudemans, M. J., Keller, M. n., Attie, A. n., Yang, J. n., Wabitsch, M. n., Carcamo-Orive, I. n., Tada, Y. n., Lusis, A. J., Shin, M. K., Molony, C. M., McLaughlin, T. n., Reaven, G. n., Montgomery, S. B., Reilly, D. n., Quertermous, T. n., Ingelsson, E. n., Knowles, J. W. 2020; 11 (1): 1465

  Abstract

  Genetic variation in the FAM13A (Family with Sequence Similarity 13 Member A) locus has been associated with several glycemic and metabolic traits in genome-wide association studies (GWAS). Here, we demonstrate that in humans, FAM13A alleles are associated with increased FAM13A expression in subcutaneous adipose tissue (SAT) and an insulin resistance-related phenotype (e.g. higher waist-to-hip ratio and fasting insulin levels, but lower body fat). In human adipocyte models, knockdown of FAM13A in preadipocytes accelerates adipocyte differentiation. In mice, Fam13a knockout (KO) have a lower visceral to subcutaneous fat (VAT/SAT) ratio after high-fat diet challenge, in comparison to their wild-type counterparts. Subcutaneous adipocytes in KO mice show a size distribution shift toward an increased number of smaller adipocytes, along with an improved adipogenic potential. Our results indicate that GWAS-associated variants within the FAM13A locus alter adipose FAM13A expression, which in turn, regulates adipocyte differentiation and contribute to changes in body fat distribution.

  View details for DOI 10.1038/s41467-020-15291-z

  View details for PubMedID 32193374

• Genomic integrity of human induced pluripotent stem cells across nine studies in the NHLBI NextGen program. Stem cell research Kanchan, K. n., Iyer, K. n., Yanek, L. R., Carcamo-Orive, I. n., Taub, M. A., Malley, C. n., Baldwin, K. n., Becker, L. C., Broeckel, U. n., Cheng, L. n., Cowan, C. n., D'Antonio, M. n., Frazer, K. A., Quertermous, T. n., Mostoslavsky, G. n., Murphy, G. n., Rabinovitch, M. n., Rader, D. J., Steinberg, M. H., Topol, E. n., Yang, W. n., Knowles, J. W., Jaquish, C. E., Ruczinski, I. n., Mathias, R. A. 2020; 46: 101803

  Abstract

  Human induced pluripotent stem cell (hiPSC) lines have previously been generated through the NHLBI sponsored NextGen program at nine individual study sites. Here, we examined the structural integrity of 506 hiPSC lines as determined by copy number variations (CNVs). We observed that 149 hiPSC lines acquired 258 CNVs relative to donor DNA. We identified six recurrent regions of CNVs on chromosomes 1, 2, 3, 16 and 20 that overlapped with cancer associated genes. Furthermore, the genes mapping to regions of acquired CNVs show an enrichment in cancer related biological processes (IL6 production) and signaling cascades (JNK cascade & NFκB cascade). The genomic region of instability on chr20 (chr20q11.2) includes transcriptomic signatures for cancer associated genes such as ID1, BCL2L1, TPX2, PDRG1 and HCK. Of these HCK shows statistically significant differential expression between carrier and non-carrier hiPSC lines. Overall, while a low level of genomic instability was observed in the NextGen generated hiPSC lines, the observation of structural instability in regions with known cancer associated genes substantiates the importance of systematic evaluation of genetic variations in hiPSCs before using them as disease/research models.

  View details for DOI 10.1016/j.scr.2020.101803

  View details for PubMedID 32442913

• Women Living with Familial Hypercholesterolemia: Challenges and Considerations Surrounding Their Care. Current atherosclerosis reports Balla, S. n., Ekpo, E. P., Wilemon, K. A., Knowles, J. W., Rodriguez, F. n. 2020; 22 (10): 60

  Abstract

  To highlight the gender-based differences in presentation and disparities in care for women with familial hypercholesterolemia (FH).Women with FH experience specific barriers to care including underrepresentation in research, significant underappreciation of risk, and interrupted therapy during childbearing. National and international registry and clinical trial data show significant healthcare disparities for women with FH. Women with FH are less likely to be on guideline-recommended high-intensity statin medications and those placed on statins are more likely to discontinue them within their first year. Women with FH are also less likely to be on regimens including non-statin agents such as PCSK9 inhibitors. As a result, women with FH are less likely to achieve target low-density lipoprotein cholesterol (LDL-C) targets, even those with prior atherosclerotic cardiovascular disease (ASCVD). FH is common, under-diagnosed, and under-treated. Disparities of care are more pronounced in women than men. Additionally, FH weighs differently on women throughout the course of their lives starting from choosing contraceptives as young girls along with lipid-lowering therapy, timing pregnancy, choosing breastfeeding or resumption of therapy, and finally deciding goals of care during menopause. Early identification and appropriate treatment prior to interruptions of therapy for childbearing can lead to marked reduction in morbidity and mortality. Women access care differently than men and increasing awareness among all providers, especially cardio-obstetricians, may improve diagnostic rates. Understanding the unique challenges women with FH face is crucial to close the gaps in care they experience.

  View details for DOI 10.1007/s11883-020-00881-5

  View details for PubMedID 32816232

• Mitochondrial dysfunction, insulin resistance and potential genetic implications. Endocrinology Sangwung, P. n., Petersen, K. F., Shulman, G. I., Knowles, J. W. 2020

  Abstract

  Insulin resistance, IR, is fundamental to the development type 2 diabetes (T2D) and is present in most prediabetic (preDM) individuals. IR has both heritable and environmental determinants centered on energy storage and metabolism. Recent insights from human genetic studies, coupled with comprehensive in vivo and ex vivo metabolic studies in humans and rodents have highlighted the critical role of reduced mitochondrial function as a predisposing condition for ectopic lipid deposition and IR. These studies support the hypothesis that reduced mitochondrial function, particularly in insulin responsive tissues such as skeletal muscle, white adipose tissue, and liver is inextricably linked to tissue and whole body IR through effects on cellular energy balance. Here we discuss these findings as well as address potential mechanisms that serve as the nexus between mitochondrial malfunction and IR.

  View details for DOI 10.1210/endocr/bqaa017

  View details for PubMedID 32060542

• RNA Interference Targeting Apolipoprotein C-III Results in Deep and Prolonged Reductions in Plasma Triglycerides Schwabe, C., Scott, R., Sullivan, D. R., Baker, J., Clifton, P., Hamilton, J., Given, B., Melquist, S., Knowles, J., Hegele, R. A., Ballantyne, C. M. LIPPINCOTT WILLIAMS & WILKINS. 2019: E987

  View details for Web of Science ID 000508228600058

• RNA Interference Targeting Hepatic Angiopoietin-Like Protein 3 Results in Prolonged Reductions in Plasma Triglycerides and LDL-C in Human Subjects Watts, G. F., Schwabe, C., Scott, R., Gladding, P., Sullivan, D. R., Baker, J., Clifton, P., Hamilton, J., Given, B., Melquist, S., Knowles, J., Hegele, R. A., Ballantyne, C. M. LIPPINCOTT WILLIAMS & WILKINS. 2019: E987–E988

  View details for Web of Science ID 000508228600059

• Precision screening for familial hypercholesterolaemia: a machine learning study applied to electronic health encounter data. The Lancet. Digital health Myers, K. D., Knowles, J. W., Staszak, D., Shapiro, M. D., Howard, W., Yadava, M., Zuzick, D., Williamson, L., Shah, N. H., Banda, J. M., Leader, J., Cromwell, W. C., Trautman, E., Murray, M. F., Baum, S. J., Myers, S., Gidding, S. S., Wilemon, K., Rader, D. J. 2019; 1 (8): e393-e402

  Abstract

  Cardiovascular outcomes for people with familial hypercholesterolaemia can be improved with diagnosis and medical management. However, 90% of individuals with familial hypercholesterolaemia remain undiagnosed in the USA. We aimed to accelerate early diagnosis and timely intervention for more than 1·3 million undiagnosed individuals with familial hypercholesterolaemia at high risk for early heart attacks and strokes by applying machine learning to large health-care encounter datasets.We trained the FIND FH machine learning model using deidentified health-care encounter data, including procedure and diagnostic codes, prescriptions, and laboratory findings, from 939 clinically diagnosed individuals with familial hypercholesterolaemia (395 of whom had a molecular diagnosis) and 83 136 individuals presumed free of familial hypercholesterolaemia, sampled from four US institutions. The model was then applied to a national health-care encounter database (170 million individuals) and an integrated health-care delivery system dataset (174 000 individuals). Individuals used in model training and those evaluated by the model were required to have at least one cardiovascular disease risk factor (eg, hypertension, hypercholesterolaemia, or hyperlipidemia). A Health Insurance Portability and Accountability Act of 1996-compliant programme was developed to allow providers to receive identification of individuals likely to have familial hypercholesterolaemia in their practice.Using a model with a measured precision (positive predictive value) of 0·85, recall (sensitivity) of 0·45, area under the precision-recall curve of 0·55, and area under the receiver operating characteristic curve of 0·89, we flagged 1 331 759 of 170 416 201 patients in the national database and 866 of 173 733 individuals in the health-care delivery system dataset as likely to have familial hypercholesterolaemia. Familial hypercholesterolaemia experts reviewed a sample of flagged individuals (45 from the national database and 103 from the health-care delivery system dataset) and applied clinical familial hypercholesterolaemia diagnostic criteria. Of those reviewed, 87% (95% Cl 73-100) in the national database and 77% (68-86) in the health-care delivery system dataset were categorised as having a high enough clinical suspicion of familial hypercholesterolaemia to warrant guideline-based clinical evaluation and treatment.The FIND FH model successfully scans large, diverse, and disparate health-care encounter databases to identify individuals with familial hypercholesterolaemia.The FH Foundation funded this study. Support was received from Amgen, Sanofi, and Regeneron.

  View details for DOI 10.1016/S2589-7500(19)30150-5

  View details for PubMedID 33323221

• Precision screening for familial hypercholesterolaemia: a machine learning study applied to electronic health encounter data LANCET DIGITAL HEALTH Myers, K. D., Knowles, J. W., Staszak, D., Shapiro, M. D., Howard, W., Yadava, M., Zuzick, D., Williamson, L., Shah, N. H., Banda, J. M., Leader, J., Cromwell, W. C., Trautman, E., Murray, M. F., Baum, S. J., Myers, S., Gidding, S. S., Wilemon, K., Rader, D. J. 2019; 1 (8): E393–E402

  View details for DOI 10.1016/S2589-7500(19)30150-5

  View details for Web of Science ID 000525874100011

• Alirocumab in Patients With Polyvascular Disease and Recent Acute Coronary Syndrome ODYSSEY OUTCOMES Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Jukema, J., Szarek, M., Zijlstra, L. E., de Silva, H., Bhatt, D. L., Bittner, V. A., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Karpov, Y., Moryusef, A., Pordy, R., Prieto, J. C., Roe, M. T., White, H. D., Zeiher, A. M., Schwartz, G. G., Steg, P., ODYSSEY OUTCOMES Comm Investigator 2019; 74 (9): 1167–76

  View details for DOI 10.1016/j.jacc.2019.03.013

  View details for Web of Science ID 000483334800001

• Risk Categorization Using New American College of Cardiology/American Heart Association Guidelines for Cholesterol Management and Its Relation to Alirocumab Treatment Following Acute Coronary Syndromes. Circulation Roe, M. T., Li, Q. H., Bhatt, D. L., Bittner, V. A., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J. W., Lopez-Jaramillo, P., Lopes, R. D., Louie, M. J., Moriarty, P. M., Szarek, M., Vogel, R., White, H. D., Zeiher, A. M., Baccara-Dinet, M. T., Steg, P. G., Schwartz, G. G., ODYSSEY OUTCOMES Investigators 2019

  View details for DOI 10.1161/CIRCULATIONAHA.119.042551

  View details for PubMedID 31475572

• SPECIFICATION OF ACMG/AMP GUIDELINES FOR VARIANT INTERPRETATION IN FAMILIAL HYPERCHOLESTEROLEMIA Chora, J. R., Iacocca, M. A., Carrie, A., Leigh, S. E., Tichy, L., Kurtz, C. L., Freiberger, T., Sijbrands, E. J., Hegele, R. A., Knowles, J. W., Bourbon, M. ELSEVIER IRELAND LTD. 2019: E68

  View details for Web of Science ID 000482110800194

• The role of insulin as a key regulator of seeding, proliferation, and mRNA transcription of human pluripotent stem cells. Stem cell research & therapy Shahbazi, M., Cundiff, P., Zhou, W., Lee, P., Patel, A., D'Souza, S. L., Abbasi, F., Quertermous, T., Knowles, J. W. 2019; 10 (1): 228

  Abstract

  BACKGROUND: Human-induced pluripotent stem cells (hiPSCs) show a great promise as a renewable source of cells with broad biomedical applications. Since insulin has been used in the maintenance of hiPSCs, in this study we explored the role of insulin in culture of these cells.METHODS: We report conditions for insulin starvation and stimulation of hiPSCs. Crystal violet staining was used to study the adhesion and proliferation of hiPSCs. Apoptosis and cell cycle assays were performed through flow cytometry. Protein arrays were used to confirm phosphorylation targets, and mRNA sequencing was used to evaluate the effect of transcriptome.RESULTS: Insulin improved the seeding and proliferation of hiPSCs. We also observed an altered cell cycle profile and increase in apoptosis in hiPSCs in the absence of insulin. Furthermore, we confirmed phosphorylation of key components of insulin signaling pathway in the presence of insulin and demonstrated the significant effect of insulin on regulation of the mRNA transcriptome of hiPSCs.CONCLUSION: Insulin is a major regulator of seeding, proliferation, phosphorylation and mRNA transcriptome in hiPSCs. Collectively, our work furthers our understanding of human pluripotency and paves the way for future studies that use hiPSCs for modeling genetic ailments affecting insulin signaling pathways.

  View details for DOI 10.1186/s13287-019-1319-5

  View details for PubMedID 31358052

• Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial. The lancet. Diabetes & endocrinology Ray, K. K., Colhoun, H. M., Szarek, M., Baccara-Dinet, M., Bhatt, D. L., Bittner, V. A., Budaj, A. J., Diaz, R., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Loizeau, V., Lopes, R. D., Moryusef, A., Murin, J., Pordy, R., Ristic, A. D., Roe, M. T., Tunon, J., White, H. D., Zeiher, A. M., Schwartz, G. G., Steg, P. G., ODYSSEY OUTCOMES Committees and Investigators, Schwartz, G. G., Steg, P. G., Bhatt, D. L., Bittner, V. A., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J. W., Szarek, M., White, H. D., Zeiher, A. M., Tricoci, P., Roe, M. T., Mahaffey, K. W., Edelberg, J. M., Hanotin, C., Lecorps, G., Moryusef, A., Pordy, R., Sasiela, W. J., Tamby, J., Aylward, P. E., Drexel, H., Sinnaeve, P., Dilic, M., Lopes, R. D., Gotcheva, N. N., Prieto, J., Yong, H., Lopez-Jaramillo, P., Pecin, I., Reiner, Z., Ostadal, P., Viigimaa, M., Nieminen, M. S., Chumburidze, V., Marx, N., Danchin, N., Liberopoulos, E., Montenegro Valdovinos, P. C., Tse, H., Kiss, R. G., Xavier, D., Zahger, D., Valgimigli, M., Kimura, T., Kim, H. S., Kim, S., Erglis, A., Laucevicius, A., Kedev, S., Yusoff, K., Ramos Lopez, G. A., Alings, M., Halvorsen, S., Correa Flores, R. M., Budaj, A., Morais, J., Dorobantu, M., Karpov, Y., Ristic, A. D., Chua, T., Murin, J., Fras, Z., Dalby, A. J., Tunon, J., de Silva, H. A., Hagstrom, E., Landmesser, U., Chiang, C., Sritara, P., Guneri, S., Parkhomenko, A., Ray, K. K., Moriarty, P. M., Vogel, R., Chaitman, B., Kelsey, S. F., Olsson, A. G., Rouleau, J., Simoons, M. L., Alexander, K., Meloni, C., Rosenson, R., Sijbrands, E. J., Tricoci, P., Alexander, J. H., Armaganijan, L., Bagai, A., Bahit, M. C., Brennan, J. M., Clifton, S., DeVore, A. D., Deloatch, S., Dickey, S., Dombrowski, K., Ducrocq, G., Eapen, Z., Endsley, P., Eppinger, A., Harrison, R. W., Hess, C. N., Hlatky, M. A., Jordan, J. D., Knowles, J. W., Kolls, B. J., Kong, D. F., Leonardi, S., Lillis, L., Maron, D. J., Marcus, J., Mathews, R., Mehta, R. H., Mentz, R. J., Moreira, H. G., Patel, C. B., Bernardez-Pereira, S., Perkins, L., Povsic, T. J., Puymirat, E., Schuyler Jones, W., Shah, B. R., Sherwood, M. W., Stringfellow, K., Sujjavanich, D., Toma, M., Trotter, C., Van Diepen, S., Wilson, M. D., Yan, A. T., Schiavi, L. B., Garrido, M., Alvarisqueta, A. F., Sassone, S. A., Bordonava, A. P., Alves De Lima, A. E., Schmidberg, J. M., Duronto, E. A., Caruso, O. C., Novaretto, L. P., Hominal, M. A., Montana, O. R., Caccavo, A., Gomez Vilamajo, O. A., Lorenzatti, A. J., Cartasegna, L. R., Paterlini, G. A., Mackinnon, I. J., Caime, G. D., Amuchastegui, M., Salomone, O., Codutti, O. R., Jure, H. O., Bono, J. O., Hrabar, A. D., Vallejos, J. A., Ahuad Guerrero, R. A., Novoa, F., Patocchi, C. A., Zaidman, C. J., Giuliano, M. E., Dran, R. D., Vico, M. L., Carnero, G. S., Guzman, P. N., Medrano Allende, J. C., Garcia Brasca, D. F., Bustamante Labarta, M. H., Nani, S., Blumberg, E. D., Colombo, H. R., Liberman, A., Fuentealba, V., Luciardi, H. L., Waisman, G. D., Berli, M. A., Garcia Duran, R. O., Cestari, H. G., Luquez, H. A., Giordano, J. A., Saavedra, S. S., Zapata, G., Costamagna, O., Llois, S., Waites, J. H., Collins, N., Soward, A., Hii, C. L., Shaw, J., Arstall, M. A., Horowitz, J., Ninio, D., Rogers, J. F., Colquhoun, D., Oqueli Flores, R. E., Roberts-Thomson, P., Raffel, O., Lehman, S. J., Aroney, C., Coverdale, S. G., Garrahy, P. J., Starmer, G., Sader, M., Carroll, P. A., Dick, R., Zweiker, R., Hoppe, U., Huber, K., Berger, R., Delle-Karth, G., Frey, B., Weidinger, F., Faes, D., Hermans, K., Pirenne, B., Leone, A., Hoffer, E., Vrolix, M. C., De Wolf, L., Wollaert, B., Castadot, M., Dujardin, K., Beauloye, C., Vervoort, G., Striekwold, H., Convens, C., Roosen, J., Barbato, E., Claeys, M., Cools, F., Terzic, I., Barakovic, F., Midzic, Z., Pojskic, B., Fazlibegovic, E., Kulic, M., Durak-Nalbantic, A., Vulic, D., Muslibegovic, A., Goronja, B., Reis, G., Sousa, L., Nicolau, J. C., Giorgeto, F. E., Silva, R. P., Nigro Maia, L., Rech, R., Rossi, P. R., Cerqueira, M. J., Duda, N., Kalil, R., Kormann, A., Abrantes, J. A., Pimentel Filho, P., Soggia, A. P., de Santos, M. O., Neuenschwander, F., Bodanese, L. C., Michalaros, Y. L., Eliaschewitz, F. G., Vidotti, M. H., Leaes, P. E., Botelho, R. V., Kaiser, S., Manenti, E. R., Precoma, D. B., Moura Jorge, J. C., de B Silva, P. G., Silveira, J. A., Saporito, W., Marin-Neto, J. A., Feitosa, G. S., Ritt, L. E., de Souza, J. A., Costa, F., Souza, W. K., Reis, H. J., Machado, L., Ayoub, J. C., Todorov, G. V., Nikolov, F. P., Velcheva, E. S., Tzekova, M. L., Benov, H. O., Petranov, S. L., Tumbev, H. S., Shehova-Yankova, N. S., Markov, D. T., Raev, D. H., Mollov, M. N., Kichukov, K. N., Ilieva-Pandeva, K. A., Ivanova, R., Gospodinov, M., Mincheva, V. M., Lazov, P. V., Dimov, B. I., Senaratne, M., Stone, J., Kornder, J., Pearce, S., Dion, D., Savard, D., Pesant, Y., Pandey, A., Robinson, S., Gosselin, G., Vizel, S., Hoag, G., Bourgeois, R., Morisset, A., Sabbah, E., Sussex, B., Kouz, S., MacDonald, P., Diaz, A., Michaud, N., Fell, D., Leung, R., Vuurmans, T., Lai, C., Nigro, F., Davies, R., Nogareda, G., Vijayaraghavan, R., Ducas, J., Lepage, S., Mehta, S., Cha, J., Dupuis, R., Fong, P., Lutchmedial, S., Rodes-Cabau, J., Fadlallah, H., Cleveland, D., Huynh, T., Bata, I., Hameed, A., Pincetti, C., Potthoff, S., Prieto, J. C., Acevedo, M., Aguirre, A., Vejar, M., Yanez, M., Araneda, G., Fernandez, M., Perez, L., Varleta, P., Florenzano, F., Huidobro, L., Raffo, C. A., Olivares, C., Nahuelpan, L., Montecinos, H., Chen, J., Dong, Y., Huang, W., Wang, J., Huang, S., Yao, Z., Li, X., Cui, L., Lin, W., Sun, Y., Wang, J., Li, J., Zhang, X., Zhu, H., Chen, D., Huang, L., Dong, S., Su, G., Xu, B., Su, X., Cheng, X., Lin, J., Zong, W., Li, H., Feng, Y., Xu, D., Yang, X., Ke, Y., Lin, X., Zhang, Z., Zheng, Z., Luo, Z., Chen, Y., Ding, C., Zhong, Y., Zheng, Y., Li, X., Peng, D., Zhao, S., Li, Y., Liu, X., Wei, M., Liu, S., Yu, Y., Qu, B., Jiang, W., Zhou, Y., Zhao, X., Yuan, Z., Guo, Y., Xu, X., Shi, X., Ge, J., Fu, G., Bai, F., Fang, W., Shou, X., Yang, X., Wang, J., Xiang, M., Sun, Y., Lu, Q., Zhang, R., Zhu, J., Xu, Y., Fan, Z., Li, T., Wu, C., Jaramillo, N., Sanchez Vallejo, G., Luna Botia, D. C., Botero Lopez, R., Molina De Salazar, D. I., Cadena Bonfanti, A. J., Cotes Aroca, C., Diego Higuera, J., Blanquicett, M., Barrera Silva, S. I., Garcia Lozada, H. J., Coronel Arroyo, J. A., Accini Mendoza, J. L., Fernandez Ruiz, R. L., Quintero Ossa, A. M., Manzur Jatin, F. G., Sotomayor Herazo, A., Castellanos Parada, J., Suarez Arambula, R., Urina Triana, M. A., Fernandez Trujillo, A. M., Strozzi, M., Car, S., Jeric, M., Milicic, D., Bencic, M. L., Pintaric, H., Prvulovic, D., Sikic, J., Persic, V., Mileta, D., Stambuk, K., Babic, Z., Tomulic, V., Lukenda, J., Mejic-Krstulovic, S., Starcevic, B., Spinar, J., Horak, D., Velicka, Z., Stasek, J., Alan, D., Machova, V., Linhart, A., Novotny, V., Kaucak, V., Rokyta, R., Naplava, R., Coufal, Z., Adamkova, V., Podpera, I., Zizka, J., Motovska, Z., Marusincova, I., Svab, P., Heinc, P., Kuchar, J., Povolny, P., Matuska, J., Poulsen, S. H., Raungaard, B., Clemmensen, P., Bang, L. E., May, O., Bottcher, M., Hove, J. D., Frost, L., Gislason, G., Larsen, J., Betton Johansen, P., Hald, F., Johansen, P., Jeppesen, J., Nielsen, T., Kristensen, K. S., Walichiewicz, P. M., Lomholdt, J. D., Klausen, I. C., Nielsen, P. K., Davidsen, F., Videbaek, L., Soots, M., Vahula, V., Hedman, A., Soopold, U., Martsin, K., Jurgenson, T., Kristjan, A., Helsinki, J. K., Vikman, S., Huikuri, H., Airaksinen, J., Coste, P., Ferrari, E., Morel, O., Montalescot, G., Machecourt, J., Barone-Rochette, G., Mansourati, J., Cottin, Y., Leclercq, F., Belhassane, A., Delarche, N., Boccara, F., Paganelli, F., Clerc, J., Schiele, F., Aboyans, V., Probst, V., Berland, J., Lefevre, T., Citron, B., Khintibidze, I., Shaburishvili, T., Pagava, Z., Ghlonti, R., Lominadze, Z., Khabeishvili, G., Hemetsberger, R., Edward, K., Rauch-Krohnert, U., Stratmann, M., Appel, K., Schmidt, E., Omran, H., Stellbrink, C., Dorsel, T., Lianopoulos, E., Vohringer, H. F., Marx, R., Zirlik, A., Schellenberg, D., Heitzer, T., Laufs, U., Werner, C., Marx, N., Gielen, S., Nuding, S., Winkelmann, B., Behrens, S., Sydow, K., Karakas, M., Simonis, G., Muenzel, T., Werner, N., Leggewie, S., Bocker, D., Braun-Dullaeus, R., Toursarkissian, N., Jeserich, M., WeiSSbrodt, M., Schaeufele, T., Weil, J., Voller, H., Waltenberger, J., Natour, M., Schmitt, S., Muller-Wieland, D., Steiner, S., Heidenreich, L., Offers, E., Gremmler, U., Killat, H., Rieker, W., Patsilinakos, S., Kartalis, A., Manolis, A., Sionis, D., Chachalis, G., Skoumas, I., Athyros, V., Vardas, P., Parthenakis, F., Alexopoulos, D., Hahalis, G., Lekakis, J., Hatzitolios, A., Fausto Ovando, S. R., Arango Benecke, J. L., Rodriguez De Leon, E. R., Yan, B. P., Siu, D. C., Turi, T., Merkely, B., Ungi, I., Lupkovics, G., Nagy, L., Katona, A., Edes, I., Muller, G., Horvath, I., Kapin, T., Szigeti, Z., Falukozy, J., Kumbla, M., Sandhu, M., Annam, S., Proddutur, N. R., Regella, R., Premchand, R. K., Mahajan, A., Pawar, S., Abhyanakar, A. D., Kerkar, P., Govinda, R. A., Oomman, A., Sinha, D., Patil, S. N., Kahali, D., Sawhney, J., Joshi, A. B., Chaudhary, S., Harkut, P., Guha, S., Porwal, S., Jujjuru, S., Pothineni, R. B., Monteiro, M. R., Khan, A., Iyengar, S. S., Grewal, J. S., Chopda, M., Fulwani, M. C., Patange, A., Sachin, P., Chopra, V. K., Goyal, N. K., Shinde, R., Manakshe, G. V., Patki, N., Sethi, S., Munusamy, V., Karna, S., Thanvi, S., Adhyapak, S., Patil, C., Pandurangi, U., Mathur, R., Gupta, J., Kalashetti, S., Bhagwat, A., Raghuraman, B., Yerra, S. K., Bhansali, P., Borse, R., Rahul, P., Das, S., Kumar, V., Abdullakutty, J., Saathe, S., Palimkar, P., Sathe, S., Atar, S., Shechter, M., Mosseri, M., Arbel, Y., Ehud, C., Ofer, H., Lotan, C., Rosenschein, U., Katz, A., Henkin, Y., Francis, A., Klutstein, M., Nikolsky, E., Zukermann, R., Turgeman, Y., Halabi, M., Marmor, A., Kornowski, R., Jonas, M., Amir, O., Hasin, Y., Rozenman, Y., Fuchs, S., Zvi, V., Hussein, O., Gavish, D., Vered, Z., Caraco, Y., Elias, M., Tov, N., Wolfovitz, E., Lishner, M., Elias, N., Piovaccari, G., De Pellegrin, A., Garbelotto, R., Guardigli, G., Marco, V., Licciardello, G., Auguadro, C., Scalise, F., Cuccia, C., Salvioni, A., Musumeci, G., Senni, M., Calabro, P., Novo, S., Faggiano, P., Metra, M., De Cesare, N. B., Berti, S., Cavallini, C., Puccioni, E., Galvani, M., Tespili, M., Piatti, P., Palvarini, M., De Luca, G., Violini, R., De Leo, A., Olivari, Z., Perrone Filardi, P., Ferratini, M., Racca, V., Dai, K., Shimatani, Y., Kamiya, H., Ando, K., Takeda, Y., Morino, Y., Hata, Y., Kimura, K., Kishi, K., Michishita, I., Uehara, H., Higashikata, T., Hirayama, A., Hirooka, K., Doi, Y., Sakagami, S., Taguchi, S., Koike, A., Fujinaga, H., Koba, S., Kozuma, K., Kawasaki, T., Ono, Y., Shimizu, M., Katsuda, Y., Wada, A., Shinke, T., Kimura, T., Ako, J., Fujii, K., Takahashi, T., Sakamoto, T., Nakao, K., Furukawa, Y., Sugino, H., Tamura, R., Mano, T., Uematsu, M., Utsu, N., Ito, K., Haraguchi, T., Sato, K., Ueda, Y., Nishibe, A., Fujimoto, K., Masutani, M., Yoon, J. H., Kim, H., Park, H. S., Chae, I., Kim, M. H., Jeong, M. H., Rha, S., Kim, C., Kim, H., Kim, H. Y., Hong, T., Tahk, S., Kim, Y., Busmane, A., Pontaga, N., Strelnieks, A., Mintale, I., Sime, I., Petrulioniene, Z., Kavaliauskiene, R., Jurgaitiene, R., Sakalyte, G., Slapikas, R., Norkiene, S., Misonis, N., Kibarskis, A., Kubilius, R., Bojovski, S., Lozance, N., Kjovkaroski, A., Doncovska, S., Ong, T. K., Kasim, S., Maskon, O., Kandasamy, B., Liew, H. B., Wan Mohamed, W. M., Garcia Castillo, A., Carrillo Calvillo, J., Fajardo Campos, P., Nunez Fragoso, J. C., Bayram Llamas, E. A., Alcocer Gamba, M. A., Carranza Madrigal, J., Gonzalez Salas, L. G., Lopez Rosas, E., Gonzalez Diaz, B., Salcido Vazquez, E., Nacoud Ackar, A., Llamas Esperon, G. A., Martinez Sanchez, C. R., Guerrero De Leon, M., Suarez Otero, R., Fanghanel Salmon, G., Perez Rios, J. A., Garza Ruiz, J. A., Breedveld, R. W., Feenema-Aardema, M., Borger-Van Der Burg, A., Hoogslag, P. A., Suryapranata, H., Oomen, A., Van Haelst, P., Wiersma, J. J., Basart, D., Van Der Wal, R. M., Zwart, P., Monraats, P., Van Kesteren, H., Karalis, I., Jukema, J., Verdel, G. J., Brueren, B. R., Troquay, R. P., Viergever, E. P., Al-Windy, N. Y., Bartels, G. L., Cornel, J. H., Hermans, W. R., Herrman, J. P., Bos, R. J., Groutars, R. G., Van Der Zwaan, C. C., Kaplan, R., Lionarons, R., Ronner, E., Groenemeijer, B. E., Bronzwaer, P. N., Liem, A. A., Rensing, B. J., Bokern, M. J., Nijmeijer, R., Hersbach, F. M., Willems, F. F., Gosselink, A. T., Rasoul, S., Elliott, J., Wilkins, G., Fisher, R., Scott, D., Hart, H., Stewart, R., Harding, S., Ternouth, I., Fisher, N., Wilson, S., Aitken, D., Anscombe, R., Davidson, L., Tomala, T., Nygard, O., Sparby, J. A., Andersen, K., Gullestad, L., Jortveit, J., Munk, P. S., Singsaas, E. G., Hurtig, U., Calderon Ticona, J. R., Durand Velasquez, J. R., Negron Miguel, S. A., Sanabria Perez, E. S., Carrion Chambilla, J. M., Chavez Ayala, C. A., Castillo Leon, R. P., Vargas Gonzales, R. J., Hernandez Zuniga, J. D., Camacho Cosavalente, L. A., Bravo Mannucci, J. E., Heredia Landeo, J., Llerena Navarro, N. C., Roldan Concha, Y. M., Rodriguez Chavez, V. E., Anchante Hernandez, H. A., Zea Nunez, C. A., Mogrovejo Ramos, W., Ferrolino, A., Sy, R. A., Tirador, L., Sy, R. G., Matiga, G., Coching, R. M., Bernan, A., Rogelio, G., Morales, D. D., Tan, E., Sulit, D. J., Wlodarczak, A., Jaworska, K., Skonieczny, G., Pawlowicz, L., Wojewoda, P., Busz-Papiez, B., Bednarski, J., Goch, A., Staneta, P., Dulak, E., Saminski, K., Krasowski, W., Sudnik, W., Zurakowski, A., Skorski, M., Miklaszewicz, B., Kubica, J., Andrzej Lipko, J., Kostarska-Srokosz, E., Piepiorka, M., Drzewiecka, A., Stasiewski, A., Blicharski, T., Bystryk, L., Szpajer, M., Korol, M., Czerski, T., Mirek-Bryniarska, E., Gniot, J., Lubinski, A., Gorny, J., Franek, E., Raczak, G., Szwed, H., Monteiro, P., Mesquita Bastos, J., Pereira, H. H., Martins, D., Seixo, F., Mendonca, C., Botelho, A., Caetano, F., Minescu, B., Istratoaie, O., Tesloianu, D. N., Cristian, G., Dumitrescu, S., Podoleanu, C. G., Constantinescu, M. C., Bengus, C. M., Militaru, C., Rosu, D., Parepa, I. R., Matei, A. V., Alexandru, T. M., Malis, M., Coman, I., Stanescu-Cioranu, R., Dimulescu, D., Shvarts, Y., Orlikova, O., Kobalava, Z., Barbarash, O. L., Markov, V., Lyamina, N., Gordienko, A., Zrazhevsky, K., Vishnevsky, A. Y., Gurevich, V., Stryuk, R., Lomakin, N. V., Bokarev, I., Khlevchuk, T., Shalaev, S., Khaisheva, L., Chizhov, P., Viktorova, I., Osokina, N., Shchekotov, V., Akatova, E., Chumakova, G., Libov, I., Voevoda, M. I., Tretyakova, T. V., Baranov, E., Shustov, S., Yakushin, S., Gordeev, I., Khasanov, N., Reshetko, O., Sotnikova, T., Molchanova, O., Nikolaev, K., Gapon, L., Baranova, E., Shogenov, Z., Kosmachova, E., Karpov, Y., Povzun, A., Egorova, L., Tyrenko, V. V., Ivanov, I. G., Ilya, M., Kanorsky, S., Simic, D., Ivanovic, N., Davidovic, G., Tasic, N., Asanin, M. R., Stojic, S., Apostolovic, S. R., Ilic, S., Putnikovic Tosic, B., Stankovic, A., Arandjelovic, A., Radovanovic, S., Todic, B., Balinovac, J., Dincic, D. V., Seferovic, P., Karadzic, A., Dodic, S., Dimkovic, S., Jakimov, T., Poh, K., Ong, H. Y., Tang I-Shing, J., Micko, K., Nociar, J., Pella, D., Fulop, P., Hranai, M., Palka, J., Mazur, J., Majercak, I., Dzupina, A., Fazekas, F., Gonsorcik, J., Bugan, V., Selecky, J., Kamensky, G., Strbova, J., Smik, R., Dukat, A., Zuran, I., Poklukar, J., Cernic Suligoj, N., Cevc, M., Cyster, H. P., Ranjith, N., Corbett, C., Bayat, J., Makotoko, E. M., du Toit Theron, H., Kapp, I. E., de V Basson, M. M., Lottering, H., Van Aswegen, D., Van Zyl, L. J., Sebastian, P. J., Pillay, T., Saaiman, J. A., Commerford, P. J., Cassimjee, S., Riaz, G., Ebrahim, I. O., Sarvan, M., Mynhardt, J. H., Reuter, H., Moodley, R., Vida, M., Cequier Fillat, A. R., Bodi Peris, V., Fuentes Jimenez, F., Marin, F., Cruz Fernandez, J. M., Hidalgo Urbano, R. J., Gil-Extremera, B., Toledo, P., Worner Diz, F., Garcia-Dorado, D., Iniguez, A., Tunon Fernandez, J., Gonzalez-Juanatey, J. R., Fernandez Portales, J., Civeira Murillo, F., Matas Pericas, L., Zamorano, J. L., De Mora Martin, M., Bruguera Cortada, J., Alonso Martin, J. J., Serrano Antolin, J. M., De Berrazueta Fernandez, J. R., Vazquez de Prada, J. A., Diaz Fernandez, J. F., Garcia Lledo, J. A., Cosin Sales, J., Botas Rodriguez, J., Gusi Tragant, G., Benedicto, A., Gonzalez-Juanatey, C., Camprubi Potau, M., Plaza Perez, I., De La Tassa, C. M., Loma-Osorio Rincon, P., Balaguer Recena, J., Escudier, J. M., Payeras, A. C., Alonso Orcajo, N., Valdivielso, P., Constantine, G., Haniffa, R., Tissera, N., Amarasekera, S., Ponnamperuma, C., Fernando, N., Fernando, K., Jayawardena, J., Wijeyasingam, S., Ranasinghe, G., Ekanayaka, R., Mendis, S., Senaratne, V., Mayurathan, G., Sirisena, T., Rajapaksha, A., Herath, J. I., Amarasena, N., Berglund, S., Rasmanis, G., Vedin, O., Witt, N., Mourtzinis, G., Nicol, P., Hansen, O., Romeo, S., Agergaard Jensen, S., Torstensson, I., Ahremark, U., Sundelin, T., Moccetti, T., Muller, C., Mach, F., Binde, R., Tsai, W., Ueng, K., Lai, W., Liu, M., Hwang, J., Yin, W., Hsieh, I., Hsieh, M., Lin, W. H., Kuo, J., Huang, T., Fang, C., Kaewsuwanna, P., Soonfuang, W., Jintapakorn, W., Sukonthasarn, A., Wongpraparut, N., Sastravaha, K., Sansanayudh, N., Kehasukcharoen, W., Piyayotai, D., Chotnoparatpat, P., Camsari, A., Kultursay, H., Mutlu, B., Ersanli, M., Demirtas, M., Kirma, C., Ural, E., Koldas, L., Karpenko, O., Prokhorov, A., Vakaluyk, I., Myshanych, H., Reshotko, D., Batushkin, V., Rudenko, L., Kovalskyi, I., Kushnir, M., Tseluyko, V., Mostovoy, Y., Stanislavchuk, M., Kyiak, Y., Karpenko, Y., Malynovsky, Y., Klantsa, A., Kutniy, O., Amosova, E., Tashchuk, V., Leshchuk, O., Rishko, M., Kopytsya, M., Yagensky, A., Vatutin, M., Bagriy, A., Barna, O. M., Ushakov, O., Dzyak, G., Goloborodko, B., Rudenko, A., Zheleznyy, V., Trevelyan, J., Zaman, A., Lee, K., Moriarty, A., Aggarwal, R. K., Clifford, P., Wong, Y., Iqbal, S. M., Subkovas, E., Braganza, D., Sarkar, D., Storey, R., Griffiths, H., McClure, S., Muthusamy, R., Smith, S., Kurian, J., Levy, T., Barr, C., Kadr, H., Gerber, R., Simaitis, A., Soran, H., Mathur, A., Brodison, A., Ayaz, M., Cheema, M., Oliver, R., Thackray, S., Mudawi, T., Rahman, G., Sultan, A., Sharman, D., Sprigings, D., Butler, R., Wilkinson, P., Lip, G. Y., Halcox, J., Gallagher, S., Ossei-Gerning, N., Vardi, G., Baldari, D., Brabham, D., Treasure Ii, C., Dahl, C., Palmer, B., Wiseman, A., Khan, A., Puri, S., Mohart, A. E., Ince, C., Flores, E., Wright, S., Cheng, S., Rosenberg, M., Rogers, W. J., Kosinski, E., Forgosh, L., Waltman, J., Khan, M., Shoukfeh, M., Dagher, G., Cambier, P., Lieber, I., Kumar, P., East, C., Krichmar, P., Hasan, M., White, L., Knickelbine, T., Haldis, T., Gillespie, E., Amidon, T., Suh, D., Arif, I., Abdallah, M., Akhter, F., Carlson, E., D'Urso, M., El-Ahdab, F., Nelson, W., Moriarty, K., Harris, B., Cohen, S., Carter, L., Doty, D., Sabatino, K., Haddad, T., Malik, A., Rao, S., Mulkay, A., Jovin, I., Klancke, K., Malhotra, V., Devarapalli, S. K., Koren, M., Chandna, H., Dodds Iii, G., Goraya, T., Bengston, J., Janik, M., Moran, J., Sumner, A., Kobayashi, J., Davis, W., Yazdani, S., Pasquini, J., Thakkar, M., Vedere, A., Leimbach, W., Rider, J., Fenton, S., Singh, N., Shah, A. V., Janosik, D., Pepine, C., Berman, B., Gelormini, J., Daniels, C., Richard, K., Keating, F., Kondo, N. I., Shetty, S., Levite, H., Waider, W., Takata, T., Abu-Fadel, M., Shah, V., Aggarwal, R., Izzo, M., Kumar, A., Hattler, B., Do, R., Link, C., Bortnick, A., Kinzfogl Iii, G., Ghitis, A., Larry, J., Teufel, E., Kuhlman, P., Mclaurin, B., Zhang, W., Thew, S., Abbas, J., White, M., Islam, O., Subherwal, S., Ranadive, N., Vakili, B., Gring, C., Henderson, D., Schuchard, T., Farhat, N., Kline, G., Mahal, S., Whitaker, J., Speirs, S., Andersen, R., Daboul, N., Horwitz, P., Zahr, F., Ponce, G., Jafar, Z., Mcgarvey, J. J., Panchal, V., Voyce, S., Blok, T., Sheldon, W., Azizad, M. M., Schmalfuss, C., Picone, M., Pederson, R., Herzog, W. J., Friedman, K., Lindsey, J., Nowins, R., Timothy, E., Leonard, P., Lepor, N., El Shahawy, M., Weintraub, H., Irimpen, A., Alonso, A., May, W., Christopher, D., Galski, T., Chu, A., Mody, F., Ramin, E., Hodes, Z., Rossi, J., Rose, G., Fairlamb, J., Lambert, C. J., Raisinghani, A., Abbate, A., Vetrovec, G., King, M., Carey, C., Gerber, J., Younis, L., Park, H. T., Vidovich, M., Knutson, T., Friedman, D., Chaleff, F., Loussararian, A., Rozeman, P., Kimmelstiel, C., Kuvin, J., Silver, K., Foster, M., Tonnessen, G., Espinoza, A., Amlani, M., Wali, A., Malozzi, C., Jong, G. T., Massey, C., Wattanakit, K., O'Donnell, P. J., Singal, D., Jaffrani, N., Banuru, S., Fisher, D., Xenakis, M., Perlmutter, N., Bhagwat, R., Strader, J. J., Blonder, R., Akyea-Djamson, A., Labroo, A., Lee, K., Marais, H. J., Claxton, E. J., Weiss, R., Kathryn, R., Berk, M., Rossi, P., Joshi, P., Khera, A., Khaira, A. S., Kumkumian, G., Lupovitch, S., Purow, J., Welka, S., Hoffman, D., Fischer, S., Soroka, E., Eagerton, D., Pancholy, S., Ray, M., Erenrich, N., Farrar, M., Pollock, S., French, W. J., Diamantis, S., Guy, D., Gimple, L., Neustel, M., Schwartz, S., Pereira, E., Albert, S., Spriggs, D., Strain, J., Mittal, S., Vo, A., Chane, M., Hall, J., Vijay, N., Lotun, K., Lester, F. M., Nahhas, A., Pope, T., Nager, P., Vohra, R., Sharma, M., Bashir, R., Ahmed, H., Berlowitz, M., Fishberg, R., Barrucco, R., Yang, E., Radin, M., Sporn, D., Stapleton, D., Eisenberg, S., Landzberg, J., Mcgough, M., Turk, S., Schwartz, M., Sundram, P. S., Jain, D., Zainea, M., Bayron, C., Karlsberg, R., Dohad, S., Lui, H., Keen, W., Westerhausen, D. J., Khurana, S., Agarwal, H., Birchem, J., Penny, W. J., Chang, M., Murphy, S., Henry, J., Schifferdecker, B., Gilbert, J. M., Chalavarya, G., Eaton, C., Schmedtje, J. F., Christenson, S., Dotani, I., Denham, D., Macdonell, A., Gibson, P., Rahman, A., Al Joundi, T., Assi, N., Conrad, G., Kotha, P., Love, M., Giesler, G., Rubenstein, H., Gamil, D., Akright, L., Krawczyk, J., Cobler, J., Wells, T., Welker, J., Foster, R., Gilmore, R., Anderson, J., Jacoby, D., Harris, B., Gardner, G., Dandillaya, R., Vora, K., Kostis, J., Hunter, J., Laxson, D., Ball, E., Wells, T., Vora, K., Ball, E., Welker, J., Lopes, R., Egydio, F., Kawakami, A., Oliveira, J., Wozniak, J., Matthews, A., Ratky, C., Valiris, J., Berdan, L., Hepditch, A., Quintero, K., Rorick, T., Westbrook, M., Pascual, A., Rovito, C., Bezault, M., Drouet, E., Simon, T., White, H. D., Alsweiler, C., Luyten, A., Butters, J., Griffith, L., Shaw, M., Grunberg, L., Islam, S., Bregeault, M., Bougon, N., Faustino, D., Fontecave, S., Murphy, J., Verrier, M., Agnetti, V., Andersen, D., Badreddine, E., Bekkouche, M., Bouancheau, C., Brigui, I., Brocklehurst, M., Cianciarulo, J., Devaul, D., Domokos, S., Gache, C., Gobillot, C., Guillou, S., Healy, J., Heath, M., Jaiwal, G., Javierre, C., Labeirie, J., Monier, M., Morales, U., Mrabti, A., Mthombeni, B., Okan, B., Smith, L., Sheller, J., Sopena, S., Pellan, V., Benbernou, F., Bengrait, N., Lamoureux, M., Kralova, K., Scemama, M., Bejuit, R., Coulange, A., Berthou, C., Repincay, J., Lorenzato, C., Etienne, A., Gouet, V., Lecorps, G., Loizeau, V., Normand, M., Ourliac, A., Rondel, C., Adamo, A., Beltran, P., Barraud, P., Dubois-Gache, H., Halle, B., Metwally, L., Mourgues, M., Sotty, M., Vincendet, M., Cotruta, R., Chengyue, Z., Fournie-Lloret, D., Morrello, C., Perthuis, A., Picault, P., Zobouyan, I., Colhoun, H. M., Dempsey, M. A., McClanahan, M. A. 2019

  Abstract

  BACKGROUND: After acute coronary syndrome, diabetes conveys an excess risk of ischaemic cardiovascular events. A reduction in mean LDL cholesterol to 1·4-1·8 mmol/L with ezetimibe or statins reduces cardiovascular events in patients with an acute coronary syndrome and diabetes. However, the efficacy and safety of further reduction in LDL cholesterol with an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) after acute coronary syndrome is unknown. We aimed to explore this issue in a prespecified analysis of the ODYSSEY OUTCOMES trial of the PCSK9 inhibitor alirocumab, assessing its effects on cardiovascular outcomes by baseline glycaemic status, while also assessing its effects on glycaemic measures including risk of new-onset diabetes.METHODS: ODYSSEY OUTCOMES was a randomised, double-blind, placebo-controlled trial, done at 1315 sites in 57 countries, that compared alirocumab with placebo in patients who had been admitted to hospital with an acute coronary syndrome (myocardial infarction or unstable angina) 1-12 months before randomisation and who had raised concentrations of atherogenic lipoproteins despite use of high-intensity statins. Patients were randomly assigned (1:1) to receive alirocumab or placebo every 2 weeks; randomisation was stratified by country and was done centrally with an interactive voice-response or web-response system. Alirocumab was titrated to target LDL cholesterol concentrations of 0·65-1·30 mmol/L. In this prespecified analysis, we investigated the effect of alirocumab on cardiovascular events by glycaemic status at baseline (diabetes, prediabetes, or normoglycaemia)-defined on the basis of patient history, review of medical records, or baseline HbA1c or fasting serum glucose-and risk of new-onset diabetes among those without diabetes at baseline. The primary endpoint was a composite of death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. ODYSSEY OUTCOMES is registered with ClinicalTrials.gov, number NCT01663402.FINDINGS: At study baseline, 5444 patients (28·8%) had diabetes, 8246 (43·6%) had prediabetes, and 5234 (27·7%) had normoglycaemia. There were no significant differences across glycaemic categories in median LDL cholesterol at baseline (2·20-2·28 mmol/L), after 4 months' treatment with alirocumab (0·80 mmol/L), or after 4 months' treatment with placebo (2·25-2·28 mmol/L). In the placebo group, the incidence of the primary endpoint over a median of 2·8 years was greater in patients with diabetes (16·4%) than in those with prediabetes (9·2%) or normoglycaemia (8·5%); hazard ratio (HR) for diabetes versus normoglycaemia 2·09 (95% CI 1·78-2·46, p<0·0001) and for diabetes versus prediabetes 1·90 (1·65-2·17, p<0·0001). Alirocumab resulted in similar relative reductions in the incidence of the primary endpoint in each glycaemic category, but a greater absolute reduction in the incidence of the primary endpoint in patients with diabetes (2·3%, 95% CI 0·4 to 4·2) than in those with prediabetes (1·2%, 0·0 to 2·4) or normoglycaemia (1·2%, -0·3 to 2·7; absolute risk reduction pinteraction=0·0019). Among patients without diabetes at baseline, 676 (10·1%) developed diabetes in the placebo group, compared with 648 (9·6%) in the alirocumab group; alirocumab did not increase the risk of new-onset diabetes (HR 1·00, 95% CI 0·89-1·11). HRs were 0·97 (95% CI 0·87-1·09) for patients with prediabetes and 1·30 (95% CI 0·93-1·81) for those with normoglycaemia (pinteraction=0·11).INTERPRETATION: After a recent acute coronary syndrome, alirocumab treatment targeting an LDL cholesterol concentration of 0·65-1·30 mmol/L produced about twice the absolute reduction in cardiovascular events among patients with diabetes as in those without diabetes. Alirocumab treatment did not increase the risk of new-onset diabetes.FUNDING: Sanofi and Regeneron Pharmaceuticals.

  View details for DOI 10.1016/S2213-8587(19)30158-5

  View details for PubMedID 31272931

• Polygenic risk scores in coronary artery disease CURRENT OPINION IN CARDIOLOGY Rao, A. S., Knowles, J. W. 2019; 34 (4): 435–40

  View details for DOI 10.1097/HCO.0000000000000629

  View details for Web of Science ID 000480700000018

• Trends in overall, cardiovascular and cancer-related mortality among individuals with diabetes reported on death certificates in the United States between 2007 and 2017 DIABETOLOGIA Kim, D., Li, A. A., Cholankeril, G., Kim, S. H., Ingelsson, E., Knowles, J. W., Harrington, R. A., Ahmed, A. 2019; 62 (7): 1185–94

  View details for DOI 10.1007/s00125-019-4870-9

  View details for Web of Science ID 000471176200009

• No evidence of a causal association of type 2 diabetes and glucose metabolism with atrial fibrillation DIABETOLOGIA Harati, H., Zanetti, D., Rao, A., Gustafsson, S., Perez, M., Ingelsson, E., Knowles, J. W. 2019; 62 (5): 800–804

  View details for DOI 10.1007/s00125-019-4836-y

  View details for Web of Science ID 000463795300008

• Trends in overall, cardiovascular and cancer-related mortality among individuals with diabetes reported on death certificates in the United States between 2007 and 2017. Diabetologia Kim, D., Li, A. A., Cholankeril, G., Kim, S. H., Ingelsson, E., Knowles, J. W., Harrington, R. A., Ahmed, A. 2019

  Abstract

  AIMS/HYPOTHESIS: The determination of diabetes as underlying cause of death by using the death certificate may result in inaccurate estimation of national mortality attributed to diabetes, because individuals who die with diabetes generally have other conditions that may contribute to their death. We investigated the trends in age-standardised mortality due to diabetes as underlying or contributing cause of death and cause-specific mortality from cardiovascular disease (CVD), complications of diabetes and cancer among individuals with diabetes listed on death certificates in the USA from 2007 to 2017.METHODS: Using the US Census and national mortality database, we calculated age-standardised mortality due to diabetes as underlying or contributing cause of death and cause-specific mortality rates among adults over 20years with diabetes listed on death certificates. A total of 2,686,590 deaths where diabetes was underlying or contributing cause of death were analysed. We determined temporal mortality rate patterns by joinpoint regression analysis with estimates of annual percentage change (APC).RESULTS: Age-standardised diabetes mortality rates compared among underlying cause of death, contributing cause of death and all-cause mortality were 32.2 vs 75.7 vs 105.1 per 100,000 individuals during the study period. The age-standardised mortality rates due to diabetes as underlying or contributing cause of death declined from 112.2 per 100,000 individuals in 2007 to 104.3 per 100,000 individuals in 2017 with the most pronounced decline noted from 2007 to 2014 (APC -1.4%; 95% CI -1.9%, -1.0%) and stabilisation in decline from 2014 to 2017 (APC 1.1%; 95% CI -0.6%, 2.8%). In terms of cause-specific mortality among individuals with diabetes listed on death certificates, the age-standardised mortality rates for CVD declined at an annual rate of 1.2% with a marked decline of 2.3% between 2007 and 2014. Age-standardised diabetes-specific mortality rates as underlying cause of death decreased from 2007 to 2009 (APC -4.5%) and remained stable from 2009 to 2017. Age-standardised mortality rates for cancer steadily decreased with an average APC of -1.4% (95% CI -1.8%, -1.0%) during the 11-year period. Mortality in the subcategory of CVD demonstrated significant differences.CONCLUSIONS/INTERPRETATION: Current national estimates capture about 30% of all-cause mortality among individuals with diabetes listed as underlying or contributing cause of death on death certificates. The age-standardised mortality due to diabetes as underlying or contributing cause of death and cause-specific mortality from CVD in individuals with diabetes listed as underlying or contributing cause of death plateaued from 2014 onwards except for hypertensive heart disease and heart failure.

  View details for PubMedID 31011776

• Body composition and atrial fibrillation: a Mendelian randomization study EUROPEAN HEART JOURNAL Tikkanen, E., Gustafsson, S., Knowles, J. W., Perez, M., Burgess, S., Ingelsson, E. 2019; 40 (16): 1277-+

  View details for DOI 10.1093/eurheartj/ehz003

  View details for Web of Science ID 000490013700010

• Polygenic risk scores in coronary artery disease. Current opinion in cardiology Rao, A. S., Knowles, J. W. 2019

  Abstract

  PURPOSE OF REVIEW: Large genome-wide association studies (GWAS) have identified variants accounting for a substantial portion of the heritable risk for coronary artery disease (CAD). These studies have not only catalyzed drug discovery but also have opened the possibility of improved risk prediction and stratification. Here we review the current state-of-the art in polygenic risk scores (PRSs) and look to the future, as these scores move towards clinical application.RECENT FINDINGS: Over the last decade, multilocus PRSs for CAD have expanded to include millions of variants and demonstrated strong association with CAD outcomes, even when adjusted for traditional risk factors. Recently, PRSs have shown better prediction of CAD outcomes than any single traditional risk factor alone. Advances in statistical methods used to generate PRSs have improved their predictive ability and transferability between populations with varied ancestries. Initial clinical studies have also demonstrated the potential of genetic information to impact shared decision-making between patients and providers, leading to improved outcomes.SUMMARY: PRSs can improve risk stratification for CAD especially in white/European populations and have the potential to alter routine clinical care. However, unlocking this potential will require additional research in PRSs in nonwhite populations and substantial investment in clinical implementation studies.

  View details for PubMedID 30994529

• Finding missed cases of familial hypercholesterolemia in health systems using machine learning. NPJ digital medicine Banda, J. M., Sarraju, A., Abbasi, F., Parizo, J., Pariani, M., Ison, H., Briskin, E., Wand, H., Dubois, S., Jung, K., Myers, S. A., Rader, D. J., Leader, J. B., Murray, M. F., Myers, K. D., Wilemon, K., Shah, N. H., Knowles, J. W. 2019; 2: 23

  Abstract

  Familial hypercholesterolemia (FH) is an underdiagnosed dominant genetic condition affecting approximately 0.4% of the population and has up to a 20-fold increased risk of coronary artery disease if untreated. Simple screening strategies have false positive rates greater than 95%. As part of the FH Foundation's FIND FH initiative, we developed a classifier to identify potential FH patients using electronic health record (EHR) data at Stanford Health Care. We trained a random forest classifier using data from known patients (n = 197) and matched non-cases (n = 6590). Our classifier obtained a positive predictive value (PPV) of 0.88 and sensitivity of 0.75 on a held-out test-set. We evaluated the accuracy of the classifier's predictions by chart review of 100 patients at risk of FH not included in the original dataset. The classifier correctly flagged 84% of patients at the highest probability threshold, with decreasing performance as the threshold lowers. In external validation on 466 FH patients (236 with genetically proven FH) and 5000 matched non-cases from the Geisinger Healthcare System our FH classifier achieved a PPV of 0.85. Our EHR-derived FH classifier is effective in finding candidate patients for further FH screening. Such machine learning guided strategies can lead to effective identification of the highest risk patients for enhanced management strategies.

  View details for DOI 10.1038/s41746-019-0101-5

  View details for PubMedID 31304370

  View details for PubMedCentralID PMC6550268

• Finding missed cases of familial hypercholesterolemia in health systems using machine learning NPJ DIGITAL MEDICINE Banda, J. M., Sarraju, A., Abbasi, F., Parizo, J., Pariani, M., Ison, H., Briskin, E., Wand, H., Dubois, S., Jung, K., Myers, S. A., Rader, D. J., Leader, J. B., Murray, M. F., Myers, K. D., Wilemon, K., Shah, N. H., Knowles, J. W. 2019; 2

  View details for DOI 10.1038/s41746-019-0101-5

  View details for Web of Science ID 000466788500001

• Impact of race/ethnicity on insulin resistance and hypertriglyceridaemia DIABETES & VASCULAR DISEASE RESEARCH Raygor, V., Abbasi, F., Lazzeroni, L. C., Kim, S., Ingelsson, E., Reaven, G. M., Knowles, J. W. 2019; 16 (2): 153–59

  View details for DOI 10.1177/1479164118813890

  View details for Web of Science ID 000465592900007

• Association of Statin Adherence With Mortality in Patients With Atherosclerotic Cardiovascular Disease JAMA CARDIOLOGY Rodriguez, F., Maron, D. J., Knowles, J. W., Virani, S. S., Lin, S., Heidenreich, P. A. 2019; 4 (3): 206–13

  View details for DOI 10.1001/jamacardio.2018.4936

  View details for Web of Science ID 000461901600006

• No evidence of a causal association of type 2 diabetes and glucose metabolism with atrial fibrillation. Diabetologia Harati, H., Zanetti, D., Rao, A., Gustafsson, S., Perez, M., Ingelsson, E., Knowles, J. W. 2019

  Abstract

  AIMS/HYPOTHESIS: Several epidemiological studies have shown an increased risk of atrial fibrillation in individuals with type 2 diabetes or milder forms of dysglycaemia. We aimed to assess whether this relation is causal using a Mendelian randomisation approach.METHODS: Two-sample Mendelian randomisation was used to obtain estimates of the influence of type 2 diabetes, fasting blood glucose (FBG), and HbA1c on the risk of atrial fibrillation. Instrumental variables were constructed using available summary statistics from meta-analyses of genome-wide association studies (GWAS) for type 2 diabetes and associated phenotypes. Pleiotropic SNPs were excluded from the analyses. The most recent GWAS meta-analysis summary statistics for atrial fibrillation, which included over 1 million individuals (approximately 60,000 individuals with atrial fibrillation) was used for outcome analysis.RESULTS: Neither type 2 diabetes (OR 1.01 [95% CI 0.98, 1.03]; p=0.37), nor FBG (OR 0.95 [95% CI 0.82, 1.09] per mmol/l; p=0.49) or HbA1c (OR 1.01 [95% CI, 0.85, 1.17] per mmol/mol [%]; p=0.88) were associated with atrial fibrillation in Mendelian randomisation analyses. We had >80% statistical power to detect ORs of 1.08, 1.06 and 1.09 or larger for type 2 diabetes, FBG and HbA1c, respectively, for associations with atrial fibrillation.CONCLUSIONS/INTERPRETATION: This Mendelian randomisation analysis does not support a causal role of clinical significance between genetically programmed type 2 diabetes, FBG or HbA1c and development of atrial fibrillation. These data suggest that drug treatment to reduce dysglycaemia is unlikely to be an effective strategy for atrial fibrillation prevention.DATA AVAILABILITY: The datasets analysed during the current study are available from the following repository: Nielsen JB, Thorolfsdottir RB, Fritsche LG, et al (2018) GWAS summary statistics for AF (N=60,620 AF cases and 970,216 controls). Center for Statistical Genetics: http://csg.sph.umich.edu/willer/public/afib2018/nielsen-thorolfsdottir-willer-NG2018-AFib-gwas-summary-statistics.tbl.gz.

  View details for PubMedID 30810766

• Body composition and atrial fibrillation: a Mendelian randomization study. European heart journal Tikkanen, E., Gustafsson, S., Knowles, J. W., Perez, M., Burgess, S., Ingelsson, E. 2019

  Abstract

  Aims: Increases in fat-free mass and fat mass have been associated with higher risk of atrial fibrillation (AF) in observational studies. It is not known whether these associations reflect independent causal processes. Our aim was to evaluate independent causal roles of fat-free mass and fat mass on AF.Methods and results: We conducted a large observational study to estimate the associations between fat-free mass and fat mass on incident AF in the UK Biobank (N=487404, N events=10365). Genome-wide association analysis was performed to obtain genetic instruments for Mendelian randomization (MR). We evaluated the causal effects of fat-free mass and fat mass on AF with two-sample method by using genetic associations from AFGen consortium as outcome. Finally, we evaluated independent causal effects of fat-free mass and fat mass with multivariate MR. Both fat-free mass and fat mass had observational associations with incident AF [hazard ratio (HR)=1.77, 95% confidence interval (CI) 1.72-1.83; HR=1.40, 95% CI 1.37-1.43 per standard deviation increase in fat-free and fat mass, respectively]. The causal effects using the inverse-variance weighted method were 1.55 (95% CI 1.38-1.75) for fat-free mass and 1.30 (95% CI 1.17-1.45) for fat mass. Weighted median, Egger regression, and penalized methods showed similar estimates. The multivariate MR analysis suggested that the causal effects of fat-free and fat mass were independent of each other (causal risk ratios: 1.37, 95% CI 1.06-1.75; 1.28, 95% CI 1.03-1.58).Conclusion: Genetically programmed increases in fat-free mass and fat mass independently cause an increased risk of AF.

  View details for PubMedID 30721963

• Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events The ODYSSEY OUTCOMES Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Szarek, M., White, H. D., Schwartz, G. G., Alings, M., Bhatt, D. L., Bittner, V. A., Chiang, C., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J., Kimura, T., Kiss, R., Lecorps, G., Mahaffey, K. W., Moryusef, A., Pordy, R., Roe, M. T., Tricoci, P., Xavier, D., Zeiher, A. M., Steg, G., Schwartz, G. G., Steg, P., Bhatt, D. L., Bittner, V. A., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J., Szarek, M., White, H. D., Zeiher, A. M., Tricoci, P., Roe, M. T., Mahaffey, K. W., Edelberg, J. M., Hanotin, C., Lecorps, G., Moryusef, A., Pordy, R., Sasiela, W. J., Tamby, J., Aylward, P. E., Drexel, H., Sinnaeve, P., Dilic, M., Gotcheva, N. N., Goodman, S. G., Prieto, J., Yong, H., Lopez-Jaramillo, P., Pecin, I., Reiner, Z., Ostadal, P., Poulsen, S., Viigimaa, M., Nieminen, M. S., Danchin, N., Chumburidze, V., Marx, N., Liberopoulos, E., Valdovinos, P., Tse, H., Kiss, R., Xavier, D., Zahger, D., Valgimigli, M., Kimura, T., Kim, H., Kim, S., Kedev, S., Erglis, A., Laucevicius, A., Yusoff, K., Lopez, R., Arturo, G., Alings, M., White, H. D., Halvorsen, S., Correa Flores, R. M., Sy, R. G., Budaj, A., Morais, J., Dorobantu, M., Karpov, Y., Ristic, A. D., Chua, T., Murin, J., Fras, Z., Dalby, A. J., Tunon, J., de Silva, H., Hagstrom, E., Muller, C., Chiang, C., Sritara, P., Guneri, S., Parkhomenko, A., Ray, K. K., Moriarty, P. M., Roe, M. T., Chaitman, B., Kelsey, S. F., Olsson, A. G., Rouleau, J., Simoons, M. L., Alexander, K., Meloni, C., Rosenson, R., Sijbrands, E. G., Alexander, J. H., Armaganijan, L., Bagai, A., Bahit, M., Brennan, J., Clifton, S., DeVore, A. D., Deloatch, S., Dickey, S., Dombrowski, K., Ducrocq, G., Eapen, Z., Endsley, P., Eppinger, A., Harrison, R. W., Hess, C., Hlatky, M. A., Jordan, J., Knowles, J. W., Kolls, B. J., Kong, D. F., Leonardi, S., Lillis, L., Maron, D. J., Marcus, J., Mathews, R., Mehta, R. H., Mentz, R. J., Moreira, H., Patel, C. B., Pereira, S., Perkins, L., Povsic, T. J., Puymirat, E., Jones, W., Shah, B. R., Sherwood, M. W., Stringfellow, K., Sujjavanich, D., Toma, M., Van Diepen, S. P., Wilson, M. D., Yan, A., Lopes, R. D., Trotter, C., Schiavi, L. B., Garrido, M., Alvarisqueta, A. F., Sassone, S. A., Bordonava, A. P., Alves De Lima, A. E., Schmidberg, J. M., Duronto, E. A., Caruso, O. C., Novaretto, L. P., Angel Hominal, M., Montana, O. R., Caccavo, A., Gomez Vilamajo, O. A., Lorenzatti, A. J., Cartasegna, L. R., Paterlini, G. A., Mackinnon, I. J., Caime, G. D., Amuchastegui, M., Salomone, R., Codutti, O. R., Jure, H. O., Bono, J. E., Hrabar, A. D., Vallejos, J. A., Ahuad Guerrero, R. A., Novoa, F., Patocchi, C. A., Zaidman, C. J., Giuliano, M. E., Dran, R. D., Vico, M. L., Carnero, G. S., Guzman, P. N., Medrano Allende, J. C., Garcia Brasca, D. F., Bustamante Labarta, M. H., Nani, S., Blumberg, E. S., Colombo, H. R., Liberman, A., Luciardi, H. L., Waisman, G. D., Berli, M. A., Duran, R., Cestari, H. G., Luquez, H. A., Giordano, J. A., Saavedra, S. S., Zapata, G., Costamagna, O., Llois, S., Waites, J. H., Collins, N., Soward, A., Aylward, P. E., Hii, C. S., Shaw, J., Arstall, M. A., Horowitz, J., Rogers, J. F., Colquhoun, D., Oqueli Flores, R. E., Roberts-Thomson, P., Raffel, O., Lehman, S. J., Aroney, C., Coverdale, S. M., Garrahy, P. J., Starmer, G., Sader, M., Carroll, P. A., Dick, R., Zweiker, R., Hoppe, U., Huber, K., Berger, R., Weidinger, F., Faes, D., Hermans, K., Pirenne, B., Leone, A., Hoffer, E., Vrolix, M. M., De Wolf, L., Wollaert, B., Castadot, M., Dujardin, K., Beauloye, C., Vervoort, G., Striekwold, H., Convens, C., Roosen, J., Barbato, E., Claeys, M., Cools, F., Terzic, I., Barakovic, F., Midzic, Z., Pojskic, B., Fazlibegovic, E., Durak-Nalbantic, A., Vulic, D., Muslibegovic, A., Goronja, B., Reis, G., Sousa, L., Nicolau, J. C., Giorgeto, F. E., Silva, R. P., Maia, L., Rech, R., Rossi, P. F., Cerqueira, M. G., Duda, N., Kalil, R., Kormann, A., Abrantes, J. M., Pimentel Filho, P., Soggia, A., de Santos, M. N., Neuenschwander, F., Bodanese, L. C., Michalaros, Y. L., Eliaschewitz, F. G., Vidotti, M. H., Leaes, P. E., Botelho, R. V., Kaiser, S., Fernandes Manenti, E. F., Precoma, D. B., Moura Jorge, J. C., Silva, P. B., Silveira, J. A., Saporito, W., Marin Neto, J. A., Feitosa, G. S., Ritt, L. F., de Souza, J. A., Costa, F., Souza, W. B., Reis, H. L., Machado, L., Aidar Ayoub, J., Todorov, G. V., Nikolov, F. P., Velcheva, E. S., Tzekova, M. L., Benov, H. O., Petranov, S. L., Tumbev, H. S., Shehova-Yankova, N. S., Markov, D. T., Raev, D. H., Mollov, M. N., Kichukov, K. N., Ilieva-Pandeva, K. A., Ivanova, R., Mincheva, V. M., Lazov, P. V., Dimov, B. I., Senaratne, M., Stone, J., Kornder, J., Pearce, S., Dion, D., Savard, D., Pesant, Y., Pandey, A., Robinson, S., Gosselin, G., Vizel, S., Hoag, G., Bourgeois, R., Morisset, A., Sabbah, E., Sussex, B., Kouz, S., MacDonald, P., Diaz, A., Michaud, N., Fell, D., Leung, R., Vuurmans, T., Lai, C., Nigro, F., Davies, R., Nogareda, G., Vijayaraghavan, R., Ducas, J., Lepage, S., Mehta, S., Cha, J., Dupuis, R., Fong, P., Rodes-Cabau, J., Fadlallah, H., Cleveland, D., Thao Huynh, Bata, I., Hameed, A., Pincetti, C., Potthoff, S., Prieto, J. C., Acevedo, M., Aguirre, A., Vejar, M., Yanez, M., Araneda, G., Fernandez, M., Perez, L., Varleta, P., Florenzano, F., Huidobro, L., Raffo, C. A., Olivares, C., Nahuelpan, L., Montecinos, H., Chen, J., Dong, Y., Huang, W., Wang, J., Huang, S., Yao, Z., Li, X., Cui, L., Lin, W., Sun, Y., Wang, J., Li, J., Zhang, X., Zhu, H., Chen, D., Huang, L., Dong, S., Su, G., Xu, B., Su, X., Cheng, X., Lin, J., Zong, W., Li, H., Feng, Y., Xu, D., Yang, X., Ke, Y., Lin, X., Zhang, Z., Zheng, Z., Luo, Z., Chen, Y., Ding, C., Zheng, Y., Li, X., Peng, D., Li, Y., Wei, M., Liu, S., Yu, Y., Qu, B., Jiang, W., Zhou, Y., Zhao, X., Yuan, Z., Guo, Y., Xu, X., Shi, X., Ge, J., Fu, G., Bai, F., Fang, W., Shou, X., Yang, X., Wang, J., Sun, Y., Lu, Q., Zhang, R., Zhu, J., Xu, Y., Fan, Z., Li, T., Wu, C., Jaramillo, N., Vallejo, G., Botia, D., Lopez, R., De Salazar, D., Bonfanti, A., Higuera, J., Silva, S., Lozada, H., Arroyo, J., Mendoza, J., Ruiz, R., Jatin, F., Herazo, A., Parada, J., Triana, M., Strozzi, M., Car, S., Milicic, D., Bencic, M., Pintaric, H., Prvulovic, D., Sikic, J., Persic, V., Mileta, D., Stambuk, K., Zdravko, B., Tomulic, V., Krstulovic, S., Starcevic, B., Spinar, J., Horak, D., Stasek, J., Alan, D., Machova, V., Linhart, A., Novotny, V., Kaucak, V., Rokyta, R., Naplava, R., Coufal, Z., Adamkova, V., Podpera, I., Zizka, J., Motovska, Z., Marusincova, I., Svab, P., Ostadal, P., Heinc, P., Kuchar, J., Povolny, P., Matuska, J., Raungaard, B., Clemmensen, P., Bang, L. E., May, O., Bottcher, M., Hove, J. D., Frost, L., Gislason, G., Larsen, J., Johansen, P., Hald, F., Jeppesen, J., Nielsen, T., Kristensen, K. S., Walichiewicz, P., Lomholdt, J. D., Klausen, I. C., Nielsen, P., Davidsen, F., Videbaek, L., Soots, M., Vahula, V., Hedman, A., Soopold, U., Martsin, K., Kristjan, A., Taskinen, M., Porthan, K., Airaksinen, J. K., Juonala, M., Kiviniemi, T., Vikman, S., Posio, P., Taurio, J., Huikuri, H., Kaikkonen, K., Coste, P., Ferrari, E., Morel, O., Montalescot, G., Barone-Rochette, G., Mansourati, J., Cottin, Y., Leclercq, F., Belhassane, A., Delarche, N., Boccara, F., Paganelli, F., Clerc, J., Schiele, F., Aboyans, V., Probst, V., Berland, J., Lefevre, T., Citron, B., Khintibidze, I., Shaburishvili, T., Pagava, Z., Ghlonti, R., Lominadze, Z., Khabeishvili, G., Hemetsberger, R., Rauch-Kroehnert, U., Stratmann, M., Appel, K., Schmidt, E., Omran, H., Stellbrink, C., Dorsel, T., Lianopoulos, E., Marx, R., Zirlik, A., Schellenberg, D., Heitzer, T., Laufs, U., Marx, N., Gielen, S., Winkelmann, B., Behrens, S., Sydow, K., Simonis, G., Muenzel, T., Werner, N., Leggewie, S., Boecker, D., Braun-Dullaeus, R., Toursarkissian, N., Jeserich, M., Weissbrodt, M., Schaeufele, T., Weil, J., Voeller, H., Waltenberger, J., Natour, M., Schmitt, S., Steiner, S., Heidenreich, L., Gremmler, U., Killat, H., Rieker, W., Patsilinakos, S., Kartalis, A., Manolis, A., Sionis, D., Liberopoulos, E., Skoumas, I., Athyros, V., Vardas, P., Parthenakis, F., Alexopoulos, D., Hahalis, G., Lekakis, J., Hatzitolios, A., Ovando, S., Valdovinos, P., Benecke, J., De Leon, E., Yan, B. Y., Siu, D. W., Turi, T., Merkely, B., Kiss, R., Ungi, I., Lupkovics, G., Nagy, L., Katona, A., Edes, I., Muller, G., Horvath, I., Kapin, T., Falukozy, J., Kumbla, M., Sandhu, M., Annam, S., Proddutur, N., Premchand, R. K., Mahajan, A., Abhyanakar, A. D., Kerkar, P., Govinda, R. A., Oomman, A., Sinha, D., Patil, S. N., Kahali, D., Sawhney, J., Joshi, A. B., Chaudhary, S., Harkut, P., Guha, S., Porwal, S., Jujjuru, S., Pothineni, R. B., Monteiro, M. R., Khan, A., Iyengar, S. S., Grewal, J., Chopda, M., Fulwani, M. C., Patange, A., Chopra, V. K., Goyal, N. K., Shinde, R., Manakshe, G. V., Patki, N., Sethi, S., Munusamy, V., Karna, S., Adhyapak, S., Pandurangi, U., Mathur, R., Kalashetti, S., Bhagwat, A., Raghuraman, B., Yerra, S., Bhansali, P., Borse, R., Das, S., Abdullakutty, J., Saathe, S., Palimkar, P., Abdullkutty, J., Sathe, S., Palimkar, P., Atar, S., Shechter, M., Mosseri, M., Arbel, Y., Lotan, C., Rosenschein, U., Katz, A., Henkin, Y., Francis, A., Klutstein, M., Nikolsky, E., Turgeman, Y., Halabi, M., Kornowski, R., Jonas, M., Amir, O., Rozenman, Y., Fuchs, S., Hussein, O., Gavish, D., Vered, Z., Caraco, Y., Elias, M., Tov, N., Lishner, M., Elias, N., Piovaccari, G., De Pellegrin, A., Guardigli, G., Licciardello, G., Auguadro, C., Cuccia, C., Salvioni, A., Musumeci, G., Calabro, P., Novo, S., Faggiano, P., De Cesare, N. B., Berti, S., Cavallini, C., Puccioni, E., Galvani, M., Tespili, M., Piatti, P., Palvarini, M., De Luca, G., Violini, R., De Leo, A., Filardi, P., Ferratini, M., Ricca, V., Dai, K., Kamiya, H., Ando, K., Takeda, Y., Morino, Y., Hata, Y., Kimura, K., Kishi, K., Michishita, I., Uehara, H., Higashikata, T., Hirayama, A., Hirooka, K., Sakagami, S., Taguchi, S., Koike, A., Fujinaga, H., Koba, S., Kozuma, K., Kawasaki, T., Ono, Y., Shimizu, M., Katsuda, Y., Wada, A., Shinke, T., Kimura, T., Ako, J., Fujii, K., Takahashi, T., Sakamoto, T., Furukawa, Y., Sugino, H., Mano, T., Utsu, N., Ito, K., Haraguchi, T., Ueda, Y., Nishibe, A., Fujimoto, K., Masutani, M., Fujimoto, K., Yoon, J., Kim, S., Park, H., Chae, I., Kim, M., Jeong, M., Rha, S., Kim, C., Kim, H., Hong, T., Tahk, S., Kim, Y., Busmane, A., Pontaga, N., Strelnieks, A., Mintale, I., Sime, I., Petrulioniene, Z., Kavaliauskiene, R., Jurgaitiene, R., Sakalyte, G., Slapikas, R., Norkiene, S., Misonis, N., Kibarskis, A., Kubilius, R., Bojovski, S., Kedev, S., Lozance, N., Kjovkaroski, A., Doncovska, S., Ong, T., Kasim, S., Maskon, O., Kandasamy, B., Yusoff, K., Liew, H. B., Mohamed, W., ODYSSEY OUTCOMES Comm Investigator 2019; 73 (4): 387–96

  View details for DOI 10.1016/j.jacc.2018.10.039

  View details for Web of Science ID 000456818200001

• Genetic Testing and Risk Scores: Impact on Familial Hypercholesterolemia FRONTIERS IN CARDIOVASCULAR MEDICINE Sarraju, A., Knowles, J. W. 2019; 6

  View details for DOI 10.3389/fcvm.2019.00005

  View details for Web of Science ID 000467190200001

• Effect of Alirocumab on Mortality After Acute Coronary Syndromes: An Analysis of the ODYSSEY OUTCOMES Randomized Clinical Trial. Circulation Steg, P. G., Szarek, M. n., Bhatt, D. L., Bittner, V. A., Brégeault, M. F., Dalby, A. J., Diaz, R. n., Edelberg, J. M., Goodman, S. G., Hanotin, C. n., Harrington, R. A., Jukema, J. W., Lecorps, G. n., Mahaffey, K. W., Moryusef, A. n., Ostadal, P. n., Parkhomenko, A. n., Pordy, R. n., Roe, M. T., Tricoci, P. n., Vogel, R. n., White, H. D., Zeiher, A. M., Schwartz, G. G. 2019

  Abstract

  Trials of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome (ACS).ODYSSEY OUTCOMES was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1-12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death.Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years' follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths ( P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events ( P<0.001) and thereby may have attenuated the number of noncardiovascular deaths. A post-hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined with achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend).Alirocumab added to intensive statin therapy has the potential to reduce death after ACS, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low.URL: https://www.clinicaltrials.gov. Unique Identifier: NCT01663402.

  View details for DOI 10.1161/CIRCULATIONAHA.118.038840

  View details for PubMedID 31117810

• Familial Hypercholesterolemia GENETIC CAUSES OF CARDIAC DISEASE Sarraju, A., Knowles, J. W., Erdmann, J., Moretti, A. 2019; 7: 185-198

  View details for DOI 10.1007/978-3-030-27371-2_6

  View details for Web of Science ID 000652016100006

• Longitudinal low density lipoprotein cholesterol goal achievement and cardiovascular outcomes among adult patients with familial hypercholesterolemia: The CASCADE FH registry. Atherosclerosis Duell, P. B., Gidding, S. S., Andersen, R. L., Knickelbine, T. n., Anderson, L. n., Gianos, E. n., Shrader, P. n., Kindt, I. n., O'Brien, E. C., McCann, D. n., Hemphill, L. C., Ahmed, C. D., Martin, S. S., Larry, J. A., Ahmad, Z. S., Kullo, I. J., Underberg, J. A., Guyton, J. n., Thompson, P. n., Wilemon, K. n., Roe, M. T., Rader, D. J., Cuchel, M. n., Linton, M. F., Shapiro, M. D., Moriarty, P. M., Knowles, J. W. 2019; 289: 85–93

  Abstract

  There are limited data from the US on outcomes of patients in specialty care for familial hypercholesterolemia (FH).CASCADE FH Registry data were analyzed to assess longitudinal changes in medication usage, in low density lipoprotein cholesterol (LDL-C) levels, and the rate of major adverse cardiovascular events (MACE (myocardial infarction, coronary revascularization, stroke or transient ischemic attack) in adults with FH followed in US specialty clinics.The cohort consisted of 1900 individuals (61% women, 87% Caucasian), with mean age of 56 ± 15 years, 37% prevalence of ASCVD at enrollment, mean pretreatment LDL-C 249 ± 68 mg/dl, mean enrollment LDL-C 145 mg/dl and 93% taking lipid lowering therapy. Over follow up of 20 ± 11 months, lipid lowering therapy use increased (mean decrease in LDL-C of 32 mg/dl (p < 0.001)). Only 48% of participants achieved LDL-C < 100 mg/dl and 22% achieved LDL-C < 70 mg/dl; ASCVD at enrollment was associated with greater likelihood of goal achievement. MACE event rates were almost 6 times higher among patients with prior ASCVD compared to those without (4.6 vs 0.8/100 patient years). Also associated with incident MACE were markers of FH severity and conventional ASCVD risk factors.With care in FH specialized clinics, LDL-C decreased, but LDL-C persisted >100 mg/dl in 52% of patients. High ASCVD event rates suggest that adults with FH warrant designation as having an ASCVD risk equivalent. Earlier and more aggressive therapy of FH is needed to prevent ASCVD events.

  View details for DOI 10.1016/j.atherosclerosis.2019.08.007

  View details for PubMedID 31487564

• Safety and Efficacy of PCSK9 Inhibitors After Heart Transplantation CANADIAN JOURNAL OF CARDIOLOGY Moayedi, Y., Kozuszko, S., Knowles, J. W., Chih, S., Oro, G., Lee, R., Fearon, W. F., Ross, H. J., Teuteberg, J. J., Khush, K. K. 2019; 35 (1)

  View details for DOI 10.1016/j.cjca.2018.11.004

  View details for Web of Science ID 000454536800017

• CRISPR-Cas9-mediated knockout of SPRY2 in human hepatocytes leads to increased glucose uptake and lipid droplet accumulation. BMC endocrine disorders Cook, N. L., Pjanic, M. n., Emmerich, A. G., Rao, A. S., Hetty, S. n., Knowles, J. W., Quertermous, T. n., Castillejo-López, C. n., Ingelsson, E. n. 2019; 19 (1): 115

  Abstract

  The prevalence of obesity and its comorbidities, including type 2 diabetes mellitus (T2DM), is dramatically increasing throughout the world; however, the underlying aetiology is incompletely understood. Genome-wide association studies (GWAS) have identified hundreds of genec susceptibility loci for obesity and T2DM, although the causal genes and mechanisms are largely unknown. SPRY2 is a candidate gene identified in GWAS of body fat percentage and T2DM, and has recently been linked to insulin production in pancreatic β-cells. In the present study, we aimed to further understand SPRY2 via functional characterisation in HepG2 cells, an in vitro model of human hepatocytes widely used to investigate T2DM and insulin resistance.CRISPR-Cas9 genome editing was used to target SPRY2 in HepG2 cells, and the functional consequences of SPRY2 knockout (KO) and overexpression subsequently assessed using glucose uptake and lipid droplet assays, measurement of protein kinase phosphorylation and RNA sequencing.The major functional consequence of SPRY2 KO was a significant increase in glucose uptake, along with elevated lipid droplet accumulation. These changes were attenuated, but not reversed, in cells overexpressing SPRY2. Phosphorylation of protein kinases across key signalling pathways (including Akt and mitogen activated protein kinases) was not altered after SPRY2 KO. Transcriptome profiling in SPRY2 KO and mock (control) cells revealed a number of differentially expressed genes related to cholesterol biosynthesis, cell cycle regulation and cellular signalling pathways. Phospholipase A2 group IIA (PLA2G2A) mRNA level was subsequently validated as significantly upregulated following SPRY2 KO, highlighting this as a potential mediator downstream of SPRY2.These findings suggest a role for SPRY2 in glucose and lipid metabolism in hepatocytes and contribute to clarifying the function of this gene in the context of metabolic diseases.

  View details for DOI 10.1186/s12902-019-0442-8

  View details for PubMedID 31664995

• Effects of Alirocumab on Cardiovascular Events After Coronary Bypass Surgery. Journal of the American College of Cardiology Goodman, S. G., Aylward, P. E., Szarek, M. n., Chumburidze, V. n., Bhatt, D. L., Bittner, V. A., Diaz, R. n., Edelberg, J. M., Hanotin, C. n., Harrington, R. A., Jukema, J. W., Kedev, S. n., Letierce, A. n., Moryusef, A. n., Pordy, R. n., Ramos López, G. A., Roe, M. T., Viigimaa, M. n., White, H. D., Zeiher, A. M., Steg, P. G., Schwartz, G. G. 2019; 74 (9): 1177–86

  Abstract

  Patients with acute coronary syndrome (ACS) and history of coronary artery bypass grafting (CABG) are at high risk for recurrent cardiovascular events and death.This study sought to determine the clinical benefit of adding alirocumab to statins in ACS patients with prior CABG in a pre-specified analysis of ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab).Patients (n = 18,924) 1 to 12 months post-ACS with elevated atherogenic lipoprotein levels despite high-intensity statin therapy were randomized to alirocumab or placebo subcutaneously every 2 weeks. Median follow-up was 2.8 years. The primary composite endpoint of major adverse cardiovascular events (MACE) comprised coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint. Patients were categorized by CABG status: no CABG (n = 16,896); index CABG after qualifying ACS, but before randomization (n = 1,025); or CABG before the qualifying ACS (n = 1,003).In each CABG category, hazard ratios (95% confidence intervals) for MACE (no CABG 0.86 [0.78 to 0.95], index CABG 0.85 [0.54 to 1.35], prior CABG 0.77 [0.61 to 0.98]) and death (0.88 [0.75 to 1.03], 0.85 [0.46 to 1.59], 0.67 [0.44 to 1.01], respectively) were consistent with the overall trial results (0.85 [0.78 to 0.93] and 0.85 [0.73 to 0.98], respectively). Absolute risk reductions (95% confidence intervals) differed across CABG categories for MACE (no CABG 1.3% [0.5% to 2.2%], index CABG 0.9% [-2.3% to 4.0%], prior CABG 6.4% [0.9% to 12.0%]) and for death (0.4% [-0.1% to 1.0%], 0.5% [-1.9% to 2.9%], and 3.6% [0.0% to 7.2%]).Among patients with recent ACS and elevated atherogenic lipoproteins despite intensive statin therapy, alirocumab was associated with large absolute reductions in MACE and death in those with CABG preceding the ACS event. (ODYSSEY OUTCOMES: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

  View details for DOI 10.1016/j.jacc.2019.07.015

  View details for PubMedID 31466614

• Safety and Efficacy of PCSK9 Inhibitors After Heart Transplantation. The Canadian journal of cardiology Moayedi, Y., Kozuszko, S., Knowles, J. W., Chih, S., Oro, G., Lee, R., Fearon, W. F., Ross, H. J., Teuteberg, J. J., Khush, K. K. 2019; 35 (1)

  Abstract

  Dyslipidemia is common in patients undergoing heart transplantation and is associated with the progression of cardiac allograft vasculopathy. Two monoclonal antibodies directed against PCSK9i-evolocumab and alirocumab-are currently available. However, their use, safety and efficacy in the post-transplant setting have not been studied. We present our experience with 6 heart transplant recipients treated with a PCSK9i. A > 70% reduction in LDL-cholesterol was observed after evolocumab therapy. PCSK9 inhibitors are a potentially lipid-lowering therapeutic option for heart transplant patients with suboptimal LDL despite maximal tolerated statin doses.

  View details for PubMedID 30595172

• Genetic Testing and Risk Scores: Impact on Familial Hypercholesterolemia. Frontiers in cardiovascular medicine Sarraju, A., Knowles, J. W. 2019; 6: 5

  Abstract

  Familial Hypercholesterolemia (FH) is an inherited lipid disorder affecting 1 in 220 individuals resulting in highly elevated low-density lipoprotein levels and risk of premature coronary disease. Pathogenic variants causing FH typically involve the LDL receptor (LDLR), apolipoprotein B-100 (APOB), and proprotein convertase subtulisin/kexin type 9 genes (PCSK9) and if identified convey a risk of early onset coronary artery disease (ASCVD) of 3- to 10-fold vs. the general population depending on the severity of the mutation. Identification of monogenic FH within a family has implications for family-based testing (cascade screening), risk stratification, and potentially management, and it has now been recommended that such testing be offered to all potential FH patients. Recently, robust genome wide association studies (GWAS) have led to the recognition that the accumulation of common, small effect alleles affecting many LDL-c raising genes can result in a clinical phenotype largely indistinguishable from monogenic FH (i.e., a risk of early onset ASCVD of ~3-fold) in those at the extreme tail of the distribution for these alleles (i.e., the top 8% of the population for a polygenic risk score). The incorporation of these genetic risk scores into clinical practice for non-FH patients may improve risk stratification but is not yet widely performed due to a less robust evidence base for utility. Here, we review the current status of FH genetic testing, potential future applications as well as challenges and pitfalls.

  View details for PubMedID 30761309

• Association of Statin Adherence With Mortality in Patients With Atherosclerotic Cardiovascular Disease. JAMA cardiology Rodriguez, F. n., Maron, D. J., Knowles, J. W., Virani, S. S., Lin, S. n., Heidenreich, P. A. 2019

  Abstract

  Statins decrease mortality in those with atherosclerotic cardiovascular disease (ASCVD), but statin adherence remains suboptimal.To determine the association between statin adherence and mortality in patients with ASCVD who have stable statin prescriptions.This retrospective cohort analysis included patients who were between ages 21 and 85 years and had 1 or more International Classification of Diseases, Ninth Revision, Clinical Modification codes for ASCVD on 2 or more dates in the previous 2 years without intensity changes to their statin prescription who were treated within the Veterans Affairs Health System between January 1, 2013, and April 2014.Statin adherence was defined by the medication possession ratio (MPR). Adherence levels were categorized as an MPR of less than 50%, 50% to 69%, 70% to 89%, and 90% or greater. For dichotomous analyses, adherence was defined as an MPR of 80% or greater.The primary outcome was death of all causes adjusted for demographic and clinical characteristics, as well as adherence to other cardiac medications.Of 347 104 eligible adults with ASCVD who had stable statin prescriptions, 5472 (1.6%) were women, 284 150 (81.9%) were white, 36 208 (10.4%) were African American, 16 323 (4.7%) were Hispanic, 4093 (1.2%) were Pacific Islander, 1293 (0.4%) were Native American, 1145 (0.3%) were Asian, and 1794 (0.5%) were other races. Patients taking moderate-intensity statin therapy were more adherent than patients taking high-intensity statin therapy (odds ratio [OR], 1.18; 95% CI, 1.16-1.20). Women were less adherent (OR, 0.89; 95% CI, 0.84-0.94), as were minority groups. Younger and older patients were less likely to be adherent compared with adults aged 65 to 74 years. During a mean (SD) of 2.9 (0.8) years of follow-up, there were 85 930 deaths (24.8%). Compared with the most adherent patients (MPR ≥ 90%), patients with an MPR of less than 50% had a hazard ratio (HR; adjusted for clinical characteristics and adherence to other cardiac medications) of 1.30 (95% CI, 1.27-1.34), those with an MPR of 50% to 69% had an HR of 1.21 (95% CI, 1.18-1.24), and those with an MPR of 70% to 89% had an HR of 1.08 (95% CI, 1.06-1.09).Using a national sample of Veterans Affairs patients with ASCVD, we found that a low adherence to statin therapy was associated with a greater risk of dying. Women, minorities, younger adults, and older adults were less likely to adhere to statins. Our findings underscore the importance of finding methods to improve adherence.

  View details for PubMedID 30758506

• Impact of race/ethnicity on insulin resistance and hypertriglyceridaemia. Diabetes & vascular disease research Raygor, V. n., Abbasi, F. n., Lazzeroni, L. C., Kim, S. n., Ingelsson, E. n., Reaven, G. M., Knowles, J. W. 2019; 16 (2): 153–59

  Abstract

  Insulin sensitivity affects plasma triglyceride concentration and both differ by race/ethnicity. The purpose of this study was to provide a comprehensive assessment of the variation in insulin sensitivity and its relationship to hypertriglyceridaemia between five race/ethnic groups.In this cross-sectional study, clinical data for 1025 healthy non-Hispanic White, Hispanic White, East Asian, South Asian and African American individuals were analysed. Insulin-mediated glucose disposal (a direct measure of peripheral insulin sensitivity) was measured using the modified insulin suppression test. Statistical analysis was performed using analysis of co-variance.Of the study participants, 63% were non-Hispanic White, 9% were Hispanic White, 11% were East Asian, 11% were South Asian and 6% were African American. Overall, non-Hispanic Whites and African Americans displayed greater insulin sensitivity than East Asians and South Asians. Triglyceride concentration was positively associated with insulin resistance in all groups, including African Americans. Nevertheless, for any given level of insulin sensitivity, African Americans had the lowest triglyceride concentrations.Insulin sensitivity, as assessed by a direct measure of insulin-mediated glucose disposal, and its relationship to triglyceride concentration vary across five race/ethnic groups. Understanding these relationships is crucial for accurate cardiovascular risk stratification and prevention.

  View details for PubMedID 31014093

• Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial. European heart journal White, H. D., Steg, P. G., Szarek, M. n., Bhatt, D. L., Bittner, V. A., Diaz, R. n., Edelberg, J. M., Erglis, A. n., Goodman, S. G., Hanotin, C. n., Harrington, R. A., Jukema, J. W., Lopes, R. D., Mahaffey, K. W., Moryusef, A. n., Pordy, R. n., Roe, M. T., Sritara, P. n., Tricoci, P. n., Zeiher, A. M., Schwartz, G. G. 2019

  Abstract

  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin-kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI.Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77-0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77-0.99; P = 0.032) and Type 2 (0.77, 0.61-0.97; P = 0.025), but not Type 4 MI.After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.

  View details for DOI 10.1093/eurheartj/ehz299

  View details for PubMedID 31121022

• Increasing Mortality Among Patients With Diabetes and Chronic Liver Disease From 2007 Through 2017. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association Kim, D. n., Cholankeril, G. n., Kim, S. H., Abbasi, F. n., Knowles, J. W., Ahmed, A. n. 2019

  View details for DOI 10.1016/j.cgh.2019.06.011

  View details for PubMedID 31220638

• Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome NEW ENGLAND JOURNAL OF MEDICINE Schwartz, G. G., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Lecorps, G., Mahaffey, K. W., Moryusef, A., Pordy, R., Quintero, K., Roe, M. T., Sasiela, W. J., Tamby, J., Tricoci, P., White, H. D., Zeiher, A. M., ODYSSEY OUTCOMES Comm Inv 2018; 379 (22): 2097–2107

  View details for DOI 10.1056/NEJMoa1801174

  View details for Web of Science ID 000451402500005

• Homozygous Familial Hypercholesterolemia in the United States: Data From the CASCADE-FH Registry Cuchel, M., Knowles, J. W., Kindt, I., Shrader, P., Hudgins, L. C., Duell, P. B., Shapiro, M. D., Rader, D. J., de Ferranti, S. D., Larry, J. A., Hemphill, L. C., Benuck, I., Andersen, R. L., Baum, S., Wilemon, K., Roe, M. T., Fishberg, R., Guyton, J., Kane, J., Ballantyne, C. M., Linton, M. F., Moriarty, P. M., Gidding, S. S. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000528619404415

• ClinVar database of global familial hypercholesterolemia-associated DNA variants. Human mutation Iacocca, M. A., Chora, J. R., Carrie, A., Freiberger, T., Leigh, S. E., Defesche, J. C., Kurtz, C. L., DiStefano, M. T., Santos, R. D., Humphries, S. E., Mata, P., Jannes, C. E., Hooper, A. J., Wilemon, K. A., Benlian, P., O'Connor, R., Garcia, J., Wand, H., Tichy, L., Sijbrands, E. J., Hegele, R. A., Bourbon, M., Knowles, J. W., ClinGen FH Variant Curation Expert Panel 2018; 39 (11): 1631–40

  Abstract

  Accurate and consistent variant classification is imperative for incorporation of rapidly developing sequencing technologies into genomic medicine for improved patient care. An essential requirement for achieving standardized and reliable variant interpretation is data sharing, facilitated by a centralized open-source database. Familial hypercholesterolemia (FH) is an exemplar of the utility of such a resource: it has a high incidence, a favorable prognosis with early intervention and treatment, and cascade screening can be offered to families if a causative variant is identified. ClinVar, an NCBI-funded resource, has become the primary repository for clinically relevant variants in Mendelian disease, including FH. Here, we present the concerted efforts made by the Clinical Genome Resource, through the FH Variant Curation Expert Panel and global FH community, to increase submission of FH-associated variants into ClinVar. Variant-level data was categorized by submitter, variant characteristics, classification method, and available supporting data. To further reform interpretation of FH-associated variants, areas for improvement in variant submissions were identified; these include a need for more detailed submissions and submission of supporting variant-level data, both retrospectively and prospectively. Collaborating to provide thorough, reliable evidence-based variant interpretation will ultimately improve the care of FH patients.

  View details for PubMedID 30311388

• ClinVar database of global familial hypercholesterolemia-associated DNA variants HUMAN MUTATION Iacocca, M. A., Chora, J. R., Carrie, A., Freiberger, T., Leigh, S. E., Defesche, J. C., Kurtz, C., DiStefano, M. T., Santos, R. D., Humphries, S. E., Mata, P., Jannes, C. E., Hooper, A. J., Wilemon, K. A., Benlian, P., O'Connor, R., Garcia, J., Wand, H., Tichy, L., Sijbrands, E. J., Hegele, R. A., Bourbon, M., Knowles, J. W., ClinGen FH Variant Curation Expert 2018; 39 (11): 1631–40

  View details for DOI 10.1002/humu.23634

  View details for Web of Science ID 000447138900016

• Large Q and S waves in lead III on the electrocardiogram distinguish patients with hypertrophic cardiomyopathy from athletes HEART Chen, A. S., Bent, R. E., Wheeler, M., Knowles, J. W., Haddad, F., Froelicher, V., Ashley, E., Perez, M. V. 2018; 104 (22): 1871–77

  View details for DOI 10.1136/heartjnl-2017-312647

  View details for Web of Science ID 000451122500013

• Genome-wide scan for circulating vascular adhesion protein-1 levels: MACROD2 as a potential transcriptional regulator of adipogenesis JOURNAL OF DIABETES INVESTIGATION Chang, Y., Hee, S., Lee, W., Li, H., Chang, T., Lin, M., Hung, Y., Lee, I., Hung, K., Assimes, T., Knowles, J. W., Nong, J., Lee, P., Chiu, Y., Chuang, L. 2018; 9 (5): 1067–74

  Abstract

  Vascular adhesion protein-1 (VAP-1) is a membrane-bound amine oxidase highly expressed in mature adipocytes and released into the circulation. VAP-1 has been strongly implicated in several pathological processes, including diabetes, inflammation, hypertension, hepatic steatosis and renal diseases, and is an important disease marker and therapeutic target. Here, we aimed to identify the genetic loci for circulating VAP-1 levels.We carried out a genomic-wide linkage scan for the quantitative trait locus of circulating VAP-1 levels in 1,100 Han Chinese individuals from 398 families in the Stanford Asian Pacific Program for Hypertension and Insulin Resistance study. Regional association fine mapping was carried out using additional single-nucleotide polymorphisms.The estimated heritability of circulating VAP-1 levels is high (h2 = 69%). The most significant quantitative trait locus for circulating VAP-1 was located at 38 cM on chromosome 20, with a maximum empirical logarithm of odds score of 4.11 (P = 6.86 × 10-6 ) in females. Regional single-nucleotide polymorphism fine mapping within a 1-unit support region showed the strongest association signals in the MACRO domain containing 2 (MACROD2) gene in females (P = 5.38 × 10-6 ). Knockdown of MACROD2 significantly suppressed VAP-1 expression in human adipocytes, as well as the expression of key adipogenic genes. Furthermore, MACROD2 expression was found to be positively associated with VAP-1 in human visceral adipose tissue.MACROD2 is a potential genetic determinant of serum VAP-1 levels, probably through transcriptional regulation of adipogenesis.

  View details for PubMedID 29364582

• Frequency of Statin Use in Patients With Low-Density Lipoprotein Cholesterol >= 190 mg/dl from the Veterans Affairs Health System AMERICAN JOURNAL OF CARDIOLOGY Rodriguez, F., Knowles, J. W., Maron, D. J., Virani, S. S., Heidenreich, P. A. 2018; 122 (5): 756–61

  View details for DOI 10.1016/j.amjcard.2018.05.008

  View details for Web of Science ID 000447960500008

• Clinical Genetic Testing for Familial Hypercholesterolemia JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Sturm, A. C., Knowles, J. W., Gidding, S. S., Ahmad, Z. S., Ahmed, C. D., Ballantyne, C. M., Baum, S. J., Bourbon, M., Carrie, A., Cuchel, M., de Ferranti, S. D., Defesche, J. C., Freiberger, T., Hershberger, R. E., Hovingh, G., Karayan, L., Kastelein, J., Kindt, I., Lane, S. R., Leigh, S. E., Linton, M. F., Mata, P., Neal, W. A., Nordestgaard, B. G., Santos, R. D., Harada-Shiba, M., Sijbrands, E. J., Stitziel, N. O., Yamashita, S., Wilemon, K. A., Ledbetter, D. H., Rader, D. J., Familial Hypercholesterolemia Fdn 2018; 72 (6): 662–80

  Abstract

  Although awareness of familial hypercholesterolemia (FH) is increasing, this common, potentially fatal, treatable condition remains underdiagnosed. Despite FH being a genetic disorder, genetic testing is rarely used. The Familial Hypercholesterolemia Foundation convened an international expert panel to assess the utility of FH genetic testing. The rationale includes the following: 1) facilitation of definitive diagnosis; 2) pathogenic variants indicate higher cardiovascular risk, which indicates the potential need for more aggressive lipid lowering; 3) increase in initiation of and adherence to therapy; and 4) cascade testing of at-risk relatives. The Expert Consensus Panel recommends that FH genetic testing become the standard of care for patients with definite or probable FH, as well as for their at-risk relatives. Testing should include the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9); other genes may also need to be considered for analysis based on patient phenotype. Expected outcomes include greater diagnoses, more effective cascade testing, initiation of therapies at earlier ages, and more accurate risk stratification.

  View details for PubMedID 30071997

• Large-Scale Phenome-Wide Association Study of PCSK9 Variants Demonstrates Protection Against Ischemic Stroke CIRCULATION-GENOMIC AND PRECISION MEDICINE Rao, A. S., Lindholm, D., Rivas, M. A., Knowles, J. W., Montgomery, S. B., Ingelsson, E. 2018; 11 (7): e002162

  Abstract

  PCSK9 inhibition is a potent new therapy for hypercholesterolemia and cardiovascular disease. Although short-term clinical trial results have not demonstrated major adverse effects, long-term data will not be available for some time. Genetic studies in large biobanks offer a unique opportunity to predict drug effects and provide context for the evaluation of future clinical trial outcomes.We tested the association of the PCSK9 missense variant rs11591147 with predefined phenotypes and phenome-wide, in 337 536 individuals of British ancestry in the UK Biobank, with independent discovery and replication. Using a Bayesian statistical method, we leveraged phenotype correlations to evaluate the phenome-wide impact of PCSK9 inhibition with higher power at a finer resolution.The T allele of rs11591147 showed a protective effect on hyperlipidemia (odds ratio, 0.63±0.04; P=2.32×10-38), coronary heart disease (odds ratio, 0.73±0.09; P=1.05×10-6), and ischemic stroke (odds ratio, 0.61±0.18; P=2.40×10-3) and was associated with increased type 2 diabetes mellitus risk adjusted for lipid-lowering medication status (odds ratio, 1.24±0.10; P=1.98×10-7). We did not observe associations with cataracts, heart failure, atrial fibrillation, and cognitive dysfunction. Leveraging phenotype correlations, we observed evidence of a protective association with cerebral infarction and vascular occlusion. These results explore the effects of direct PCSK9 inhibition; off-target effects cannot be predicted using this approach.This result represents the first genetic evidence in a large cohort for the protective effect of PCSK9 inhibition on ischemic stroke and corroborates exploratory evidence from clinical trials. PCSK9 inhibition was not associated with variables other than those related to LDL (low-density lipoprotein) cholesterol, atherosclerosis, and type 2 diabetes mellitus, suggesting that other effects are either small or absent.

  View details for PubMedID 29997226

• Frequency of Statin Use in Patients With Low-Density Lipoprotein Cholesterol ≥190 mg/dl from the Veterans Affairs Health System. The American journal of cardiology Rodriguez, F., Knowles, J. W., Maron, D. J., Virani, S. S., Heidenreich, P. A. 2018

  Abstract

  Patients with low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dl have severe hypercholesterolemia and are at markedly increased risk for adverse cardiovascular events. This study sought to examine the prevalence and treatment of patients with uncontrolled severe hypercholesterolemia in the Veterans Affairs (VA) Health System. The study population was comprised of VA outpatients ≥21 years of age without atherosclerotic disease or diabetes mellitus and an index LDL-C ≥190 mg/dl during April 2011 to March 2014. Patients needed to have filled medications at the VA within the past 6 months. Patient and facility-level predictors of statin use, high-intensity statin use, and statin intensification were analyzed using multivariate logistic regressions. There were a total of 63,576 patients meeting inclusion criteria, including 8,553 (13.5%) women and 26,879 (29.0%) nonwhite patients. The mean (±S.D.) age was 55 (±13) years and the mean of the most recent LDL-C values was 207 ± 22 mg/dl. Only 52% of all eligible patients were on any statin therapy and 9.7% received high-intensity statin therapy. High-intensity statin use increased from 8.6% in 2011 to 13.6% in 2014 (p < 0.001). In adjusted analysis, patients <35 or >75 years of age were less likely to be on a statin (p < 0.001). Women were less likely to be treated than men, odds ratio = 0.88; 95% confidence interval (0.83, 0.92). Similar patterns were observed for predictors of high-intensity statin use and statin intensification. In conclusion, only half of high-risk VA patients with uncontrolled severe hypercholesterolemia were treated with statins and a small minority was on high-intensity statin therapy.

  View details for PubMedID 30055758

• ADAPTATION OF ACMG/AMP GUIDELINES FOR STANDARDIZED VARIANT INTERPRETATION IN FAMILIAL HYPERCHOLESTEROLEMIA Iacocca, M. A., Chora, J., Carrie, A., Leigh, S. E., Tichy, L., DiStefano, M. T., Defesche, J., Kurtz, C. L., Sijbrands, E. J., Freiberger, T., Hegele, R. A., Knowles, J. W., Bourbon, M. ELSEVIER IRELAND LTD. 2018: 51

  View details for DOI 10.1016/j.atherosclerosissup.2018.04.153

  View details for Web of Science ID 000434628100149

• Short-Term Repeatability of Insulin Resistance Indexes in Older Adults: The Atherosclerosis Risk in Communities Study JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Poon, A. K., Meyer, M. L., Reaven, G., Knowles, J. W., Selvin, E., Pankow, J. S., Couper, D., Loehr, L., Heiss, G. 2018; 103 (6): 2175–81

  Abstract

  The homeostatic model assessment of insulin resistance (HOMA-IR) and triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) ratio (TG/HDL-C) are insulin resistance indexes routinely used in clinical and population-based studies; however, their short-term repeatability is not well characterized.To quantify the short-term repeatability of insulin resistance indexes and their analytes, consisting of fasting glucose and insulin for HOMA-IR and TG and HDL-C for TG/HDL-C.Prospective cohort study.A total of 102 adults 68 to 88 years old without diabetes attended an initial examination and repeated examination (mean, 46 days; range, 28 to 102 days). Blood samples were collected, processed, shipped, and assayed following a standardized protocol.Repeatability was quantified using the intraclass correlation coefficient (ICC) and within-person coefficient of variation (CV). Minimum detectable change (MDC95) and minimum detectable difference with 95% confidence (MDD95) were quantified.For HOMA-IR, insulin, and fasting glucose, the ICCs were 0.70, 0.68, and 0.70, respectively; their respective within-person CVs were 30.4%, 28.8%, and 5.6%. For TG/HDL-C, TG, and HDL-C, the ICCs were 0.80, 0.68, and 0.91, respectively; their respective within-person CVs were 23.0%, 20.6%, and 8.2%. The MDC95 was 2.3 for HOMA-IR and 1.4 for TG/HDL-C. The MDD95 for a sample of n = 100 was 0.8 for HOMA-IR and 0.6 for TG/HDL-C.Short-term repeatability was fair to good for HOMA-IR and excellent for TG/HDL-C according to suggested benchmarks, reflecting the short-term variability of their analytes. These measurement properties can inform the use of these indexes in clinical and population-based studies.

  View details for PubMedID 29618016

• Large Q and S waves in lead III on the electrocardiogram distinguish patients with hypertrophic cardiomyopathy from athletes. Heart (British Cardiac Society) Chen, A. S., Bent, R. E., Wheeler, M., Knowles, J. W., Haddad, F., Froelicher, V., Ashley, E., Perez, M. V. 2018

  Abstract

  OBJECTIVE: To identify electrocardiographic findings, especially deep Q and S waves in lead III, that differentiate athletes from patients with hypertrophic cardiomyopathy (HCM).METHODS: Digital ECGs of athletes and patients with HCM followed at the Stanford Center for Inherited Cardiovascular Disease were studied retrospectively. All patients with HCM had an echocardiogram performed. A multivariable logistic regression model was used to calculate ORs for various demographic and ECG characteristics. Linear regression was used to correlate ECG characteristics with echocardiogram findings.RESULTS: We studied 1124 athletes and 240 patients with HCM. The average Q+Swave amplitude in lead III (IIIQ+S) was significantly higher in patients with HCM compared with athletes (0.71±0.69mV vs 0.21±0.17mV, p<0.001). In patients with HCM, IIIQ+S directly correlated with interventricular septal (IVS) thickness on echocardiography (rho=0.45, p<0.001). In a multivariable analysis adjusted for demographic and ECG characteristics, higher IIIQ+S values remained independently associated with HCM compared with athletes (OR=4.2 per 0.5mV, p<0.001). In subgroup analyses of young patients, African-American subjects and subjects without left axis deviation (LAD), IIIQ+S remained associated with HCM. The addition of IIIQ+S>1.0 mV as an abnormal finding to the International Criteria for athletic ECG interpretation improved sensitivity from 64.2% to 70.4%, with a minimal decrease in specificity.CONCLUSION: Large Q and S waves in lead III distinguished athletes from patients with HCM, independent of axis and well-known ECG markers associated with HCM. The correlation between IVS thickness in patients with HCM and IIIQ+S suggests a partial explanation for this association.

  View details for PubMedID 29680808

• Cardiovascular disease: The rise of the genetic risk score PLOS MEDICINE Knowles, J. W., Ashley, E. A. 2018; 15 (3): e1002546

  Abstract

  In a Perspective, Joshua Knowles and Euan Ashley discuss the potential for use of genetic risk scores in clinical practice.

  View details for PubMedID 29601582

• First Trimester Plasma Glucose Values in Women without Diabetes are Associated with Risk for Congenital Heart Disease in Offspring. The Journal of pediatrics Helle, E. I., Biegley, P. n., Knowles, J. W., Leader, J. B., Pendergrass, S. n., Yang, W. n., Reaven, G. R., Shaw, G. M., Ritchie, M. n., Priest, J. R. 2018; 195: 275–78

  Abstract

  In a retrospective study of 19 171 mother-child dyads, elevated random plasma glucose values during early pregnancy were directly correlated with increased risk for congenital heart disease in offspring. Plasma glucose levels proximal to the period of cardiac development may represent a modifiable risk factor for congenital heart disease in expectant mothers without diabetes.

  View details for PubMedID 29254757

  View details for PubMedCentralID PMC5869072

• Health disparities among adult patients with a phenotypic diagnosis of familial hypercholesterolemia in the CASCADE-FH (TM) patient registry ATHEROSCLEROSIS Amrock, S. M., Duell, P., Knickelbine, T., Martin, S. S., O'Brien, E. C., Watson, K. E., Mitri, J., Kindt, I., Shrader, P., Baum, S. J., Hemphill, L. C., Ahmed, C. D., Andersen, R. L., Kullo, I. J., McCann, D., Larry, J. A., Murray, M. F., Fishberg, R., Guyton, J. R., Wilemon, K., Roe, M. T., Rader, D. J., Ballantyne, C. M., Underberg, J. A., Thompson, P., Duffy, D., Linton, M. F., Shapiro, M. D., Moriarty, P. M., Knowles, J. W., Ahmad, Z. S. 2017; 267: 19–26

  Abstract

  Most familial hypercholesterolemia (FH) patients remain undertreated, and it is unclear what role health disparities may play for FH patients in the US. We sought to describe sex and racial/ethnic disparities in a national registry of US FH patients.We analyzed data from 3167 adults enrolled in the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE-FH) registry. Logistic regression was used to evaluate for disparities in LDL-C goals and statin use, with adjustments for covariates including age, cardiovascular risk factors, and statin intolerance.In adjusted analyses, women were less likely than men to achieve treated LDL-C of <100 mg/dL (OR 0.68, 95% CI, 0.57-0.82) or ≥50% reduction from pretreatment LDL-C (OR 0.79, 95% CI, 0.65-0.96). Women were less likely than men to receive statin therapy (OR, 0.60, 95% CI, 0.50-0.73) and less likely to receive a high-intensity statin (OR, 0.60, 95% CI, 0.49-0.72). LDL-C goal achievement also varied by race/ethnicity: compared with whites, Asians and blacks were less likely to achieve LDL-C levels <100 mg/dL (Asians, OR, 0.47, 95% CI, 0.24-0.94; blacks, OR, 0.49, 95% CI, 0.32-0.74) or ≥50% reduction from pretreatment LDL-C (Asians, OR 0.56, 95% CI, 0.32-0.98; blacks, OR 0.62, 95% CI, 0.43-0.90).In a contemporary US population of FH patients, we identified differences in LDL-C goal attainment and statin usage after stratifying the population by either sex or race/ethnicity. Our findings suggest that health disparities contribute to the undertreatment of US FH patients. Increased efforts are warranted to raise awareness of these disparities.

  View details for PubMedID 29080546

• Relationship between simple markers of insulin resistance and coronary artery calcification JOURNAL OF CLINICAL LIPIDOLOGY Reaven, G. M., Knowles, J. W., Leonard, D., Barlow, C. E., Willis, B. L., Haskell, W. L., Maron, D. J. 2017; 11 (4): 1007–12

  Abstract

  Insulin resistance in apparently healthy persons is associated with a cluster of metabolic abnormalities that promote coronary atherosclerosis. Identifying these individuals before manifest disease would provide useful clinical information.We hypothesized that combining 2 simple markers of insulin resistance, prediabetes (PreDM) and triglyceride (TG) concentration ≥150 mg/dL, would identify apparently healthy persons with adverse cardiometabolic risk profiles and increased coronary artery calcium (CAC) compared with those with neither or only 1 abnormality.A cross-sectional analysis was performed using data from 25,886 apparently healthy individuals (18,453 men and 7433 women) evaluated at the Cooper Clinic from 1998 to 2015. Participants were divided into those with a normal fasting glucose concentrations (<100 mg/dL = normal fasting glucose) or PreDM (fasting plasma glucose ≥100 and <126 mg/dL) and further subdivided into those with a plasma TG concentration <150 or ≥150 mg/dL. These 4 groups were compared on the basis of multiple coronary artery disease risk factors and the presence of CAC determined during their evaluation.Participants with PreDM and a TG concentration ≥150 mg/dL had a significantly more adverse coronary artery disease risk profile than individuals with either abnormality or only 1 abnormality (PreDM or TG concentration ≥150 mg/dL). Furthermore, the odds of detectable CAC were higher in participants with PreDM and a TG ≥ 150 mg/dL than in participants with neither or only 1 abnormality.The presence of 2 markers of insulin resistance, PreDM and TG concentration ≥150 mg/dL, is associated with increased cardiometabolic risk and detectable CAC within a population of apparently healthy individuals.

  View details for PubMedID 28652190

• Cascade Screening for Familial Hypercholesterolemia and the Use of Genetic Testing JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Knowles, J. W., Rader, D. J., Khoury, M. J. 2017; 318 (4): 381–82

  View details for PubMedID 28742895

  View details for PubMedCentralID PMC6166431

• Identification of Genetic Regulatory Networks for Insulin Resistance in Multiple Populations of Diverse Ethnicities Shu Le, Zhao Yuqi, Lusis, A. J., Hao Ke, Quertermous, T., Knowles, J. W., Yang Xia, GENESIS Consortium LIPPINCOTT WILLIAMS & WILKINS. 2017

  View details for Web of Science ID 000520552700310

• Access to Nonstatin Lipid-Lowering Therapies in Patients at High Risk of Atherosclerotic Cardiovascular Disease CIRCULATION Knowles, J. W., Howard, W. B., Karayan, L., Baum, S. J., Wilemon, K. A., Ballantyne, C. M., Myers, K. D. 2017; 135 (22): 2204–6

  View details for PubMedID 28446516

• Leveraging Human Genetics to Understand the Relation of LDL Cholesterol with Type 2 Diabetes. Clinical chemistry Ingelsson, E., Knowles, J. W. 2017

  View details for DOI 10.1373/clinchem.2016.268565

  View details for PubMedID 28515096

• Analysis of Transcriptional Variability in a Large Human iPSC Library Reveals Genetic and Non-genetic Determinants of Heterogeneity CELL STEM CELL Carcamo-Orive, I., Hoffman, G. E., Cundiff, P., Beckmann, N. D., D'Souza, S. L., Knowles, J. W., Patel, A., Papatsenko, D., Abbasi, F., Reaven, G. M., Whalen, S., Lee, P., Shahbazi, M., Henrion, M. Y., Zhu, K., Wang, S., Roussos, P., Schadt, E. E., Pandey, G., Chang, R., Quertermous, T., Lemischka, I. 2017; 20 (4): 518-?

  Abstract

  Variability in induced pluripotent stem cell (iPSC) lines remains a concern for disease modeling and regenerative medicine. We have used RNA-sequencing analysis and linear mixed models to examine the sources of gene expression variability in 317 human iPSC lines from 101 individuals. We found that ∼50% of genome-wide expression variability is explained by variation across individuals and identified a set of expression quantitative trait loci that contribute to this variation. These analyses coupled with allele-specific expression show that iPSCs retain a donor-specific gene expression pattern. Network, pathway, and key driver analyses showed that Polycomb targets contribute significantly to the non-genetic variability seen within and across individuals, highlighting this chromatin regulator as a likely source of reprogramming-based variability. Our findings therefore shed light on variation between iPSC lines and illustrate the potential for our dataset and other similar large-scale analyses to identify underlying drivers relevant to iPSC applications.

  View details for DOI 10.1016/j.stem.2016.11.005

  View details for Web of Science ID 000398350800015

  View details for PubMedCentralID PMC5384872

• The role of registries and genetic databases in familial hypercholesterolemia. Current opinion in lipidology Kindt, I., Mata, P., Knowles, J. W. 2017; 28 (2): 152-160

  Abstract

  To review how leveraging familial hypercholesterolemia registries can impact molecular genetic research and precision medicine.Familial hypercholesterolemia is both much more common and more phenotypically heterogeneous than previously thought with some evidence for significant genotype to phenotype correlations. Genetic testing for familial hypercholesterolemia is becoming both more widely available and cheaper, spurring conversations about its clinical utility.In most countries, familial hypercholesterolemia is underdiagnosed and diagnosed later in life, often after the onset of coronary heart disease (CHD). Familial hypercholesterolemia is undertreated; low goal attainment and additional modifiable risk factors further increase CHD risk. Familial hypercholesterolemia epitomizes the goal of precision medicine to define a subset of individuals with a high risk of morbidity and mortality through genetic diagnosis to manage and treat the risk accordingly. Genetic cascade screening can be used to identify familial hypercholesterolemia patients at a younger age and start timely treatment to prevent CHD. Familial hypercholesterolemia registries are tools for clinical research and improving healthcare planning and patient care. As genotype and phenotype correlations in familial hypercholesterolemia become increasingly understood, this information will likely play a more important role in diagnosis and treatment especially as the cost of genetic testing continues to decline.

  View details for DOI 10.1097/MOL.0000000000000398

  View details for PubMedID 28169870

• PREDICTORS OF STATIN USE FOR PATIENTS WITH LDL CHOLESTEROL ABOVE 190MG/DL: INSIGHTS FROM THE VETERANS AFFAIRS HEALTH CARE SYSTEM Rodriguez, F., Knowles, J., Maron, D., Virani, S., Heidenreich, P. ELSEVIER SCIENCE INC. 2017: 1693

  View details for Web of Science ID 000397342302415

• Induced Pluripotent Stem Cell-Derived Endothelial Cells in Insulin Resistance and Metabolic Syndrome. Arteriosclerosis, thrombosis, and vascular biology Carcamo-Orive, I. n., Huang, N. F., Quertermous, T. n., Knowles, J. W. 2017; 37 (11): 2038–42

  Abstract

  Insulin resistance leads to a number of metabolic and cellular abnormalities including endothelial dysfunction that increase the risk of vascular disease. Although it has been particularly challenging to study the genetic determinants that predispose to abnormal function of the endothelium in insulin-resistant states, the possibility of deriving endothelial cells from induced pluripotent stem cells generated from individuals with detailed clinical phenotyping, including accurate measurements of insulin resistance accompanied by multilevel omic data (eg, genetic and genomic characterization), has opened new avenues to study this relationship. Unfortunately, several technical barriers have hampered these efforts. In the present review, we summarize the current status of induced pluripotent stem cell-derived endothelial cells for modeling endothelial dysfunction associated with insulin resistance and discuss the challenges to overcoming these limitations.

  View details for PubMedID 28729365

  View details for PubMedCentralID PMC5669062

• Impact of a Genetic Risk Score for Coronary Artery Disease on Reducing Cardiovascular Risk: A Pilot Randomized Controlled Study. Frontiers in cardiovascular medicine Knowles, J. W., Zarafshar, S. n., Pavlovic, A. n., Goldstein, B. A., Tsai, S. n., Li, J. n., McConnell, M. V., Absher, D. n., Ashley, E. A., Kiernan, M. n., Ioannidis, J. P., Assimes, T. L. 2017; 4: 53

  Abstract

  We tested whether providing a genetic risk score (GRS) for coronary artery disease (CAD) would serve as a motivator to improve adherence to risk-reducing strategies.We randomized 94 participants with at least moderate risk of CAD to receive standard-of-care with (N = 49) or without (N = 45) their GRS at a subsequent 3-month follow-up visit. Our primary outcome was change in low density lipoprotein cholesterol (LDL-C) between the 3- and 6-month follow-up visits (ΔLDL-C). Secondary outcomes included other CAD risk factors, weight loss, diet, physical activity, risk perceptions, and psychological outcomes. In pre-specified analyses, we examined whether there was a greater motivational effect in participants with a higher GRS.Sixty-five participants completed the protocol including 30 participants in the GRS arm. We found no change in the primary outcome between participants receiving their GRS and standard-of-care participants (ΔLDL-C: -13 vs. -9 mg/dl). Among participants with a higher GRS, we observed modest effects on weight loss and physical activity. All other secondary outcomes were not significantly different, including anxiety and worry.Adding GRS to standard-of-care did not change lipids, adherence, or psychological outcomes. Potential modest benefits in weight loss and physical activity for participants with high GRS need to be validated in larger trials.

  View details for PubMedID 28856136

• Is ACS in Young Patients a "Canary in the Coal Mine" for Familial Hypercholesterolemia? Journal of the American College of Cardiology Knowles, J. W., Sarraju, A. n. 2017; 70 (14): 1741–43

  View details for PubMedID 28958331

• Association Between Intensity of Statin Therapy and Mortality in Patients With Atherosclerotic Cardiovascular Disease. JAMA cardiology Rodriguez, F., Maron, D. J., Knowles, J. W., Virani, S. S., Lin, S., Heidenreich, P. A. 2017; 2 (1): 47-54

  Abstract

  High-intensity statin therapy is recommended for the secondary prevention of atherosclerotic cardiovascular disease (ASCVD). Nevertheless, statin therapy in general, and high-intensity statin therapy in particular, is underused in patients with established ASCVD.To determine the association between all-cause mortality and intensity of statin therapy in the Veterans Affairs health care system.A retrospective cohort analysis was conducted of patients aged 21 to 84 years with ASCVD treated in the Veterans Affairs health care system from April 1, 2013, to April 1, 2014. Patients who were included had 1 or more International Classification of Diseases, Ninth Revision codes for ASCVD on 2 or more different dates in the prior 2 years.Intensity of statin therapy was defined by the 2013 American College of Cardiology/American Heart Association guidelines, and use was defined as a filled prescription in the prior 6 months. Patients were excluded if they were taking a higher statin dose in the prior 5 years.The primary outcome was death from all causes adjusted for the propensity to receive high-intensity statins.The study sample included 509 766 eligible adults with ASCVD at baseline (mean [SD] age, 68.5 [8.8] years; 499 598 men and 10 168 women), including 150 928 (29.6%) receiving high-intensity statin therapy, 232 293 (45.6%) receiving moderate-intensity statin therapy, 33 920 (6.7%) receiving low-intensity statin therapy, and 92 625 (18.2%) receiving no statins. During a mean follow-up of 492 days, there was a graded association between intensity of statin therapy and mortality, with 1-year mortality rates of 4.0% (5103 of 126 139) for those receiving high-intensity statin therapy, 4.8% (9703 of 200 709) for those receiving moderate-intensity statin therapy, 5.7% (1632 of 28 765) for those receiving low-intensity statin therapy, and 6.6% (4868 of 73 728) for those receiving no statin (P < .001). After adjusting for the propensity to receive high-intensity statins, the hazard ratio for mortality was 0.91 (95% CI, 0.88-0.93) for those receiving high- vs moderate-intensity statins. The magnitude of benefit of high- vs moderate-intensity statins was similar, for an incident cohort hazard ratio of 0.93 (95% CI, 0.85-1.01). For patients aged 76 to 84 years, the hazard ratio was 0.91 (95% CI, 0.87-0.95). Patients treated with maximal doses of high-intensity statins had lower mortality (hazard ratio, 0.90; 95% CI, 0.87-0.94) compared with those receiving submaximal doses.We found a graded association between intensity of statin therapy and mortality in a national sample of patients with ASCVD. High-intensity statins were associated with a small but significant survival advantage compared with moderate-intensity statins, even among older adults. Maximal doses of high-intensity statins were associated with a further survival benefit.

  View details for DOI 10.1001/jamacardio.2016.4052

  View details for PubMedID 27829091

• Analysis of Transcriptional Variability in a Large Human iPSC Library Reveals Genetic and Non-genetic Determinants of Heterogeneity. Cell stem cell Carcamo-Orive, I., Hoffman, G. E., Cundiff, P., Beckmann, N. D., D'Souza, S. L., Knowles, J. W., Patel, A., Papatsenko, D., Abbasi, F., Reaven, G. M., Whalen, S., Lee, P., Shahbazi, M., Henrion, M. Y., Zhu, K., Wang, S., Roussos, P., Schadt, E. E., Pandey, G., Chang, R., Quertermous, T., Lemischka, I. 2016

  Abstract

  Variability in induced pluripotent stem cell (iPSC) lines remains a concern for disease modeling and regenerative medicine. We have used RNA-sequencing analysis and linear mixed models to examine the sources of gene expression variability in 317 human iPSC lines from 101 individuals. We found that ∼50% of genome-wide expression variability is explained by variation across individuals and identified a set of expression quantitative trait loci that contribute to this variation. These analyses coupled with allele-specific expression show that iPSCs retain a donor-specific gene expression pattern. Network, pathway, and key driver analyses showed that Polycomb targets contribute significantly to the non-genetic variability seen within and across individuals, highlighting this chromatin regulator as a likely source of reprogramming-based variability. Our findings therefore shed light on variation between iPSC lines and illustrate the potential for our dataset and other similar large-scale analyses to identify underlying drivers relevant to iPSC applications.

  View details for DOI 10.1016/j.stem.2016.11.005

  View details for PubMedID 28017796

• Use of high-intensity statins for patients with atherosclerotic cardiovascular disease in the Veterans Affairs Health System: Practice impact of the new cholesterol guidelines AMERICAN HEART JOURNAL Rodriguez, F., Lin, S., Maron, D. J., Knowles, J. W., Virani, S. S., Heidenreich, P. A. 2016; 182: 97-102

  Abstract

  The November 2013 American College of Cardiology/American Heart Association cholesterol guidelines recommend the use of high-intensity statins for patients with atherosclerotic cardiovascular disease (ASCVD). We sought to determine how these guidelines are being adopted at the Veterans Affairs (VA) Health System and identify treatment gaps.We examined administrative data from the VA 12 months prior to the index dates of April 1, 2013, and after April 1, 2014, to identify patients ≤75 years of age with ≥2 codes for ASCVD. We identified those on high-intensity statin therapy (atorvastatin 40 mg or 80 mg, rosuvastatin 20 mg or 40 mg, and simvastatin 80 mg) during the 6 months after the index date.The study sample included 331,927 and 326,759 eligible adults with ASCVD before and after the release of the new guidelines, respectively. Overall, high-intensity statin use increased from 28% to 35% after guideline release. High-intensity statin use was lowest in Hispanics and Native Americans, although all groups showed an increase over time. Among those on low- or moderate-intensity statin therapy, 15.6% were intensified to a high-intensity statin after guideline release. Groups less likely to undergo statin intensification were older adults (odds ratio=0.78 for each 10-year increase, 95% CI 0.76-0.81), women (odds ratio=0.86, 95% CI 0.75-0.99), and certain minority groups. Academic teaching hospitals and hospitals on the West Coast were more likely to intensify statins after release of the new guidelines.High-intensity statin use increased in the VA following release of the American College of Cardiology/American Heart Association cholesterol treatment guidelines, although disparities persist for certain patient groups including older adults, women, and certain minority groups.

  View details for DOI 10.1016/j.ahj.2016.09.007

  View details for Web of Science ID 000389136600012

  View details for PubMedID 27914506

• Novel Therapies for Familial Hypercholesterolemia. Current treatment options in cardiovascular medicine Parizo, J., Sarraju, A., Knowles, J. W. 2016; 18 (11): 64-?

  Abstract

  Both HeFH and HoFH require dietary and lifestyle modification. Pharmacotherapy of adult HeFH patients is largely driven by the American Heart Association (AHA) algorithm. A high-potency statin is started initially with a goal low-density lipoprotein cholesterol (LDL-C) reduction of >50 %. The LDL-C target is adjusted to <100 or <70 mg/dL in subjects with coronary artery disease (CAD) with ezetimibe being second line. If necessary, a third adjunctive therapy, such as a PSCK9 inhibitor (not yet approved in children) or bile acid-binding resin, can be added. Finally, LDL-C apheresis can be considered in patients with LDL-C >300 mg/dL (or >200 mg/dL with significant CAD, although now approved for LDL-C as low as 160 mg/dL with CAD). Due to the early, severe LDL-C elevation in HoFH patients, concerning natural history, rarity of the condition, and nuances of treatment, all HoFH patients should be treated at a pediatric or adult center with HoFH experience. LDL-C apheresis should be considered as early as 5 years of age. However, apheresis availability and tolerability is limited and pharmacotherapy is required. Generally, the AHA algorithm with reference to the European Atherosclerosis Society Consensus Panel recommendations is reasonable with all patients initiated on high-dose, high-potency statin, ezetimibe, and bile acid-binding resins. In most, additional LDL-C lowering is required with PCSK9 inhibitors and/or lomitapide or mipomersen. Liver transplantation can also be considered at experienced centers as a last resort.

  View details for DOI 10.1007/s11936-016-0486-2

  View details for PubMedID 27620638

• Metabolic Markers to Predict Incident Diabetes Mellitus in Statin-Treated Patients (from the Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Trials). American journal of cardiology Kohli, P., Knowles, J. W., Sarraju, A., Waters, D. D., Reaven, G. 2016; 118 (9): 1275-1281

  Abstract

  The goal of this analysis was to evaluate the ability of insulin resistance, identified by the presence of prediabetes mellitus (PreDM) combined with either an elevated triglyceride (TG >1.7 mmol/l) or body mass index (BMI ≥27.0 kg/m(2)), to identify increased risk of statin-associated type 2 diabetes mellitus (T2DM). Consequently, a retrospective analysis of data from subjects without diabetes in the Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels randomized controlled trials was performed, subdividing participants into 4 experimental groups: (1) normal fasting glucose (NFG) and TG ≤1.7 mmol/l (42%); (2) NFG and TG >1.7 mmol/l (22%); (3) PreDM and TG ≤1.7 mmol/l (20%); and (4) PreDM and TG >1.7 mmol/l (15%). Comparable groupings were created substituting BMI values (kg/m(2) <27.0 and ≥27.0) for TG concentrations. Patients received atorvastatin or placebo for a median duration of 4.9 years. Incident T2DM, defined by developing at least 2 fasting plasma glucose (FPG) concentrations ≥126 mg/dl, an increase in FPG ≥37 mg/dl, or a clinical diagnosis of T2DM, was observed in 8.2% of the total population. T2DM event rates (statin or placebo) varied from a low of 2.8%/3.2% (NFG and TG ≤1.7 mmol/l) to a high of 22.8%/7.6% (PreDM and TG >1.7 mmol/l) with intermediate values for only an elevated TG >1.7 mmol/l (5.2%/4.3%) or only PreDM (12.8%/7.6%). Comparable differences were observed when BMI values were substituted for TG concentrations. In conclusion, these data suggest that (1) the diabetogenic impact of statin treatment is relatively modest in general; (2) the diabetogenic impact is accentuated relatively dramatically as FPG and TG concentrations and BMI increase; and (3) PreDM, TG concentrations, and BMI identify people at highest risk of statin-associated T2DM.

  View details for DOI 10.1016/j.amjcard.2016.07.054

  View details for PubMedID 27614854

• Nat1 Deficiency Is Associated with Mitochondrial Dysfunction and Exercise Intolerance in Mice CELL REPORTS Chennamsetty, I., Coronado, M., Contrepois, K., Keller, M. P., Carcamo-Orive, I., Sandin, J., Fajardo, G., Whittle, A. J., Fathzadeh, M., Snyder, M., Reaven, G., Attie, A. D., Bernstein, D., Quertermous, T., Knowles, J. W. 2016; 17 (2): 527-540

  Abstract

  We recently identified human N-acetyltransferase 2 (NAT2) as an insulin resistance (IR) gene. Here, we examine the cellular mechanism linking NAT2 to IR and find that Nat1 (mouse ortholog of NAT2) is co-regulated with key mitochondrial genes. RNAi-mediated silencing of Nat1 led to mitochondrial dysfunction characterized by increased intracellular reactive oxygen species and mitochondrial fragmentation as well as decreased mitochondrial membrane potential, biogenesis, mass, cellular respiration, and ATP generation. These effects were consistent in 3T3-L1 adipocytes, C2C12 myoblasts, and in tissues from Nat1-deficient mice, including white adipose tissue, heart, and skeletal muscle. Nat1-deficient mice had changes in plasma metabolites and lipids consistent with a decreased ability to utilize fats for energy and a decrease in basal metabolic rate and exercise capacity without altered thermogenesis. Collectively, our results suggest that Nat1 deficiency results in mitochondrial dysfunction, which may constitute a mechanistic link between this gene and IR.

  View details for DOI 10.1016/j.celrep.2016.09.005

  View details for Web of Science ID 000385850700019

  View details for PubMedID 27705799

  View details for PubMedCentralID PMC5097870

• US physician practices for diagnosing familial hypercholesterolemia: data from the CASCADE-FH registry JOURNAL OF CLINICAL LIPIDOLOGY Ahmad, Z. S., Andersen, R. L., Andersen, L. H., O'Brien, E. C., Kindt, I., Shrader, P., Vasandani, C., Newman, C. B., DeGoma, E. M., Baum, S. J., Hemphill, L. C., Hudgins, L. C., Ahmed, C. D., Kullo, I. J., Gidding, S. S., Duffy, D., Neal, W., Wilemon, K., Roe, M. T., Rader, D. J., Ballantyne, C. M., Linton, M. F., Duell, P. B., Shapiro, M. D., Moriarty, P. M., Knowles, J. W. 2016; 10 (5): 1223-1229

  Abstract

  In the US familial hypercholesterolemia (FH), patients are underidentified, despite an estimated prevalence of 1:200 to 1:500. Criteria to identify FH patients include Simon Broome, Dutch Lipid Clinic Network (DLCN), or Make Early Diagnosis to Prevent Early Deaths (MEDPED). The use of these criteria in US clinical practices remains unclear.To characterize the FH diagnostic criteria applied by US lipid specialists participating in the FH Foundation's CASCADE FH (CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia) patient registry.We performed an observational, cross-sectional analysis of diagnostic criteria chosen for each adult patient, both overall and by baseline patient characteristics, at 15 clinical sites that had contributed data to the registry as of September 8, 2015. A sample of 1867 FH adults was analyzed. The median age at FH diagnosis was 50 years, and the median pretreatment low-density lipoprotein cholesterol (LDL-C) value was 238 mg/dL. The main outcome was the diagnostic criteria chosen. Diagnostic criteria were divided into five nonexclusive categories: "clinical diagnosis," MEDPED, Simon Broome, DLCN, and other.Most adults enrolled in CASCADE FH (55.0%) received a "clinical diagnosis." The most commonly used formal criteria was Simon-Broome only (21%), followed by multiple diagnostic criteria (16%), MEDPED only (7%), DLCN only (1%), and other (0.5%), P < .0001. Of the patients with only a "clinical diagnosis," 93% would have met criteria for Simon Broome, DLCN, or MEDPED based on the data available in the registry.Our findings demonstrate heterogeneity in the application of FH diagnostic criteria in the United States. A nationwide consensus definition may lead to better identification, earlier treatment, and ultimately CHD prevention.

  View details for DOI 10.1016/j.jac1.2016.07.011

  View details for PubMedID 27678440

• Hypertriglyceridemia: A simple approach to identify insulin resistance and enhanced cardio-metabolic risk in patients with prediabetes. Diabetes research and clinical practice Abbasi, F., Kohli, P., Reaven, G. M., Knowles, J. W. 2016; 120: 156-161

  Abstract

  Prediabetes (PreDM) is a metabolically heterogeneous condition, differing in degree of insulin resistance and risk of type 2 diabetes mellitus and coronary heart disease (CHD). This study was initiated to evaluate the hypothesis that a fasting plasma triglyceride (TG) concentration ⩾1.7mmol/L can aid in identifying the subset of individuals with PreDM who are most insulin resistant and at greatest risk to develop CHD as well as type 2 diabetes mellitus.In this cross-sectional study, measurements were made of: (1) steady-state plasma glucose (SSPG) concentration during the insulin suppression test to ascertain degree of insulin resistance and (2) conventional CHD risk factors in 587 apparently healthy individuals with normal fasting plasma glucose (NFG, n=370) or PreDM (n=217).Subjects with PreDM were significantly (P<0.001) more insulin resistant (higher SSPG concentrations) and had a more adverse CHD risk profile than those with NFG. A TG concentration ⩾1.7mmol/L identified a subset of individuals with PreDM (38%) who had a higher mean SSPG concentration (11.3±3.5mmol/L vs. 9.3±3.9mmol/L, P<0.001), were more likely to be insulin resistant (66% vs. 39%, P<0.001), and had a more adverse CHD risk factor profile.Measurement of fasting TG concentration in individuals with PreDM may provide a simple clinical approach to identify those who are insulin resistant, at enhanced risk of CHD, and more likely to develop type 2 diabetes mellitus.

  View details for DOI 10.1016/j.diabres.2016.07.024

  View details for PubMedID 27565692

• Standards of Evidence and Mechanistic Inference in Autosomal Recessive Hypercholesterolemia ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Priest, J. R., Knowles, J. W. 2016; 36 (8): 1465-1466

  View details for DOI 10.1161/ATVBAHA.116.307714

  View details for Web of Science ID 000381474000002

  View details for PubMedID 27466618

• Statins in Familial Hypercholesterolemia Translating Evidence to Action JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Knowles, J. W. 2016; 68 (3): 261–64

  View details for PubMedID 27417003

• Enough Evidence, Time to Act! CIRCULATION Rodriguez, F., Knowles, J. W. 2016; 134 (1): 20-23

  View details for DOI 10.1161/CIRCULATIONAHA.116.023010

  View details for Web of Science ID 000378900300006

  View details for PubMedID 27358433

• Treatment Gaps in Adults With Heterozygous Familial Hypercholesterolemia in the United States Data From the CASCADE-FH Registry CIRCULATION-CARDIOVASCULAR GENETICS DeGoma, E. M., Ahmad, Z. S., O'Brien, E. C., Kindt, I., Shrader, P., Newman, C. B., Pokharel, Y., Baum, S. J., Hemphill, L. C., Hudgins, L. C., Ahmed, C. D., Gidding, S. S., Duffy, D., Neal, W., Wilemon, K., Roe, M. T., Rader, D. J., Ballantyne, C. M., Linton, M. F., Duell, P. B., Shapiro, M. D., Moriarty, P. M., Knowles, J. W. 2016; 9 (3): 240-?

  Abstract

  Cardiovascular disease burden and treatment patterns among patients with familial hypercholesterolemia (FH) in the United States remain poorly described. In 2013, the FH Foundation launched the Cascade Screening for Awareness and Detection (CASCADE) of FH Registry to address this knowledge gap.We conducted a cross-sectional analysis of 1295 adults with heterozygous FH enrolled in the CASCADE-FH Registry from 11 US lipid clinics. Median age at initiation of lipid-lowering therapy was 39 years, and median age at FH diagnosis was 47 years. Prevalent coronary heart disease was reported in 36% of patients, and 61% exhibited 1 or more modifiable risk factors. Median untreated low-density lipoprotein cholesterol (LDL-C) was 239 mg/dL. At enrollment, median LDL-C was 141 mg/dL; 42% of patients were taking high-intensity statin therapy and 45% received >1 LDL-lowering medication. Among FH patients receiving LDL-lowering medication(s), 25% achieved an LDL-C <100 mg/dL and 41% achieved a ≥50% LDL-C reduction. Factors associated with prevalent coronary heart disease included diabetes mellitus (adjusted odds ratio 1.74; 95% confidence interval 1.08-2.82) and hypertension (2.48; 1.92-3.21). Factors associated with a ≥50% LDL-C reduction from untreated levels included high-intensity statin use (7.33; 1.86-28.86) and use of >1 LDL-lowering medication (1.80; 1.34-2.41).FH patients in the CASCADE-FH Registry are diagnosed late in life and often do not achieve adequate LDL-C lowering, despite a high prevalence of coronary heart disease and risk factors. These findings highlight the need for earlier diagnosis of FH and initiation of lipid-lowering therapy, more consistent use of guideline-recommended LDL-lowering therapy, and comprehensive management of traditional coronary heart disease risk factors.

  View details for DOI 10.1161/CIRCGENETICS.116.001381

  View details for PubMedID 27013694

• Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity NATURE MEDICINE Burridge, P. W., Li, Y. F., Matsa, E., Wu, H., Ong, S., Sharma, A., Holmstrom, A., Chang, A. C., Coronado, M. J., Ebert, A. D., Knowles, J. W., Telli, M. L., Witteles, R. M., Blau, H. M., Bernstein, D., Altman, R. B., Wu, J. C. 2016; 22 (5): 547-556

  Abstract

  Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but it causes a dose-related cardiotoxicity that can lead to heart failure in a subset of patients. At present, it is not possible to predict which patients will be affected by doxorubicin-induced cardiotoxicity (DIC). Here we demonstrate that patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can recapitulate the predilection to DIC of individual patients at the cellular level. hiPSC-CMs derived from individuals with breast cancer who experienced DIC were consistently more sensitive to doxorubicin toxicity than hiPSC-CMs from patients who did not experience DIC, with decreased cell viability, impaired mitochondrial and metabolic function, impaired calcium handling, decreased antioxidant pathway activity, and increased reactive oxygen species production. Taken together, our data indicate that hiPSC-CMs are a suitable platform to identify and characterize the genetic basis and molecular mechanisms of DIC.

  View details for DOI 10.1038/nm.4087

  View details for PubMedID 27089514

• Impact of Septal Reduction on Left Atrial Size and Diastole in Hypertrophic Cardiomyopathy ECHOCARDIOGRAPHY-A JOURNAL OF CARDIOVASCULAR ULTRASOUND AND ALLIED TECHNIQUES Finocchiaro, G., Haddad, F., Kobayashi, Y., Lee, D., Pavlovic, A., Schnittger, I., Sinagra, G., Magavern, E., Myers, J., Froelicher, V., Knowles, J. W., Ashley, E. 2016; 33 (5): 686-694

  Abstract

  Both myectomy and alcohol septal ablation (ASA) can substantially reduce left ventricular (LV) outflow obstruction, relieve symptoms, and improve outcomes in hypertrophic cardiomyopathy (HCM). It is unclear whether septal reduction decreases left atrial (LA) size and improves diastolic function. The aim of this study was to analyze the consequences of septal reduction on LA size and diastolic function in a cohort of patients with HCM.Forty patients (mean age: 50 ± 14, male sex 64%) with HCM who underwent septal reduction (myectomy or alcohol septal ablation) were studied. Retrospective analyses of echocardiograms preprocedure, postprocedure, and at 1 year of follow-up were performed.Thirty-one patients had septal myectomy and 9 ASA. The degree of reduction in rest peak LV outflow tract gradient was significant (57 ± 32 vs. 23 ± 20 mmHg at 1 year, P < 0.001). Maximal interventricular septal thickness decreased from 22 ± 6 mm preprocedure to 19 ± 4 mm postprocedure (P < 0.001); moderate-to-severe mitral regurgitation (MR) was initially present in 34% of the sample and only 2% after the procedure. Average LA volume index (LAVI) decreased from 63 ± 20 to 55 ± 20 mL/m(2) at the 1-year follow-up (P < 0.001). We did not observe a significant improvement in diastolic function at Doppler (E/A 1.2 ± 0.4 vs. 1.1 ± 0.5, P = 0.07; E' 7.6 ± 3.6 vs. 6.9 ± 3.0, P = 0.4) pre- and postprocedure, respectively). At 1 year, only 5% of the patients were severely symptomatic (NYHA III). On multivariate analysis, a significant change in the LVOT gradient during stress (Δ gradient ≥30 mmHg) was the only variable independently associated with LAVI reverse remodeling >10 mL/m(2) [OR = 6.4 (CI 95% 1.12-36.44), P = 0.04].Septal reduction is effective in the relief of LV obstruction and symptoms in patients with HCM. The hemodynamic changes result in a significant LA reverse remodeling, but not in an improvement of diastolic function in these patients.

  View details for DOI 10.1111/echo.13158

  View details for PubMedID 26926154

• Usual Blood Pressure and New-Onset Diabetes Risk JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Knowles, J. W., Reaven, G. 2016; 67 (13): 1656–57

  View details for DOI 10.1016/j.jacc.2015.12.065

  View details for Web of Science ID 000372893300019

  View details for PubMedID 27150694

• Cardiometabolic Effects of Glucagon-Like Peptide-1 Agonists. Current atherosclerosis reports Sarraju, A., Kim, S. H., Knowles, J. W. 2016; 18 (2): 7-?

  Abstract

  Cardiovascular disease is the leading cause of death among adults in the USA. Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) are known risk factors for cardiovascular disease. Despite the development of numerous effective anti-glycemic therapies, we have been unable to completely mitigate cardiovascular risk with glucose lowering alone, and prevention of cardiovascular disease in patients with diabetes is primarily achieved with the use of medications that address other risk factors such as anti-hypertensives or statins. Glucagon-like peptide-1 (GLP-1) is a key hormone in the pathophysiology of diabetes. GLP-1 agonists have been recently approved for the treatment of T2DM as well as for chronic weight management. In this review, we aim to explore the effects of GLP-1 agonists on cardiovascular health with a focus on cardiometabolic variables and cardiac function.

  View details for DOI 10.1007/s11883-016-0558-5

  View details for PubMedID 26782825

• Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene. journal of clinical investigation Knowles, J. W., Xie, W., Zhang, Z., Chennamsetty, I., Assimes, T. L., Paananen, J., Hansson, O., Pankow, J., Goodarzi, M. O., Carcamo-Orive, I., Morris, A. P., Chen, Y. I., Mäkinen, V., Ganna, A., Mahajan, A., Guo, X., Abbasi, F., Greenawalt, D. M., Lum, P., Molony, C., Lind, L., Lindgren, C., Raffel, L. J., Tsao, P. S., Schadt, E. E., Rotter, J. I., Sinaiko, A., Reaven, G., Yang, X., Hsiung, C. A., Groop, L., Cordell, H. J., Laakso, M., Hao, K., Ingelsson, E., Frayling, T. M., Weedon, M. N., Walker, M., Quertermous, T. 2016; 126 (1): 403-?

  View details for DOI 10.1172/JCI85921

  View details for PubMedID 26727231

  View details for PubMedCentralID PMC4701558

• Maternal Midpregnancy Glucose Levels and Risk of Congenital Heart Disease in Offspring JAMA PEDIATRICS Priest, J. R., Yang, W., Reaven, G., Knowles, J. W., Shaw, G. M. 2015; 169 (12): 1112-1116

  Abstract

  There is a well-described association between maternal diabetes mellitus and risk of congenital heart disease (CHD) in offspring. Although the clinical diagnoses of type 2 diabetes or gestational diabetes are strong risk factors for CHD, subclinical abnormalities of glucose and insulin metabolism are common within the general population and could also confer risk for CHD. We hypothesize that continuous measures of blood analytes related to maternal diabetes are related to odds of cardiac malformations.To explore the potential association of 2 different CHD phenotypes in offspring with maternal midpregnancy measures of glucose and insulin.Case-control study from a population-based cohort of 277 pregnant women in southern and central California carrying infants with tetralogy of Fallot (TOF) (n = 55), dextrotransposition of the great arteries (dTGA) (n = 42), or healthy infants without CHD (n = 180). Serum samples were collected from 2003 through 2007. The analysis was conducted from March through June 2015.Blood analytes related to maternal glucose metabolism were measured from random nonfasting second-trimester blood samples. We measured serum insulin levels by a validated radioimmunoassay, and we measured glucose levels. Multivariable logistic regression models estimated the association between these levels and case status.Serum glucose values were elevated in the maternal samples for offspring with TOF (median, 97.0 mg/dL [to convert to millimoles per liter, multiply by 0.0555]) relative to controls (median, 91.5 mg/dL) (P = .01, Wilcoxon rank sum test), a phenomenon not observed in the maternal samples for offspring with dTGA (median, 90.0 mg/dL) relative to controls (P = .18, Wilcoxon rank sum test). Serum insulin levels were significantly different between controls (median, 18.8 μIU/mL [to convert to picomoles per liter, multiply by 6.945]) and maternal samples for offspring with dTGA (median, 13.1 μIU/mL; P = .048, Wilcoxon rank sum test) but not with TOF (median, 14.3 μIU/mL; P = .35, Wilcoxon rank sum test). Relative to maternal blood glucose levels of infants without cardiac malformations, we observed that maternal blood glucose levels in models including insulin were strongly associated with odds of TOF (adjusted odds ratio = 7.54; 95% CI, 2.30-24.69) but not with dTGA (adjusted odds ratio = 1.16; 95% CI, 0.28-4.79).These results represent a direct correlation of glucose as a continuous variable to odds of specific cardiac malformations. The association between serum glucose and odds of TOF indicates the need for additional epidemiological and mechanistic investigations into the risk conferred by insulin signaling and glucose metabolism during early pregnancy.

  View details for DOI 10.1001/jamapediatrics.2015.2831

  View details for Web of Science ID 000366334600014

  View details for PubMedID 26457543

  View details for PubMedCentralID PMC4996656

• The Agenda for Familial Hypercholesterolemia A Scientific Statement From the American Heart Association CIRCULATION Gidding, S. S., Champagne, M., de Ferranti, S. D., Defesche, J., Ito, M. K., Knowles, J. W., McCrindle, B., Raal, F., Rader, D., Santos, R. D., Lopes-Virella, M., Watts, G. F., Wierzbicki, A. S., Amer Heart Assoc 2015; 132 (22): 2167–92

  View details for DOI 10.1161/CIR.0000000000000297

  View details for Web of Science ID 000366187100010

  View details for PubMedID 26510694

• Familial Hypercholesterolemia and the 2013 American College of Cardiology/American Heart Association Guidelines: Myths, Oversimplification, and Misinterpretation Versus Facts AMERICAN JOURNAL OF CARDIOLOGY Knowles, J. W., Stone, N. J., Ballantyne, C. M. 2015; 116 (3): 481-484

  Abstract

  Familial hypercholesterolemia (FH) is a genetic condition resulting in severe, lifelong elevations in low-density lipoprotein cholesterol and a marked increased risk of early-onset coronary disease. FH is treatable when identified, yet is vastly under-recognized and undertreated. Although the 2013 American College of Cardiology/American Heart Association guidelines on the treatment of cholesterol presented a paradigm shift, we believe that there have been serious oversimplifications, misinterpretations, and erroneous reporting about the current ACC/AHA cholesterol guidelines that have contributed to suboptimal care for these subjects. In summary, the ACC/AHA guidelines place tremendous emphasis on the identification of patients with FH, the initiation of high-intensity statin therapy, the need to obtain follow-up lipid values to assess the efficacy and compliance to lifestyle and medical therapy, and the role of nonstatin drugs when needed for optimal care of the individual patient.

  View details for Web of Science ID 000359034100024

  View details for PubMedID 26043952

• Using Genetic Variants to Assess the Relationship Between Circulating Lipids and Type 2 Diabetes DIABETES Fall, T., Xie, W., Poon, W., Yaghootkar, H., Maegi, R., Knowles, J. W., Lyssenko, V., Weedon, M., Frayling, T. M., Ingelsson, E. 2015; 64 (7): 2676-2684

  Abstract

  The effects of dyslipidemia on the risk of type 2 diabetes (T2D) and related traits are not clear. We used regression models and 140 lipid-associated genetic variants to estimate associations between circulating HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and triglycerides and T2D and related traits. Each genetic test was corrected for effects of variants on the other two lipid types and surrogates of adiposity. We used the largest data sets available: 34,840 T2D case and 114,981 control subjects from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis) consortium and up to 133,010 individuals without diabetes for insulin secretion and sensitivity from the MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium) and GENESIS (GENEticS of Insulin Sensitivity) studies. Eight of 21 associations between groups of variants and diabetes traits were significant at the nominal level, including those between genetically determined lower HDL-C (β = -0.12, P = 0.03) and T2D and genetically determined lower LDL-C (β = -0.21, P = 5 × 10(-6)) and T2D. Although some of these may represent causal associations, we discuss why caution must be used when using Mendelian randomization in the context of circulating lipid levels and diabetes traits. In conclusion, we found evidence of links between genetic variants associated with lipids and T2D, but deeper knowledge of the underlying genetic mechanisms of specific lipid variants is needed before drawing definite conclusions about causality based on Mendelian randomization methodology.

  View details for DOI 10.2337/db14-1710

  View details for Web of Science ID 000356934000049

  View details for PubMedID 25948681

• Systematic Comparison of Digital Electrocardiograms From Healthy Athletes and Patients With Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology Bent, R. E., Wheeler, M. T., Hadley, D., Knowles, J. W., Pavlovic, A., Finocchiaro, G., Haddad, F., Salisbury, H., Race, S., Shmargad, Y., Matheson, G. O., Kumar, N., Saini, D., Froelicher, V., Ashley, E., Perez, M. V. 2015; 65 (22): 2462-2463

  View details for DOI 10.1016/j.jacc.2015.03.559

  View details for PubMedID 26046742

• Prevalence and Prognostic Role of Right Ventricular Involvement in Stress-Induced Cardiomyopathy JOURNAL OF CARDIAC FAILURE Finocchiaro, G., Kobayashi, Y., Magavern, E., Zhou, J. Q., Ashley, E., Sinagra, G., Schnittger, I., Knowles, J. W., Fearon, W. F., Haddad, F., Tremmel, J. A. 2015; 21 (5): 419-425

  Abstract

  Stress-induced cardiomyopathy (SCM) is a reversible cardiomyopathy observed in patients without significant coronary disease. The aim of this study was to assess the incidence and clinical significance of right ventricular (RV) involvement in SCM.We retrospectively analyzed echocardiograms from 40 consecutive patients who presented with SCM at Stanford University Medical Center from September 2000 to November 2010. The primary end point was overall mortality. RV involvement was observed in 20 patients (50%; global RV hypokinesia in 15 patients and focal RV apical akinesia in 5 patients). The independent correlates of RV involvement were older age (odds ratio [OR] 1.09, 95% confidence interval [CI] 1.02-1.7two, P = .01) and LVEF (per 10% decrease: OR 3.60, CI 1.77-7.32; P = .02). At a mean follow-up of 44 ± 32 months, 12 patients (30%) died (in-hospital death in 3 patients). At multivariate analysis, the presence of an RV fractional area change <35% emerged as an independent predictor of death (OR 3.6, CI 1.06-12.41; P = .04).RV involvement is a common finding in SCM, and may present as either global or focal RV apical involvement. Both older age and lower LVEF are associated with a higher risk of RV involvement, which appears to be a major predictor of death.

  View details for DOI 10.1016/j.cardfail.2015.02.001

  View details for PubMedID 25704104

• Cardiopulmonary responses and prognosis in hypertrophic cardiomyopathy: a potential role for comprehensive noninvasive hemodynamic assessment. JACC. Heart failure Finocchiaro, G., Haddad, F., Knowles, J. W., Caleshu, C., Pavlovic, A., Homburger, J., Shmargad, Y., Sinagra, G., Magavern, E., Wong, M., Perez, M., Schnittger, I., Myers, J., Froelicher, V., Ashley, E. A. 2015; 3 (5): 408-418

  Abstract

  This study sought to discover the key determinants of exercise capacity, maximal oxygen consumption (oxygen uptake [Vo2]), and ventilatory efficiency (ventilation/carbon dioxide output [VE/Vco2] slope) and assess the prognostic potential of metabolic exercise testing in hypertrophic cardiomyopathy (HCM).The intrinsic mechanisms leading to reduced functional tolerance in HCM are unclear.The study sample included 156 HCM patients consecutively enrolled from January 1, 2007 to January 1, 2012 with a complete clinical assessment, including rest and stress echocardiography and cardiopulmonary exercise test (CPET) with impedance cardiography. Patients were also followed for the composite outcome of cardiac-related death, heart transplant, and functional deterioration leading to septal reduction therapy (myectomy or septal alcohol ablation).Abnormalities in CPET responses were frequent, with 39% (n = 61) of the sample showing a reduced exercise tolerance (Vo2 max <80% of predicted) and 19% (n = 30) characterized by impaired ventilatory efficiency (VE/Vco2 slope >34). The variables most strongly associated with exercise capacity (expressed in metabolic equivalents), were peak cardiac index (r = 0.51, p < 0.001), age (r = -0.25, p < 0.01), male sex (r = 0.24, p = 0.02), and indexed right ventricular end-diastolic area (r = 0.31, p = 0.002), resulting in an R(2) of 0.51, p < 0.001. Peak cardiac index was the main predictor of peak Vo2 (r = 0.61, p < 0.001). The variables most strongly related to VE/VCO2 slope were E/E' (r = 0.23, p = 0.021) and indexed left atrial volume index (LAVI) (r = 0.34, p = 0.005) (model R(2) = 0.15). The composite endpoint occurred in 21 (13%) patients. In an exploratory analysis, 3 variables were independently associated with the composite outcome (mean follow-up 27 ± 11 months): peak Vo2 <80% of predicted (hazard ratio: 4.11; 95% confidence interval [CI]: 1.46 to 11.59; p = 0.008), VE/Vco2 slope >34 (hazard ratio: 3.14; 95% CI: 1.26 to 7.87; p = 0.014), and LAVI >40 ml/m(2) (hazard ratio: 3.32; 95% CI: 1.08 to 10.16; p = 0.036).In HCM, peak cardiac index is the main determinant of exercise capacity, but it is not significantly related to ventilatory efficiency. Peak Vo2, ventilatory inefficiency, and LAVI are associated with an increased risk of major events in the short-term follow-up.

  View details for DOI 10.1016/j.jchf.2014.11.011

  View details for PubMedID 25863972

• Genetically Determined Height and Coronary Artery Disease NEW ENGLAND JOURNAL OF MEDICINE Nelson, C. P., Hamby, S. E., Saleheen, D., Hopewell, J. C., Zeng, L., Assimes, T. L., Kanoni, S., WILLENBORG, C., Burgess, S., Amouyel, P., Anand, S., Blankenberg, S., Boehm, B. O., Clarke, R. J., Collins, R., Dedoussis, G., Farrall, M., Franks, P. W., Groop, L., Hall, A. S., Hamsten, A., Hengstenberg, C., Hovingh, G. K., Ingelsson, E., Kathiresan, S., Kee, F., Koenig, I. R., Kooner, J., Lehtimaeki, T., Maerz, W., Mcpherson, R., Metspalu, A., NIEMINEN, M. S., O'Donnell, C. J., Palmer, C. N., Peters, A., Perola, M., Reilly, M. P., Ripatti, S., Roberts, R., Salomaa, V., Shah, S. H., Schreiber, S., Siegbahn, A., Thorsteinsdottir, U., Veronesi, G., Wareham, N., Willer, C. J., Zalloua, P. A., Erdmann, J., Deloukas, P., Watkins, H., Schunkert, H., Danesh, J., Thompson, J. R., Samani, N. J. 2015; 372 (17): 1608-1618

  Abstract

  The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear.We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes.We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quartile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis.There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.).

  View details for DOI 10.1056/NEJMoa1404881

  View details for Web of Science ID 000353294000006

  View details for PubMedID 25853659

• Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene JOURNAL OF CLINICAL INVESTIGATION Knowles, J. W., Xie, W., Zhang, Z., Chennemsetty, I., Assimes, T. L., Paananen, J., Hansson, O., Pankow, J., Goodarzi, M. O., Carcamo-Orive, I., Morris, A. P., Chen, Y. I., Maekinen, V., Ganna, A., Mahajan, A., Guo, X., Abbasi, F., Greenawalt, D. M., Lum, P., Molony, C., Lind, L., Lindgren, C., Raffel, L. J., Tsao, P. S., Schadt, E. E., Rotter, J. I., Sinaiko, A., Reaven, G., Yang, X., Hsiung, C. A., Groop, L., Cordell, H. J., Laakso, M., Hao, K., Ingelsson, E., Frayling, T. M., Weedon, M. N., Walker, M., Quertermous, T. 2015; 125 (4): 1739-1751

  Abstract

  Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.

  View details for DOI 10.1172/JCI74592

  View details for Web of Science ID 000352248600037

  View details for PubMedID 25798622

• The Independent Predictive Value of Peak Oxygen Consumption, Left ventricular Strain and Atrial Remodelling in Patients With Dilated Cardiomyopathy Boulate, D., Banerjee, D., Ariyama, M., Wheeler, M., Knowles, J. W., Kobayashi, Y., Perez, M., Wu, J., Schnittger, I., Kouznetsova, T., Myers, J., Haddad, F., Ashley, E. A. ELSEVIER SCIENCE INC. 2015: S186

  View details for Web of Science ID 000353251500484

• PCSK9 Inhibition: Current Concepts and Lessons from Human Genetics CURRENT ATHEROSCLEROSIS REPORTS Rodriguez, F., Knowles, J. W. 2015; 17 (3)

  Abstract

  Low-density lipoprotein cholesterol (LDL-C) plays a central role in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). Statins are the cornerstone of therapy for the treatment of elevated LDL-C and for the primary and secondary prevention of ASCVD. However, some patients are intolerant of statins or are unable to achieve acceptable lipid levels on statin-based regimens alone. Proprotein convertase subtilisin/kexin type 9 (PCSK9) serves as an important regulator of hepatocyte LDL receptor expression and degradation, and recent genetic studies have highlighted the critical role of PCSK9 in human disease. Gain-of-function mutations in PCSK9 are associated with familial hypercholesterolemia, whereas loss-of-function mutations are protective against ASCVD. Therefore, PCSK9 inhibition offers a promising supplement or alternative to statin therapy in the reduction of LDL-C. Numerous phase II and III randomized control trials have demonstrated the tolerability of monoclonal antibodies against PCSK9 and their efficacy in lowering LDL-C by an additional 40-70 %. In this article, we review the growing role of PSCK9 inhibition in LDL-C reduction for diverse patient populations.

  View details for DOI 10.1007/s11883-015-0487-8

  View details for Web of Science ID 000349629400002

  View details for PubMedID 25637042

• 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

• 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

• Corrigendum: Simple, standardized incorporation of genetic risk into non-genetic risk prediction tools for complex traits: coronary heart disease as an example. Frontiers in genetics Goldstein, B. A., Knowles, J. W., Salfati, E., Ioannidis, J. P., Assimes, T. L. 2015; 6: 231-?

  Abstract

  [This corrects the article on p. 254 in vol. 5, PMID: 25136350.].

  View details for DOI 10.3389/fgene.2015.00231

  View details for PubMedID 26217377

• Genetic Applications in Coronary Artery Disease CARDIOVASCULAR GENETICS AND GENOMICS IN CLINICAL PRACTICE Pan, S., Kim, J., Mehta, N. N., Knowles, J. W., Shah, S. J., Arnett, D. K. 2015: 253–64

  View details for Web of Science ID 000346457500021

• Genetic Evidence for a Normal-Weight "Metabolically Obese" Phenotype Linking Insulin Resistance, Hypertension, Coronary Artery Disease, and Type 2 Diabetes DIABETES Yaghootkar, H., Scott, R. A., White, C. C., Zhang, W., Speliotes, E., Munroe, P. B., Ehret, G. B., Bis, J. C., Fox, C. S., Walker, M., Borecki, I. B., Knowles, J. W., Yerges-Armstrong, L., Ohlsson, C., Perry, J. R., Chambers, J. C., Kooner, J. S., Franceschini, N., Langenberg, C., Hivert, M., Dastani, Z., Richards, J. B., Semple, R. K., Frayling, T. M. 2014; 63 (12): 4369-4377

  Abstract

  The mechanisms that predispose to hypertension, coronary artery disease (CAD), and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy-a reduction in subcutaneous adipose tissue-it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, CAD, and T2D. We aimed to test the hypothesis that common alleles associated with IR also influence the wider clinical and biochemical profile of monogenic IR. We selected 19 common genetic variants associated with fasting insulin-based measures of IR. We used hierarchical clustering and results from genome-wide association studies of eight nondisease outcomes of monogenic IR to group these variants. We analyzed genetic risk scores against disease outcomes, including 12,171 T2D cases, 40,365 CAD cases, and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (β = 0.018; P = 4 × 10(-29)), lower HDL cholesterol (β = -0.020; P = 7 × 10(-37)), greater hepatic steatosis (β = 0.021; P = 3 × 10(-4)), higher alanine transaminase (β = 0.002; P = 3 × 10(-5)), lower sex-hormone-binding globulin (β = -0.010; P = 9 × 10(-13)), and lower adiponectin (β = -0.015; P = 2 × 10(-26)). The same risk alleles were associated with lower BMI (per-allele β = -0.008; P = 7 × 10(-8)) and increased visceral-to-subcutaneous adipose tissue ratio (β = -0.015; P = 6 × 10(-7)). Individuals carrying ≥17 fasting insulin-raising alleles (5.5% population) were slimmer (0.30 kg/m(2)) but at increased risk of T2D (odds ratio [OR] 1.46; per-allele P = 5 × 10(-13)), CAD (OR 1.12; per-allele P = 1 × 10(-5)), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg [per-allele P = 2 × 10(-5)] and 0.67 mmHg [per-allele P = 2 × 10(-4)], respectively) compared with individuals carrying ≤9 risk alleles (5.5% population). Our results provide genetic evidence for a link between the three diseases of the "metabolic syndrome" and point to reduced subcutaneous adiposity as a central mechanism.

  View details for DOI 10.2337/db14-0318

  View details for Web of Science ID 000345335500045

  View details for PubMedCentralID PMC4392920

• Genetic evidence for a normal-weight "metabolically obese" phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes. Diabetes Yaghootkar, H., Scott, R. A., White, C. C., Zhang, W., Speliotes, E., Munroe, P. B., Ehret, G. B., Bis, J. C., Fox, C. S., Walker, M., Borecki, I. B., Knowles, J. W., Yerges-Armstrong, L., Ohlsson, C., Perry, J. R., Chambers, J. C., Kooner, J. S., Franceschini, N., Langenberg, C., Hivert, M. F., Dastani, Z., Richards, J. B., Semple, R. K., Frayling, T. M. 2014; 63 (12): 4369-77

  Abstract

  The mechanisms that predispose to hypertension, coronary artery disease (CAD), and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy-a reduction in subcutaneous adipose tissue-it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, CAD, and T2D. We aimed to test the hypothesis that common alleles associated with IR also influence the wider clinical and biochemical profile of monogenic IR. We selected 19 common genetic variants associated with fasting insulin-based measures of IR. We used hierarchical clustering and results from genome-wide association studies of eight nondisease outcomes of monogenic IR to group these variants. We analyzed genetic risk scores against disease outcomes, including 12,171 T2D cases, 40,365 CAD cases, and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (β = 0.018; P = 4 × 10(-29)), lower HDL cholesterol (β = -0.020; P = 7 × 10(-37)), greater hepatic steatosis (β = 0.021; P = 3 × 10(-4)), higher alanine transaminase (β = 0.002; P = 3 × 10(-5)), lower sex-hormone-binding globulin (β = -0.010; P = 9 × 10(-13)), and lower adiponectin (β = -0.015; P = 2 × 10(-26)). The same risk alleles were associated with lower BMI (per-allele β = -0.008; P = 7 × 10(-8)) and increased visceral-to-subcutaneous adipose tissue ratio (β = -0.015; P = 6 × 10(-7)). Individuals carrying ≥17 fasting insulin-raising alleles (5.5% population) were slimmer (0.30 kg/m(2)) but at increased risk of T2D (odds ratio [OR] 1.46; per-allele P = 5 × 10(-13)), CAD (OR 1.12; per-allele P = 1 × 10(-5)), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg [per-allele P = 2 × 10(-5)] and 0.67 mmHg [per-allele P = 2 × 10(-4)], respectively) compared with individuals carrying ≤9 risk alleles (5.5% population). Our results provide genetic evidence for a link between the three diseases of the "metabolic syndrome" and point to reduced subcutaneous adiposity as a central mechanism.

  View details for DOI 10.2337/db14-0318

  View details for PubMedID 25048195

  View details for PubMedCentralID PMC4392920

• Reducing the burden of disease and death from familial hypercholesterolemia: A call to action AMERICAN HEART JOURNAL Knowles, J. W., O'Brien, E. C., Greendale, K., Wilemon, K., Genest, J., Sperling, L. S., Neal, W. A., Rader, D. J., Khoury, M. J. 2014; 168 (6): 807–11

  Abstract

  Familial hypercholesterolemia (FH) is a genetic disease characterized by substantial elevations of low-density lipoprotein cholesterol, unrelated to diet or lifestyle. Untreated FH patients have 20 times the risk of developing coronary artery disease, compared with the general population. Estimates indicate that as many as 1 in 500 people of all ethnicities and 1 in 250 people of Northern European descent may have FH; nevertheless, the condition remains largely undiagnosed. In the United States alone, perhaps as little as 1% of FH patients have been diagnosed. Consequently, there are potentially millions of children and adults worldwide who are unaware that they have a life-threatening condition. In countries like the Netherlands, the United Kingdom, and Spain, cascade screening programs have led to dramatic improvements in FH case identification. Given that there are currently no systematic approaches in the United States to identify FH patients or affected relatives, the patient-centric nonprofit FH Foundation convened a national FH Summit in 2013, where participants issued a "call to action" to health care providers, professional organizations, public health programs, patient advocacy groups, and FH experts, in order to bring greater attention to this potentially deadly, but (with proper diagnosis) eminently treatable, condition.

  View details for PubMedID 25458642

  View details for PubMedCentralID PMC4683103

• RV remodeling in college athletes engaged in mixed strength and endurance training: do the current echocardiographic reference values apply? Finocchiaro, G., Knowles, J. W., Perez, M., Schnittger, I., Magavern, E., Puryear, J., Sinagra, G., Froelicher, V., Ashley, E., Haddad, F. OXFORD UNIV PRESS. 2014: 729–30

  View details for Web of Science ID 000343001304294

• Multi-ethnic fine-mapping of 14 central adiposity loci HUMAN MOLECULAR GENETICS Liu, C., Buchkovich, M. L., Winkler, T. W., Heid, I. M., Borecki, I. B., Fox, C. S., Mohlke, K. L., North, K. E., Cupples, L., African Ancestry Anthropometry Gen, GIANT Consortium 2014; 23 (17): 4738-4744

  Abstract

  The Genetic Investigation of Anthropometric Traits (GIANT) consortium identified 14 loci in European Ancestry (EA) individuals associated with waist-to-hip ratio (WHR) adjusted for body mass index. These loci are wide and narrowing the signals remains necessary. Twelve of 14 loci identified in GIANT EA samples retained strong associations with WHR in our joint EA/individuals of African Ancestry (AA) analysis (log-Bayes factor >6.1). Trans-ethnic analyses at five loci (TBX15-WARS2, LYPLAL1, ADAMTS9, LY86 and ITPR2-SSPN) substantially narrowed the signals to smaller sets of variants, some of which are in regions that have evidence of regulatory activity. By leveraging varying linkage disequilibrium structures across different populations, single-nucleotide polymorphisms (SNPs) with strong signals and narrower credible sets from trans-ethnic meta-analysis of central obesity provide more precise localizations of potential functional variants and suggest a possible regulatory role. Meta-analysis results for WHR were obtained from 77 167 EA participants from GIANT and 23 564 AA participants from the African Ancestry Anthropometry Genetics Consortium. For fine mapping we interrogated SNPs within ± 250 kb flanking regions of 14 previously reported index SNPs from loci discovered in EA populations by performing trans-ethnic meta-analysis of results from the EA and AA meta-analyses. We applied a Bayesian approach that leverages allelic heterogeneity across populations to combine meta-analysis results and aids in fine-mapping shared variants at these locations. We annotated variants using information from the ENCODE Consortium and Roadmap Epigenomics Project to prioritize variants for possible functionality.

  View details for DOI 10.1093/hmg/ddu183

  View details for Web of Science ID 000340238200023

  View details for PubMedID 24760767

  View details for PubMedCentralID PMC4119415

• Impact of latent obstruction on exercise tolerance in hypertrophic cardiomyopathy Finocchiaro, G., Haddad, F., Knowles, J. W., Pavlovic, A., Sinagra, G., Magavern, E., Wong, M., Myers, J., Froelicher, V., Ashley, E. A. OXFORD UNIV PRESS. 2014: 927

  View details for Web of Science ID 000343001305289

• Hyperuricaemia: the unintended consequence of insulin resistance/compensatory hyperinsulinaemia. Philanthropy gone awry. Journal of internal medicine Knowles, J. W., Reaven, G. 2014; 276 (2): 196-198

  View details for DOI 10.1111/joim.12209

  View details for PubMedID 24471887

• Simple, standardized incorporation of genetic risk into non-genetic risk prediction tools for complex traits: coronary heart disease as an example FRONTIERS IN GENETICS Goldstein, B. A., Knowles, J. W., Salfati, E., Ioannidis, J. P., Assimes, T. L. 2014; 5

  Abstract

  Genetic risk assessment is becoming an important component of clinical decision-making. Genetic Risk Scores (GRSs) allow the composite assessment of genetic risk in complex traits. A technically and clinically pertinent question is how to most easily and effectively combine a GRS with an assessment of clinical risk derived from established non-genetic risk factors as well as to clearly present this information to patient and health care providers.We illustrate a means to combine a GRS with an independent assessment of clinical risk using a log-link function. We apply the method to the prediction of coronary heart disease (CHD) in the Atherosclerosis Risk in Communities (ARIC) cohort. We evaluate different constructions based on metrics of effect change, discrimination, and calibration.The addition of a GRS to a clinical risk score (CRS) improves both discrimination and calibration for CHD in ARIC. RESULTS are similar regardless of whether external vs. internal coefficients are used for the CRS, risk factor single nucleotide polymorphisms (SNPs) are included in the GRS, or subjects with diabetes at baseline are excluded. We outline how to report the construction and the performance of a GRS using our method and illustrate a means to present genetic risk information to subjects and/or their health care provider.The proposed method facilitates the standardized incorporation of a GRS in risk assessment.

  View details for DOI 10.3389/fgene.2014.00254

  View details for Web of Science ID 000347445200001

• Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity. Diabetes Dimas, A. S., Lagou, V., Barker, A., Knowles, J. W., Mägi, R., Hivert, M., Benazzo, A., Rybin, D., Jackson, A. U., Stringham, H. M., Song, C., Fischer-Rosinsky, A., Boesgaard, T. W., Grarup, N., Abbasi, F. A., Assimes, T. L., Hao, K., Yang, X., Lecoeur, C., Barroso, I., Bonnycastle, L. L., Böttcher, Y., Bumpstead, S., Chines, P. S., Erdos, M. R., Graessler, J., Kovacs, P., Morken, M. A., Narisu, N., Payne, F., Stancakova, A., Swift, A. J., Tönjes, A., Bornstein, S. R., Cauchi, S., Froguel, P., Meyre, D., Schwarz, P. E., Häring, H., Smith, U., Boehnke, M., Bergman, R. N., Collins, F. S., Mohlke, K. L., Tuomilehto, J., Quertemous, T., Lind, L., Hansen, T., Pedersen, O., Walker, M., Pfeiffer, A. F., Spranger, J., Stumvoll, M., Meigs, J. B., Wareham, N. J., Kuusisto, J., Laakso, M., Langenberg, C., Dupuis, J., Watanabe, R. M., Florez, J. C., Ingelsson, E., McCarthy, M. I., Prokopenko, I. 2014; 63 (6): 2158-2171

  Abstract

  Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci and indices of proinsulin processing, insulin secretion and insulin sensitivity. We included data from up to 58,614 non-diabetic subjects with basal measures, and 17,327 with dynamic measures. We employed additive genetic models with adjustment for sex, age and BMI, followed by fixed-effects inverse variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (including TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without detectable change in fasting glucose. The final group contained twenty risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.

  View details for DOI 10.2337/db13-0949

  View details for PubMedID 24296717

• Re: "Temporal relationship between uric acid concentration and risk of diabetes in a community-based study population". American journal of epidemiology Knowles, J. W., Reaven, G. 2014; 179 (9): 1147-1148

  View details for DOI 10.1093/aje/kwu055

  View details for PubMedID 24670373

• Latent obstruction and left atrial size are predictors of clinical deterioration leading to septal reduction in hypertrophic cardiomyopathy. Journal of cardiac failure Finocchiaro, G., Haddad, F., Pavlovic, A., Sinagra, G., Schnittger, I., Knowles, J. W., Perez, M., Magavern, E., Myers, J., Ashley, E. 2014; 20 (4): 236-243

  Abstract

  Exercise echocardiography is a reliable tool to assess left ventricular (LV) dynamic obstruction in hypertrophic cardiomyopathy (HCM). The aim of this study was to determine the role of exercise echocardiography in the evaluation of latent obstruction and in predicting clinical deterioration in HCM patients.We considered 283 HCM patients studied with exercise echocardiography. The end point was clinical deterioration leading to septal reduction (myectomy or alcohol septal ablation). LV latent obstruction was present at enrollment in 67 patients (24%). During a mean follow-up of 42 ± 31 months, 42 patients had clinical deterioration leading to septal reduction therapy: in 12/67 (22%) patients with a latent obstruction at enrollment, in 28/84 (33%) patients with obstruction at rest, and in 2/132 (1.5%) with obstruction neither at rest or during stress. Multivariate analysis identified the following variables as independently associated with the end point: LV gradient >30 mm Hg at rest (hazard ratio [HR] 2.56, 95% CI 1.27-5.14; P = .009), LV gradient >30 mm Hg during stress (HR 4.96, 95% CI 1.81-13.61; P = .002), and indexed left atrial volume (LAVi ) >40 mL/m(2) (HR 2.86, 95% CI 1.47-5.55; P = .002). In patients with a latent obstruction, the strongest independent predictor of outcome was LAVi >40 mL/m(2) (HR 3.75, 95% CI 1.12-12.51; P = .032).Assessment of LV gradient during stress with exercise echocardiography is an important tool for the evaluation of latent obstruction in HCM and may have a role in risk stratification of these patients.

  View details for DOI 10.1016/j.cardfail.2014.01.014

  View details for PubMedID 24486928

• Rationale and design of the familial hypercholesterolemia foundation CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia registry. American heart journal O'Brien, E. C., Roe, M. T., Fraulo, E. S., Peterson, E. D., Ballantyne, C. M., Genest, J., Gidding, S. S., Hammond, E., Hemphill, L. C., Hudgins, L. C., Kindt, I., Moriarty, P. M., Ross, J., Underberg, J. A., Watson, K., Pickhardt, D., Rader, D. J., Wilemon, K., Knowles, J. W. 2014; 167 (3): 342-349 e17

  Abstract

  Familial hypercholesterolemia (FH) is a hereditary condition caused by various genetic mutations that lead to significantly elevated low-density lipoprotein cholesterol levels and resulting in a 20-fold increased lifetime risk for premature cardiovascular disease. Although its prevalence in the United States is 1 in 300 to 500 individuals, <10% of FH patients are formally diagnosed, and many are not appropriately treated. Contemporary data are needed to more fully characterize FH disease prevalence, treatment strategies, and patient experiences in the United States.The Familial Hypercholesterolemia Foundation (a patient-led nonprofit organization) has established the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE FH) Registry as a national, multicenter initiative to identify US FH patients, track their treatment, and clinical and patient-reported outcomes over time. The CASCADE FH will use multiple enrollment strategies to maximize identification of FH patients. Electronic health record screening of health care systems will provide an efficient mechanism to identify undiagnosed patients. A group of specialized lipid clinics will enter baseline and annual follow-up data on demographics, laboratory values, treatment, and clinical events. Patients meeting prespecified low-density lipoprotein or total cholesterol criteria suspicious for FH will have the opportunity to self-enroll in an online patient portal with information collected directly from patients semiannually. Registry patients will be provided information on cascade screening and will complete an online pedigree to assist with notification of family members.The Familial Hypercholesterolemia Foundation CASCADE FH Registry represents a novel research paradigm to address gaps in knowledge and barriers to comprehensive FH screening, identification, and treatment.

  View details for DOI 10.1016/j.ahj.2013.12.008

  View details for PubMedID 24576518

• Rationale and design of the familial hypercholesterolemia foundation CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia registry. American heart journal O'Brien, E. C., Roe, M. T., Fraulo, E. S., Peterson, E. D., Ballantyne, C. M., Genest, J., Gidding, S. S., Hammond, E., Hemphill, L. C., Hudgins, L. C., Kindt, I., Moriarty, P. M., Ross, J., Underberg, J. A., Watson, K., Pickhardt, D., Rader, D. J., Wilemon, K., Knowles, J. W. 2014; 167 (3): 342-349 e17

  Abstract

  Familial hypercholesterolemia (FH) is a hereditary condition caused by various genetic mutations that lead to significantly elevated low-density lipoprotein cholesterol levels and resulting in a 20-fold increased lifetime risk for premature cardiovascular disease. Although its prevalence in the United States is 1 in 300 to 500 individuals, <10% of FH patients are formally diagnosed, and many are not appropriately treated. Contemporary data are needed to more fully characterize FH disease prevalence, treatment strategies, and patient experiences in the United States.The Familial Hypercholesterolemia Foundation (a patient-led nonprofit organization) has established the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE FH) Registry as a national, multicenter initiative to identify US FH patients, track their treatment, and clinical and patient-reported outcomes over time. The CASCADE FH will use multiple enrollment strategies to maximize identification of FH patients. Electronic health record screening of health care systems will provide an efficient mechanism to identify undiagnosed patients. A group of specialized lipid clinics will enter baseline and annual follow-up data on demographics, laboratory values, treatment, and clinical events. Patients meeting prespecified low-density lipoprotein or total cholesterol criteria suspicious for FH will have the opportunity to self-enroll in an online patient portal with information collected directly from patients semiannually. Registry patients will be provided information on cascade screening and will complete an online pedigree to assist with notification of family members.The Familial Hypercholesterolemia Foundation CASCADE FH Registry represents a novel research paradigm to address gaps in knowledge and barriers to comprehensive FH screening, identification, and treatment.

  View details for DOI 10.1016/j.ahj.2013.12.008

  View details for PubMedID 24576518

• Unexplained double-chambered left ventricle associated with contracting right ventricular aneurysm and right atrial enlargement. Echocardiography (Mount Kisco, N.Y.) Finocchiaro, G., Murphy, D., Pavlovic, A., Haddad, F., Shiran, H., Sinagra, G., Ashley, E. A., Knowles, J. W. 2014; 31 (3): E80-4

  View details for DOI 10.1111/echo.12467

  View details for PubMedID 24299065

• Unexplained double-chambered left ventricle associated with contracting right ventricular aneurysm and right atrial enlargement. Echocardiography (Mount Kisco, N.Y.) Finocchiaro, G., Murphy, D., Pavlovic, A., Haddad, F., Shiran, H., Sinagra, G., Ashley, E. A., Knowles, J. W. 2014; 31 (3): E80-4

  Abstract

  In this article, we describe a double-chambered left ventricle (LV) associated with a functional right ventricular (RV) aneurysm and right atrial (RA) enlargement in an asymptomatic 24-year-old woman with a family history of sudden cardiac death. We will discuss the differential diagnosis, genetic testing and possible prognostic implications.

  View details for DOI 10.1111/echo.12467

  View details for PubMedID 24299065

• Prevalence and clinical correlates of right ventricular dysfunction in patients with hypertrophic cardiomyopathy. American journal of cardiology Finocchiaro, G., Knowles, J. W., Pavlovic, A., Perez, M., Magavern, E., Sinagra, G., Haddad, F., Ashley, E. A. 2014; 113 (2): 361-367

  Abstract

  Hypertrophic cardiomyopathy (HC) is a disease that mainly affects the left ventricle (LV), however recent studies have suggested that it can also be associated with right ventricular (RV) dysfunction. The objective of this study was to determine the prevalence of RV dysfunction in patients with HC and its relation with LV function and outcome. A total of 324 consecutive patients with HC who received care at Stanford Hospital from 1999 to 2012 were included in the study. A group of 99 prospectively recruited age- and gender-matched healthy volunteers were used as controls. RV function was quantified using the RV fractional area change, tricuspid annular plane systolic excursion (TAPSE), and RV myocardial performance index (RVMPI). Compared with the controls, the patients with HC had a higher RVMPI (0.51 ± 0.18 vs 0.25 ± 0.06, p <0.001) and lower TAPSE (20 ± 3 vs 24 ± 4, p <0.001). RV dysfunction based on an RVMPI >0.4 and TAPSE <16 mm was found in 71% and 11% of the HC and control groups, respectively. Worst LV function and greater pulmonary pressures were independent correlates of RV dysfunction. At an average follow-up of 3.7 ± 2.3 years, 17 patients had died and 4 had undergone heart transplantation. LV ejection fraction <50% and TAPSE <16 mm were independent correlates of outcome (hazard ratio 3.98, 95% confidence interval 1.22 to 13.04, p = 0.02; and hazard ratio 3.66, 95% confidence interval 1.38 to 9.69, p = 0.009, respectively). In conclusion, RV dysfunction based on the RVMPI is common in patients with HC and more frequently observed in patients with LV dysfunction and pulmonary hypertension. RV dysfunction based on the TAPSE was independently associated with an increased likelihood of death or transplantation.

  View details for DOI 10.1016/j.amjcard.2013.09.045

  View details for PubMedID 24230980

• How does morphology impact on diastolic function in hypertrophic cardiomyopathy? A single centre experience. BMJ open Finocchiaro, G., Haddad, F., Pavlovic, A., Magavern, E., Sinagra, G., Knowles, J. W., Myers, J., Ashley, E. A. 2014; 4 (6)

  Abstract

  It is unclear if morphology impacts on diastole in hypertrophic cardiomyopathy (HCM). We sought to determine the relationship between various parameters of diastolic function and morphology in a large HCM cohort.Tertiary referral centre from Stanford, California, USA.383 patients with HCM and normal systolic function between 1999 and 2011. A group of 100 prospectively recruited age-matched and sex-matched healthy participants were used as controls.Echocardiograms were assessed by two blinded board-certified cardiologists. HCM morphology was classified as described in the literature (reverse, sigmoid, symmetric, apical and undefined).Reverse curvature morphology was most commonly observed (218 (57%). Lateral mitral annular E'<12 cm/s was present in 86% of reverse, 88% of sigmoid, 79% of symmetric, 86% of apical and 81% of undefined morphology, p=0.65. E/E' was similarly elevated (E/E': 12.3±7.9 in reverse curvature, 12.1±6.1 in sigmoid, 12.7±9.5 in symmetric, 9.4±4.0 in apical, 12.7±7.9 in undefined morphology, p=0.71) and indexed left atrial volume (LAVi)>40 mL/m(2) was present in 47% in reverse curvature, 33% in sigmoid, 32% in symmetric, 37% in apical and 32% in undefined, p=0.09. Each morphology showed altered parameters of diastolic function when compared with the control population. Left ventricular (LV) obstruction was independently associated with all three diastolic parameters considered, in particular with LAVi>40 mL/m(2) (OR 2.04 (95% CI 1.23 to 3.39), p=0.005), E/E'>15 (OR 4.66 (95% CI 2.51 to 8.64), p<0.001) and E'<8 (OR 2.55 (95% CI 1.42 to 4.53), p=0.001). Other correlates of diastolic dysfunction were age, LV wall thickness and moderate-to-severe mitral regurgitation.In HCM, diastolic dysfunction is present to similar degrees independently from the morphological pattern. The main correlates of diastolic dysfunction are LV obstruction, age, degree of hypertrophy and degree of mitral regurgitation.

  View details for DOI 10.1136/bmjopen-2014-004814

  View details for PubMedID 24928584

  View details for PubMedCentralID PMC4067898

• How does morphology impact on diastolic function in hypertrophic cardiomyopathy? A single centre experience. BMJ open Finocchiaro, G., Haddad, F., Pavlovic, A., Magavern, E., Sinagra, G., Knowles, J. W., Myers, J., Ashley, E. A. 2014; 4 (6)

  View details for DOI 10.1136/bmjopen-2014-004814

  View details for PubMedID 24928584

• Simple, standardized incorporation of genetic risk into non-genetic risk prediction tools for complex traits: coronary heart disease as an example. Frontiers in genetics Goldstein, B. A., Knowles, J. W., Salfati, E., Ioannidis, J. P., Assimes, T. L. 2014; 5: 254-?

  Abstract

  Genetic risk assessment is becoming an important component of clinical decision-making. Genetic Risk Scores (GRSs) allow the composite assessment of genetic risk in complex traits. A technically and clinically pertinent question is how to most easily and effectively combine a GRS with an assessment of clinical risk derived from established non-genetic risk factors as well as to clearly present this information to patient and health care providers.We illustrate a means to combine a GRS with an independent assessment of clinical risk using a log-link function. We apply the method to the prediction of coronary heart disease (CHD) in the Atherosclerosis Risk in Communities (ARIC) cohort. We evaluate different constructions based on metrics of effect change, discrimination, and calibration.The addition of a GRS to a clinical risk score (CRS) improves both discrimination and calibration for CHD in ARIC. RESULTS are similar regardless of whether external vs. internal coefficients are used for the CRS, risk factor single nucleotide polymorphisms (SNPs) are included in the GRS, or subjects with diabetes at baseline are excluded. We outline how to report the construction and the performance of a GRS using our method and illustrate a means to present genetic risk information to subjects and/or their health care provider.The proposed method facilitates the standardized incorporation of a GRS in risk assessment.

  View details for DOI 10.3389/fgene.2014.00254

  View details for PubMedID 25136350

• Trans-ethnic fine mapping identifies a novel independent locus at the 3 ' end of CDKAL1 and novel variants of several susceptibility loci for type 2 diabetes in a Han Chinese population DIABETOLOGIA Kuo, J. Z., Sheu, W. H., Assimes, T. L., Hung, Y., Absher, D., Chiu, Y., Mak, J., Wang, J., Kwon, S., Hsu, C., Goodarzi, M. O., Lee, I., Knowles, J. W., Miller, B. E., Lee, W., Juang, J. J., Wang, T., Guo, X., Taylor, K. D., Chuang, L., Hsiung, C. A., Quertermous, T., Rotter, J. I., Chen, Y. I. 2013; 56 (12): 2619-2628

  Abstract

  Candidate gene and genome-wide association studies have identified ∼60 susceptibility loci for type 2 diabetes. A majority of these loci have been discovered and tested only in European populations. The aim of this study was to assess the presence and extent of trans-ethnic effects of these loci in an East Asian population.A total of 9,335 unrelated Chinese Han individuals, including 4,535 with type 2 diabetes and 4,800 non-diabetic ethnically matched controls, were genotyped using the Illumina 200K Metabochip. We tested 50 established loci for type 2 diabetes and related traits (fasting glucose, fasting insulin, 2 h glucose). Disease association with the additive model of inheritance was analysed with logistic regression.We found that 14 loci significantly transferred to the Chinese population, with two loci (p = 5.7 × 10(-12) for KCNQ1; p = 5.0 × 10(-8) for CDKN2A/B-CDKN2BAS) reaching independent genome-wide statistical significance. Five of these 14 loci had similar lead single-nucleotide polymorphisms (SNPs) as were found in the European studies while the other nine were different. Further stepwise conditional analysis identified a total of seven secondary signals and an independent novel locus at the 3' end of CDKAL1.These results suggest that many loci associated with type 2 diabetes are commonly shared between European and Chinese populations. Identification of population-specific SNPs may increase our understanding of the genetic architecture underlying type 2 diabetes in different ethnic populations.

  View details for DOI 10.1007/s00125-013-3047-1

  View details for Web of Science ID 000326599300010

  View details for PubMedID 24013783

  View details for PubMedCentralID PMC3825282

• Genetic and Functional Analyses Identify NAT2 as a Human Insulin Sensitivity Gene Knowles, J. W., Hao, K., Xie, W., Weedon, M. N., Zhang, Z., Paaanen, J., Goodarzi, M. O., Hansson, O., Pankow, J. S., Chenemsetty, I., Carcamo-Orive, I., Assimes, T., Morris, A., Chen, Y. I., Schadt, E. E., Makinen, V., Yang, X., Abbasi, F., Attie, A., Keller, M., Greenawalt, D., Rotter, J. I., Sinako, A., Hsiung, A., Cordell, H. J., Reaven, G., Groop, L., Laakso, M., Ingelsson, E., Frayling, T. M., Walker, M., Quertermous, T., GENESIS, RISC, EUGENE2 ULSAM, GUARDIAN, SAPPHIRe Consortia LIPPINCOTT WILLIAMS & WILKINS. 2013

  View details for Web of Science ID 000332162901245

• Variation in Use of Left Ventriculography in the Veterans Affairs Health Care System CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Heidenreich, P. A., Lin, S., Knowles, J. W., Perez, M., Maddox, T. M., Ho, M. P., Rumsfeld, J. S., Sahay, A., Massie, B. M., Tsai, T. T., Witteles, R. M. 2013; 6 (6): 687-693

  Abstract

  Contrast left ventriculography is a method of measuring left ventricular function usually performed at the discretion of the invasive cardiologist during cardiac catheterization. We sought to determine variation in the use of left ventriculography in the Veterans Affairs (VA) Health Care System.We identified adult patients who underwent cardiac catheterization including coronary angiography between 2000 and 2009 in the VA Health Care System. We determined patient and hospital predictors of the use of left ventriculography as well as the variation in use across VA facilities. Results were validated using data from the VA's Clinical Assessment, Reporting, and Tracking (CART) program. Of 457 170 cardiac catheterization procedures among 336 853 patients, left ventriculography was performed on 263 695 (58%) patients. Use of left ventriculography decreased over time (64% in 2000 to 50% in 2009) and varied markedly across facilities (<1->95% of cardiac catheterizations). Patient factors explained little of the large variation in use between facilities. When the cohort was restricted to those with an echocardiogram in the prior 30 days and no intervening event, left ventriculography was still performed in 50% of cases.There is large variation in the use of left ventriculography across VA facilities that is not explained by patient characteristics.

  View details for DOI 10.1161/CIRCOUTCOMES.113.000199

  View details for Web of Science ID 000330362400017

  View details for PubMedID 24192569

• Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes. Diabetes Yaghootkar, H., Lamina, C., Scott, R. A., Dastani, Z., Hivert, M., Warren, L. L., Stancáková, A., Buxbaum, S. G., Lyytikäinen, L., Henneman, P., Wu, Y., Cheung, C. Y., Pankow, J. S., Jackson, A. U., Gustafsson, S., Zhao, J. H., Ballantyne, C. M., Xie, W., Bergman, R. N., Boehnke, M., El Bouazzaoui, F., Collins, F. S., Dunn, S. H., Dupuis, J., Forouhi, N. G., Gillson, C., Hattersley, A. T., Hong, J., Kähönen, M., Kuusisto, J., Kedenko, L., Kronenberg, F., Doria, A., Assimes, T. L., Ferrannini, E., Hansen, T., Hao, K., Häring, H., Knowles, J. W., Lindgren, C. M., Nolan, J. J., Paananen, J., Pedersen, O., Quertermous, T., Smith, U., Lehtimäki, T., Liu, C., Loos, R. J., McCarthy, M. I., Morris, A. D., Vasan, R. S., Spector, T. D., Teslovich, T. M., Tuomilehto, J., Van Dijk, K. W., Viikari, J. S., Zhu, N., Langenberg, C., Ingelsson, E., Semple, R. K., Sinaiko, A. R., Palmer, C. N., Walker, M., Lam, K. S., Paulweber, B., Mohlke, K. L., Van Duijn, C., Raitakari, O. T., Bidulescu, A., Wareham, N. J., Laakso, M., Waterworth, D. M., Lawlor, D. A., Meigs, J. B., Richards, J. B., Frayling, T. M. 2013; 62 (10): 3589-3598

  Abstract

  Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics-based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI -0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95% CI -0.38 to -0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: -0.03 SD; 95% CI -0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.

  View details for DOI 10.2337/db13-0128

  View details for PubMedID 23835345

  View details for PubMedCentralID PMC3781444

• Exercise capacity in patients with hypertrophic cardiomyopathy: non-invasive hemodynamic responses to exercise and association with clinical and imaging variables Finocchiaro, G., Haddad, F., Pavlovic, A., Sinagra, G., Wong, M., Knowles, J. K., Perez, M., Myers, J., Ashley, E. OXFORD UNIV PRESS. 2013: 532–33

  View details for Web of Science ID 000327744603194

• Prognostic role of exercise echocardiography in patients with hypertrophic cardiomyopathy Finocchiaro, G., Haddad, F., Pavlovic, A., Sinagra, G., Magavern, E., Knowles, J. K., Ashley, E. OXFORD UNIV PRESS. 2013: 167

  View details for Web of Science ID 000327744601055

• The shared allelic architecture of adiponectin levels and coronary artery disease ATHEROSCLEROSIS Dastani, Z., Johnson, T., Kronenberg, F., Nelson, C. P., Assimes, T. L., Maerz, W., Richards, J. B. 2013; 229 (1): 145-148

  Abstract

  OBJECTIVE: A large body of epidemiologic data strongly suggests an association between excess adiposity and coronary artery disease (CAD). Low adiponectin levels, a hormone secreted only from adipocytes, have been associated with an increased risk of CAD in observational studies. However, these associations cannot clarify whether this relationship is causal or due to a shared set of causal factors or even confounding. Genome-wide association studies have identified common variants that influence adiponectin levels, providing valuable tools to examine the genetic relationship between adiponectin and CAD. METHODS: Using 145 genome wide significant SNPs for adiponectin from the ADIPOGen consortium (n = 49,891), we tested whether adiponectin-decreasing alleles influenced risk of CAD in the CARDIoGRAM consortium (n = 85,274). RESULTS: In single-SNP analysis, 5 variants among 145 SNPs were associated with increased risk of CAD after correcting for multiple testing (P < 4.4 × 10(-4)). Using a multi-SNP genotypic risk score to test whether adiponectin levels and CAD have a shared genetic etiology, we found that adiponectin-decreasing alleles increased risk of CAD (P = 5.4 × 10(-7)). CONCLUSION: These findings demonstrate that adiponectin levels and CAD have a shared allelic architecture and provide rationale to undertake a Mendelian randomization studies to understand if this relationship is causal.

  View details for DOI 10.1016/j.atherosclerosis.2013.03.034

  View details for Web of Science ID 000320594700023

• Genome-wide characterization of shared and distinct genetic components that influence blood lipid levels in ethnically diverse human populations. American journal of human genetics Coram, M. A., Duan, Q., Hoffmann, T. J., Thornton, T., Knowles, J. W., Johnson, N. A., Ochs-Balcom, H. M., Donlon, T. A., Martin, L. W., Eaton, C. B., Robinson, J. G., Risch, N. J., Zhu, X., Kooperberg, C., Li, Y., Reiner, A. P., Tang, H. 2013; 92 (6): 904-916

  Abstract

  Blood lipid concentrations are heritable risk factors associated with atherosclerosis and cardiovascular diseases. Lipid traits exhibit considerable variation among populations of distinct ancestral origin as well as between individuals within a population. We performed association analyses to identify genetic loci influencing lipid concentrations in African American and Hispanic American women in the Women's Health Initiative SNP Health Association Resource. We validated one African-specific high-density lipoprotein cholesterol locus at CD36 as well as 14 known lipid loci that have been previously implicated in studies of European populations. Moreover, we demonstrate striking similarities in genetic architecture (loci influencing the trait, direction and magnitude of genetic effects, and proportions of phenotypic variation explained) of lipid traits across populations. In particular, we found that a disproportionate fraction of lipid variation in African Americans and Hispanic Americans can be attributed to genomic loci exhibiting statistical evidence of association in Europeans, even though the precise genes and variants remain unknown. At the same time, we found substantial allelic heterogeneity within shared loci, characterized both by population-specific rare variants and variants shared among multiple populations that occur at disparate frequencies. The allelic heterogeneity emphasizes the importance of including diverse populations in future genetic association studies of complex traits such as lipids; furthermore, the overlap in lipid loci across populations of diverse ancestral origin argues that additional knowledge can be gleaned from multiple populations.

  View details for DOI 10.1016/j.ajhg.2013.04.025

  View details for PubMedID 23726366

  View details for PubMedCentralID PMC3675231

• Genome-wide Characterization of Shared and Distinct Genetic Components that Influence Blood Lipid Levels in Ethnically Diverse Human Populations AMERICAN JOURNAL OF HUMAN GENETICS Coram, M. A., Duan, Q., Hoffmann, T. J., Thornton, T., Knowles, J. W., Johnson, N. A., Ochs-Balcom, H. M., Donlon, T. A., Martin, L. W., Eaton, C. B., Robinson, J. G., Risch, N. J., Zhu, X., Kooperberg, C., Li, Y., Reiner, A. P., Tang, H. 2013; 92 (6): 904-916

  Abstract

  Blood lipid concentrations are heritable risk factors associated with atherosclerosis and cardiovascular diseases. Lipid traits exhibit considerable variation among populations of distinct ancestral origin as well as between individuals within a population. We performed association analyses to identify genetic loci influencing lipid concentrations in African American and Hispanic American women in the Women's Health Initiative SNP Health Association Resource. We validated one African-specific high-density lipoprotein cholesterol locus at CD36 as well as 14 known lipid loci that have been previously implicated in studies of European populations. Moreover, we demonstrate striking similarities in genetic architecture (loci influencing the trait, direction and magnitude of genetic effects, and proportions of phenotypic variation explained) of lipid traits across populations. In particular, we found that a disproportionate fraction of lipid variation in African Americans and Hispanic Americans can be attributed to genomic loci exhibiting statistical evidence of association in Europeans, even though the precise genes and variants remain unknown. At the same time, we found substantial allelic heterogeneity within shared loci, characterized both by population-specific rare variants and variants shared among multiple populations that occur at disparate frequencies. The allelic heterogeneity emphasizes the importance of including diverse populations in future genetic association studies of complex traits such as lipids; furthermore, the overlap in lipid loci across populations of diverse ancestral origin argues that additional knowledge can be gleaned from multiple populations.

  View details for DOI 10.1016/j.ajhg.2013.04.025

  View details for Web of Science ID 000320415300007

  View details for PubMedCentralID PMC3675231

• Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nature genetics Den Hoed, M., Eijgelsheim, M., Esko, T., Brundel, B. J., Peal, D. S., Evans, D. M., Nolte, I. M., Segrè, A. V., Holm, H., Handsaker, R. E., Westra, H., Johnson, T., Isaacs, A., Yang, J., Lundby, A., Zhao, J. H., Kim, Y. J., Go, M. J., Almgren, P., Bochud, M., Boucher, G., Cornelis, M. C., Gudbjartsson, D., Hadley, D., van der Harst, P., Hayward, C., den Heijer, M., Igl, W., Jackson, A. U., Kutalik, Z., Luan, J., Kemp, J. P., Kristiansson, K., Ladenvall, C., Lorentzon, M., Montasser, M. E., Njajou, O. T., O'Reilly, P. F., Padmanabhan, S., St Pourcain, B., Rankinen, T., Salo, P., Tanaka, T., Timpson, N. J., Vitart, V., Waite, L., Wheeler, W., Zhang, W., Draisma, H. H., Feitosa, M. F., Kerr, K. F., Lind, P. A., Mihailov, E., Onland-Moret, N. C., Song, C., Weedon, M. N., Xie, W., Yengo, L., Absher, D., Albert, C. M., Alonso, A., Arking, D. E., de Bakker, P. I., Balkau, B., Barlassina, C., Benaglio, P., Bis, J. C., Bouatia-Naji, N., Brage, S., Chanock, S. J., Chines, P. S., Chung, M., Darbar, D., Dina, C., Dörr, M., Elliott, P., Felix, S. B., Fischer, K., Fuchsberger, C., de Geus, E. J., Goyette, P., Gudnason, V., Harris, T. B., Hartikainen, A., Havulinna, A. S., Heckbert, S. R., Hicks, A. A., Hofman, A., Holewijn, S., Hoogstra-Berends, F., Hottenga, J., Jensen, M. K., Johansson, A., Junttila, J., Kääb, S., Kanon, B., Ketkar, S., Khaw, K., Knowles, J. W., Kooner, A. S., Kors, J. A., Kumari, M., Milani, L., Laiho, P., Lakatta, E. G., Langenberg, C., Leusink, M., Liu, Y., Luben, R. N., Lunetta, K. L., Lynch, S. N., Markus, M. R., Marques-Vidal, P., Mateo Leach, I., McArdle, W. L., McCarroll, S. A., Medland, S. E., Miller, K. A., Montgomery, G. W., Morrison, A. C., Müller-Nurasyid, M., Navarro, P., Nelis, M., O'Connell, J. R., O'Donnell, C. J., Ong, K. K., Newman, A. B., Peters, A., Polasek, O., Pouta, A., Pramstaller, P. P., Psaty, B. M., Rao, D. C., Ring, S. M., Rossin, E. J., Rudan, D., Sanna, S., Scott, R. A., Sehmi, J. S., Sharp, S., Shin, J. T., Singleton, A. B., Smith, A. V., Soranzo, N., Spector, T. D., Stewart, C., Stringham, H. M., Tarasov, K. V., Uitterlinden, A. G., Vandenput, L., Hwang, S., Whitfield, J. B., Wijmenga, C., Wild, S. H., Willemsen, G., Wilson, J. F., Witteman, J. C., Wong, A., Wong, Q., Jamshidi, Y., Zitting, P., Boer, J. M., Boomsma, D. I., Borecki, I. B., van Duijn, C. M., Ekelund, U., Forouhi, N. G., Froguel, P., Hingorani, A., Ingelsson, E., Kivimaki, M., Kronmal, R. A., Kuh, D., Lind, L., Martin, N. G., Oostra, B. A., Pedersen, N. L., Quertermous, T., Rotter, J. I., van der Schouw, Y. T., Verschuren, W. M., Walker, M., Albanes, D., Arnar, D. O., Assimes, T. L., Bandinelli, S., Boehnke, M., de Boer, R. A., Bouchard, C., Caulfield, W. L., Chambers, J. C., Curhan, G., Cusi, D., Eriksson, J., Ferrucci, L., van Gilst, W. H., Glorioso, N., de Graaf, J., Groop, L., Gyllensten, U., Hsueh, W., Hu, F. B., Huikuri, H. V., Hunter, D. J., Iribarren, C., Isomaa, B., Jarvelin, M., Jula, A., Kähönen, M., Kiemeney, L. A., van der Klauw, M. M., Kooner, J. S., Kraft, P., Iacoviello, L., Lehtimäki, T., Lokki, M. L., Mitchell, B. D., Navis, G., Nieminen, M. S., Ohlsson, C., Poulter, N. R., Qi, L., Raitakari, O. T., Rimm, E. B., Rioux, J. D., Rizzi, F., Rudan, I., Salomaa, V., Sever, P. S., Shields, D. C., Shuldiner, A. R., Sinisalo, J., Stanton, A. V., Stolk, R. P., Strachan, D. P., Tardif, J., Thorsteinsdottir, U., Tuomilehto, J., van Veldhuisen, D. J., Virtamo, J., Viikari, J., Vollenweider, P., Waeber, G., Widen, E., Cho, Y. S., Olsen, J. V., Visscher, P. M., Willer, C., Franke, L., Erdmann, J., Thompson, J. R., Pfeufer, A., Sotoodehnia, N., Newton-Cheh, C., Ellinor, P. T., Stricker, B. H., Metspalu, A., Perola, M., Beckmann, J. S., Smith, G. D., Stefansson, K., Wareham, N. J., Munroe, P. B., Sibon, O. C., Milan, D. J., Snieder, H., Samani, N. J., Loos, R. J. 2013; 45 (6): 621-631

  Abstract

  Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

  View details for DOI 10.1038/ng.2610

  View details for PubMedID 23583979

• Genetic variants associated with glycine metabolism and their role in insulin sensitivity and type 2 diabetes. Diabetes Xie, W., Wood, A. R., Lyssenko, V., Weedon, M. N., Knowles, J. W., Alkayyali, S., Assimes, T. L., Quertermous, T., Abbasi, F., Paananen, J., Häring, H., Hansen, T., Pedersen, O., Smith, U., Laakso, M., Dekker, J. M., Nolan, J. J., Groop, L., Ferrannini, E., Adam, K., Gall, W. E., Frayling, T. M., Walker, M. 2013; 62 (6): 2141-2150

  Abstract

  Circulating metabolites associated with insulin sensitivity may represent useful biomarkers, but their causal role in insulin sensitivity and diabetes is less certain. We previously identified novel metabolites correlated with insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. The top-ranking metabolites were in the glutathione and glycine biosynthesis pathways. We aimed to identify common genetic variants associated with metabolites in these pathways and test their role in insulin sensitivity and type 2 diabetes. With 1,004 nondiabetic individuals from the RISC study, we performed a genome-wide association study (GWAS) of 14 insulin sensitivity-related metabolites and one metabolite ratio. We replicated our results in the Botnia study (n = 342). We assessed the association of these variants with diabetes-related traits in GWAS meta-analyses (GENESIS [including RISC, EUGENE2, and Stanford], MAGIC, and DIAGRAM). We identified four associations with three metabolites-glycine (rs715 at CPS1), serine (rs478093 at PHGDH), and betaine (rs499368 at SLC6A12; rs17823642 at BHMT)-and one association signal with glycine-to-serine ratio (rs1107366 at ALDH1L1). There was no robust evidence for association between these variants and insulin resistance or diabetes. Genetic variants associated with genes in the glycine biosynthesis pathways do not provide consistent evidence for a role of glycine in diabetes-related traits.

  View details for DOI 10.2337/db12-0876

  View details for PubMedID 23378610

  View details for PubMedCentralID PMC3661655

• Genetic Predisposition to Higher Blood Pressure Increases Coronary Artery Disease Risk HYPERTENSION Lieb, W., Jansen, H., Loley, C., Pencina, M. J., Nelson, C. P., Newton-Cheh, C., Kathiresan, S., Reilly, M. P., Assimes, T. L., Boerwinkle, E., Hall, A. S., Hengstenberg, C., Laaksonen, R., McPherson, R., Thorsteinsdottir, U., Ziegler, A., Peters, A., Thompson, J. R., Koenig, I. R., Erdmann, J., Samani, N. J., Vasan, R. S., Schunkert, H. 2013; 61 (5): 995-?

  Abstract

  Hypertension is a risk factor for coronary artery disease. Recent genome-wide association studies have identified 30 genetic variants associated with higher blood pressure at genome-wide significance (P<5 × 10(-8)). If elevated blood pressure is a causative factor for coronary artery disease, these variants should also increase coronary artery disease risk. Analyzing genome-wide association data from 22 233 coronary artery disease cases and 64 762 controls, we observed in the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) consortium that 88% of these blood pressure-associated polymorphisms were likewise positively associated with coronary artery disease, that is, they had an odds ratio >1 for coronary artery disease, a proportion much higher than expected by chance (P=4 × 10(-5)). The average relative coronary artery disease risk increase per each of the multiple blood pressure-raising alleles observed in the consortium was 3.0% for systolic blood pressure-associated polymorphisms (95% confidence interval, 1.8%-4.3%) and 2.9% for diastolic blood pressure-associated polymorphisms (95% confidence interval, 1.7%-4.1%). In substudies, individuals carrying most systolic blood pressure- and diastolic blood pressure-related risk alleles (top quintile of a genetic risk score distribution) had 70% (95% confidence interval, 50%-94%) and 59% (95% confidence interval, 40%-81%) higher odds of having coronary artery disease, respectively, as compared with individuals in the bottom quintile. In conclusion, most blood pressure-associated polymorphisms also confer an increased risk for coronary artery disease. These findings are consistent with a causal relationship of increasing blood pressure to coronary artery disease. Genetic variants primarily affecting blood pressure contribute to the genetic basis of coronary artery disease.

  View details for DOI 10.1161/HYPERTENSIONAHA.111.00275

  View details for Web of Science ID 000317718200025

• Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity. Circulation Liang, P., Lan, F., Lee, A. S., Gong, T., Sanchez-Freire, V., Wang, Y., Diecke, S., Sallam, K., Knowles, J. W., Wang, P. J., Nguyen, P. K., Bers, D. M., Robbins, R. C., Wu, J. C. 2013; 127 (16): 1677-1691

  Abstract

  Cardiotoxicity is a leading cause for drug attrition during pharmaceutical development and has resulted in numerous preventable patient deaths. Incidents of adverse cardiac drug reactions are more common in patients with preexisting heart disease than the general population. Here we generated a library of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with various hereditary cardiac disorders to model differences in cardiac drug toxicity susceptibility for patients of different genetic backgrounds.Action potential duration and drug-induced arrhythmia were measured at the single cell level in hiPSC-CMs derived from healthy subjects and patients with hereditary long QT syndrome, familial hypertrophic cardiomyopathy, and familial dilated cardiomyopathy. Disease phenotypes were verified in long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy hiPSC-CMs by immunostaining and single cell patch clamp. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and the human ether-a-go-go-related gene expressing human embryonic kidney cells were used as controls. Single cell PCR confirmed expression of all cardiac ion channels in patient-specific hiPSC-CMs as well as hESC-CMs, but not in human embryonic kidney cells. Disease-specific hiPSC-CMs demonstrated increased susceptibility to known cardiotoxic drugs as measured by action potential duration and quantification of drug-induced arrhythmias such as early afterdepolarizations and delayed afterdepolarizations.We have recapitulated drug-induced cardiotoxicity profiles for healthy subjects, long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy patients at the single cell level for the first time. Our data indicate that healthy and diseased individuals exhibit different susceptibilities to cardiotoxic drugs and that use of disease-specific hiPSC-CMs may predict adverse drug responses more accurately than the standard human ether-a-go-go-related gene test or healthy control hiPSC-CM/hESC-CM screening assays.

  View details for DOI 10.1161/CIRCULATIONAHA.113.001883

  View details for PubMedID 23519760

  View details for PubMedCentralID PMC3870148

• Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity. Circulation Liang, P., Lan, F., Lee, A. S., Gong, T., Sanchez-Freire, V., Wang, Y., Diecke, S., Sallam, K., Knowles, J. W., Wang, P. J., Nguyen, P. K., Bers, D. M., Robbins, R. C., Wu, J. C. 2013; 127 (16): 1677-1691

  View details for DOI 10.1161/CIRCULATIONAHA.113.001883

  View details for PubMedID 23519760

• Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nature genetics Den Hoed, M., Eijgelsheim, M., Esko, T., Brundel, B. J., Peal, D. S., Evans, D. M., Nolte, I. M., Segrè, A. V., Holm, H., Handsaker, R. E., Westra, H., Johnson, T., Isaacs, A., Yang, J., Lundby, A., Zhao, J. H., Kim, Y. J., Go, M. J., Almgren, P., Bochud, M., Boucher, G., Cornelis, M. C., Gudbjartsson, D., Hadley, D., van der Harst, P., Hayward, C., den Heijer, M., Igl, W., Jackson, A. U., Kutalik, Z., Luan, J., Kemp, J. P., Kristiansson, K., Ladenvall, C., Lorentzon, M., Montasser, M. E., Njajou, O. T., O'Reilly, P. F., Padmanabhan, S., St Pourcain, B., Rankinen, T., Salo, P., Tanaka, T., Timpson, N. J., Vitart, V., Waite, L., Wheeler, W., Zhang, W., Draisma, H. H., Feitosa, M. F., Kerr, K. F., Lind, P. A., Mihailov, E., Onland-Moret, N. C., Song, C., Weedon, M. N., Xie, W., Yengo, L., Absher, D., Albert, C. M., Alonso, A., Arking, D. E., de Bakker, P. I., Balkau, B., Barlassina, C., Benaglio, P., Bis, J. C., Bouatia-Naji, N., Brage, S., Chanock, S. J., Chines, P. S., Chung, M., Darbar, D., Dina, C., Dörr, M., Elliott, P., Felix, S. B., Fischer, K., Fuchsberger, C., de Geus, E. J., Goyette, P., Gudnason, V., Harris, T. B., Hartikainen, A., Havulinna, A. S., Heckbert, S. R., Hicks, A. A., Hofman, A., Holewijn, S., Hoogstra-Berends, F., Hottenga, J., Jensen, M. K., Johansson, A., Junttila, J., Kääb, S., Kanon, B., Ketkar, S., Khaw, K., Knowles, J. W., Kooner, A. S., Kors, J. A., Kumari, M., Milani, L., Laiho, P., Lakatta, E. G., Langenberg, C., Leusink, M., Liu, Y., Luben, R. N., Lunetta, K. L., Lynch, S. N., Markus, M. R., Marques-Vidal, P., Mateo Leach, I., McArdle, W. L., McCarroll, S. A., Medland, S. E., Miller, K. A., Montgomery, G. W., Morrison, A. C., Müller-Nurasyid, M., Navarro, P., Nelis, M., O'Connell, J. R., O'Donnell, C. J., Ong, K. K., Newman, A. B., Peters, A., Polasek, O., Pouta, A., Pramstaller, P. P., Psaty, B. M., Rao, D. C., Ring, S. M., Rossin, E. J., Rudan, D., Sanna, S., Scott, R. A., Sehmi, J. S., Sharp, S., Shin, J. T., Singleton, A. B., Smith, A. V., Soranzo, N., Spector, T. D., Stewart, C., Stringham, H. M., Tarasov, K. V., Uitterlinden, A. G., Vandenput, L., Hwang, S., Whitfield, J. B., Wijmenga, C., Wild, S. H., Willemsen, G., Wilson, J. F., Witteman, J. C., Wong, A., Wong, Q., Jamshidi, Y., Zitting, P., Boer, J. M., Boomsma, D. I., Borecki, I. B., van Duijn, C. M., Ekelund, U., Forouhi, N. G., Froguel, P., Hingorani, A., Ingelsson, E., Kivimaki, M., Kronmal, R. A., Kuh, D., Lind, L., Martin, N. G., Oostra, B. A., Pedersen, N. L., Quertermous, T., Rotter, J. I., van der Schouw, Y. T., Verschuren, W. M., Walker, M., Albanes, D., Arnar, D. O., Assimes, T. L., Bandinelli, S., Boehnke, M., de Boer, R. A., Bouchard, C., Caulfield, W. L., Chambers, J. C., Curhan, G., Cusi, D., Eriksson, J., Ferrucci, L., van Gilst, W. H., Glorioso, N., de Graaf, J., Groop, L., Gyllensten, U., Hsueh, W., Hu, F. B., Huikuri, H. V., Hunter, D. J., Iribarren, C., Isomaa, B., Jarvelin, M., Jula, A., Kähönen, M., Kiemeney, L. A., van der Klauw, M. M., Kooner, J. S., Kraft, P., Iacoviello, L., Lehtimäki, T., Lokki, M. L., Mitchell, B. D., Navis, G., Nieminen, M. S., Ohlsson, C., Poulter, N. R., Qi, L., Raitakari, O. T., Rimm, E. B., Rioux, J. D., Rizzi, F., Rudan, I., Salomaa, V., Sever, P. S., Shields, D. C., Shuldiner, A. R., Sinisalo, J., Stanton, A. V., Stolk, R. P., Strachan, D. P., Tardif, J., Thorsteinsdottir, U., Tuomilehto, J., van Veldhuisen, D. J., Virtamo, J., Viikari, J., Vollenweider, P., Waeber, G., Widen, E., Cho, Y. S., Olsen, J. V., Visscher, P. M., Willer, C., Franke, L., Erdmann, J., Thompson, J. R., Pfeufer, A., Sotoodehnia, N., Newton-Cheh, C., Ellinor, P. T., Stricker, B. H., Metspalu, A., Perola, M., Beckmann, J. S., Smith, G. D., Stefansson, K., Wareham, N. J., Munroe, P. B., Sibon, O. C., Milan, D. J., Snieder, H., Samani, N. J., Loos, R. J. 2013; 45 (6): 621-631

  Abstract

  Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

  View details for DOI 10.1038/ng.2610

  View details for PubMedID 23583979

• Measurement of insulin-mediated glucose uptake: direct comparison of the modified insulin suppression test and the euglycemic, hyperinsulinemic clamp. Metabolism Knowles, J. W., Assimes, T. L., Tsao, P. S., Natali, A., Mari, A., Quertermous, T., Reaven, G. M., Abbasi, F. 2013; 62 (4): 548-553

  Abstract

  Two direct measurements of peripheral insulin sensitivity are the M value derived from the euglycemic, hyperinsulinemic clamp (EC) and the steady-state plasma glucose (SSPG) concentration derived from the insulin suppression test (IST). Prior work suggests that these measures are highly correlated, but the agreement between them is unknown. To determine the agreement between SSPG and M and to develop transformation equations to convert SSPG to M and vice versa, we directly compared these two measurements in the same individuals.A total of 15 nondiabetic subjects (9 women and 6 men) underwent both an EC and a modified version of the IST within a median interval of 5days. We performed standard correlation metrics of the two measures and developed transformation regression equations for the two measures.The mean±SD age of the subjects was 57±7years and body mass index, 27.7±3.9kg/m(2). The median (interquartile range) SSPG concentration was 6.7 (5.1, 9.8) mmol/L and M value, 49.6 (28.9, 64.2) μmol/min/kg-LBM. There was a highly significant correlation between SSPG and M (r=-0.87, P <0.001). The relationship was best fit by regression models with exponential/logarithmic functions (R(2)=0.85). Bland-Altman plots demonstrated an excellent agreement between these measures of insulin action.The SSPG and M are highly related measures of insulin sensitivity and the results provide the means to directly compare the two measurements.

  View details for DOI 10.1016/j.metabol.2012.10.002

  View details for PubMedID 23151437

• Role of international registries in enhancing the care of familial hypercholesterolaemia. International journal of evidence-based healthcare Hammond, E. n., Watts, G. F., Rubinstein, Y. n., Farid, W. n., Livingston, M. n., Knowles, J. W., Lochmüller, H. n., Bellgard, M. n., Dawkins, H. J. 2013; 11 (2): 134–39

  Abstract

  Familial hypercholesterolaemia (FH) is a relatively common genetic disorder associated with high risk of coronary heart disease that is preventable by early diagnosis and treatment. In a previous article, we reviewed the evidence for clinical management, models of care and health economic evaluations. The present commentary emphasises that collective action is needed to strengthen our approaches to evidence-based care, including better diagnosis and access to effective therapies. We detail how contemporary innovations in inter-operable, web-based, open-source and secure registries can provide the supporting infrastructure to: (i) address a current gap in the flow of data for measuring the quality of healthcare; (ii) support basic research through provision of high-quality, de-identified aggregate data; (iii) enable equitable access to clinical trials; and (iv) support efforts to disseminate evidence for best practice and information for care services. We describe how these aspects of enabling infrastructure will be incorporated into the development of a National FH Registry for Australasia, and proffer that a coordinated response to FH would be enhanced through a global network of inter-operable registries.

  View details for DOI 10.1111/1744-1609.12023

  View details for PubMedID 23750577

• Large-scale association analysis identifies new risk loci for coronary artery disease NATURE GENETICS Deloukas, P., Kanoni, S., Willenborg, C., Farrall, M., Assimes, T. L., Thompson, J. R., Ingelsson, E., Saleheen, D., Erdmann, J., Goldstein, B. A., Stirrups, K., Koenig, I. R., Cazier, J., Johansson, A., Hall, A. S., Lee, J., Willer, C. J., Chambers, J. C., Esko, T., Folkersen, L., Goel, A., Grundberg, E., Havulinna, A. S., Ho, W. K., Hopewell, J. C., Eriksson, N., Kleber, M. E., Kristiansson, K., Lundmark, P., Lyytikainen, L., Rafelt, S., Shungin, D., Strawbridge, R. J., Thorleifsson, G., Tikkanen, E., Van Zuydam, N., Voight, B. F., Waite, L. L., Zhang, W., Ziegler, A., Absher, D., Altshuler, D., Balmforth, A. J., Barroso, I., Braund, P. S., Burgdorf, C., Claudi-Boehm, S., Cox, D., Dimitriou, M., Do, R., Doney, A. S., El Mokhtari, N., Eriksson, P., Fischer, K., Fontanillas, P., Franco-Cereceda, A., Gigante, B., Groop, L., Gustafsson, S., Hager, J., Hallmans, G., Han, B., Hunt, S. E., Kang, H. M., Illig, T., Kessler, T., Knowles, J. W., Kolovou, G., Kuusisto, J., Langenberg, C., Langford, C., Leander, K., Lokki, M., Lundmark, A., McCarthy, M. I., Meisinger, C., Melander, O., Mihailov, E., Maouche, S., Morris, A. D., Mueller-Nurasyid, M., Nikus, K., Peden, J. F., Rayner, N. W., Rasheed, A., Rosinger, S., Rubin, D., Rumpf, M. P., Schaefer, A., Sivananthan, M., Song, C., Stewart, A. F., Tan, S., Thorgeirsson, G., van der Schoot, C. E., Wagner, P. J., Wells, G. A., Wild, P. S., Yang, T., Amouyel, P., Arveiler, D., Basart, H., Boehnke, M., Boerwinkle, E., Brambilla, P., Cambien, F., Cupples, A. L., de Faire, U., Dehghan, A., Diemert, P., Epstein, S. E., Evans, A., Ferrario, M. M., Ferrieres, J., Gauguier, D., Go, A. S., Goodall, A. H., Gudnason, V., Hazen, S. L., Holm, H., Iribarren, C., Jang, Y., Kahonen, M., Kee, F., Kim, H., Klopp, N., Koenig, W., Kratzer, W., Kuulasmaa, K., Laakso, M., Laaksonen, R., Lee, J., Lind, L., Ouwehand, W. H., Parish, S., Park, J. E., Pedersen, N. L., Peters, A., Quertermous, T., Rader, D. J., Salomaa, V., Schadt, E., Shah, S. H., Sinisalo, J., Stark, K., Stefansson, K., Tregouet, D., Virtamo, J., Wallentin, L., Wareham, N., Zimmermann, M. E., Nieminen, M. S., Hengstenberg, C., Sandhu, M. S., Pastinen, T., Syvanen, A., Hovingh, G. K., Dedoussis, G., Franks, P. W., Lehtimaki, T., Metspalu, A., Zalloua, P. A., Siegbahn, A., Schreiber, S., Ripatti, S., Blankenberg, S. S., Perola, M., Clarke, R., Boehm, B. O., O'Donnell, C., Reilly, M. P., Maerz, W., Collins, R., Kathiresan, S., Hamsten, A., Kooner, J. S., Thorsteinsdottir, U., Danesh, J., Palmer, C. N., Roberts, R., Watkins, H., Schunkert, H., Samani, N. J. 2013; 45 (1): 25-U52

  Abstract

  Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.

  View details for DOI 10.1038/ng.2480

  View details for Web of Science ID 000312838800009

  View details for PubMedID 23202125

• Large-scale association analysis identifies new risk loci for coronary artery disease. Nature genetics Deloukas, P., Kanoni, S., Willenborg, C., Farrall, M., Assimes, T. L., Thompson, J. R., Ingelsson, E., Saleheen, D., Erdmann, J., Goldstein, B. A., Stirrups, K., König, I. R., Cazier, J., Johansson, A., Hall, A. S., Lee, J., Willer, C. J., Chambers, J. C., Esko, T., Folkersen, L., Goel, A., Grundberg, E., Havulinna, A. S., Ho, W. K., Hopewell, J. C., Eriksson, N., Kleber, M. E., Kristiansson, K., Lundmark, P., Lyytikäinen, L., Rafelt, S., Shungin, D., Strawbridge, R. J., Thorleifsson, G., Tikkanen, E., Van Zuydam, N., Voight, B. F., Waite, L. L., Zhang, W., Ziegler, A., Absher, D., Altshuler, D., Balmforth, A. J., Barroso, I., Braund, P. S., Burgdorf, C., Claudi-Boehm, S., Cox, D., Dimitriou, M., Do, R., Doney, A. S., El Mokhtari, N., Eriksson, P., Fischer, K., Fontanillas, P., Franco-Cereceda, A., Gigante, B., Groop, L., Gustafsson, S., Hager, J., Hallmans, G., Han, B., Hunt, S. E., Kang, H. M., Illig, T., Kessler, T., Knowles, J. W., Kolovou, G., Kuusisto, J., Langenberg, C., Langford, C., Leander, K., Lokki, M., Lundmark, A., McCarthy, M. I., Meisinger, C., Melander, O., Mihailov, E., Maouche, S., Morris, A. D., Müller-Nurasyid, M., Nikus, K., Peden, J. F., Rayner, N. W., Rasheed, A., Rosinger, S., Rubin, D., Rumpf, M. P., Schäfer, A., Sivananthan, M., Song, C., Stewart, A. F., Tan, S., Thorgeirsson, G., van der Schoot, C. E., Wagner, P. J., Wells, G. A., Wild, P. S., Yang, T., Amouyel, P., Arveiler, D., Basart, H., Boehnke, M., Boerwinkle, E., Brambilla, P., Cambien, F., Cupples, A. L., de Faire, U., Dehghan, A., Diemert, P., Epstein, S. E., Evans, A., Ferrario, M. M., Ferrières, J., Gauguier, D., Go, A. S., Goodall, A. H., Gudnason, V., Hazen, S. L., Holm, H., Iribarren, C., Jang, Y., Kähönen, M., Kee, F., Kim, H., Klopp, N., Koenig, W., Kratzer, W., Kuulasmaa, K., Laakso, M., Laaksonen, R., Lee, J., Lind, L., Ouwehand, W. H., Parish, S., Park, J. E., Pedersen, N. L., Peters, A., Quertermous, T., Rader, D. J., Salomaa, V., Schadt, E., Shah, S. H., Sinisalo, J., Stark, K., Stefansson, K., Trégouët, D., Virtamo, J., Wallentin, L., Wareham, N., Zimmermann, M. E., Nieminen, M. S., Hengstenberg, C., Sandhu, M. S., Pastinen, T., Syvänen, A., Hovingh, G. K., Dedoussis, G., Franks, P. W., Lehtimäki, T., Metspalu, A., Zalloua, P. A., Siegbahn, A., Schreiber, S., Ripatti, S., Blankenberg, S. S., Perola, M., Clarke, R., Boehm, B. O., O'Donnell, C., Reilly, M. P., März, W., Collins, R., Kathiresan, S., Hamsten, A., Kooner, J. S., Thorsteinsdottir, U., Danesh, J., Palmer, C. N., Roberts, R., Watkins, H., Schunkert, H., Samani, N. J. 2013; 45 (1): 25-33

  Abstract

  Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.

  View details for DOI 10.1038/ng.2480

  View details for PubMedID 23202125

• Impact of Type 2 Diabetes Susceptibility Loci on Variation in Physiologic Glycaemic Traits in Non-Diabetic Individuals Dimas, A. S., Gomes, V. I., Knowles, J., Maegi, R., Barker, A., Hivert, M., Benazzo, A., Rybin, D., Assimes, T. I., Ouertermous, T., Walker, M., Florez, J. C., Barroso, I., Langenberg, C., Dupuis, J., Watanabe, R., McCarthy, M., Ingelsson, E., Prokopenko, I., GENESIS, MAGIC, DIAGRAM LIPPINCOTT WILLIAMS & WILKINS. 2012

  View details for Web of Science ID 000208885005020

• Mendelian Randomization Studies Do Not Support a Causal Effect of Plasma Lipids on Insulin Sensitivity Fall, T., Xie, W., Hao, K., Arnlov, J., Abbasi, F., Schadt, E. E., Boran, G., Hansen, T., Greenawalt, D., Nolan, J. J., Pedersen, O., Haering, H., Ferrannini, E., Syvanen, A., Quertermous, T., Smith, U., Assimes, T. L., Laakso, M., Walker, M., Knowles, J. W., Weedon, M. N., Ingelsson, E., Frayling, T. M., GENESIS Investigators LIPPINCOTT WILLIAMS & WILKINS. 2012

  View details for Web of Science ID 000208885001108

• Exploring Predisposition and Treatment Response-the Promise of Genomics PROGRESS IN CARDIOVASCULAR DISEASES Pan, S., Knowles, J. W. 2012; 55 (1): 56-63

  Abstract

  Spurred by large-scale public and private efforts as well as technological developments, the last few years have seen a major leap forward in our understanding of the genetic basis of cardiovascular disease. This revolution is in its infancy and will continue to alter the medical landscape for years to come. There is a need within the general cardiology community to develop a better understanding about how these developments may alter routine clinical care. In this review, we will provide an overview of the current state of genetics as pertains to rare cardiovascular diseases and then review advances in the discovery of the genetic basis of common disease with the potential for improved risk assessment and drug development. We will also outline a few recent examples of pharmacogenetic advances that are already starting to become a part of clinical management and finally discuss the promise as well as the challenges in using next-generation sequencing technologies to provide personalized cardiovascular care.

  View details for DOI 10.1016/j.pcad.2012.04.006

  View details for Web of Science ID 000307087800007

  View details for PubMedID 22824110

• Randomized Trial of Personal Genomics for Preventive Cardiology Design and Challenges CIRCULATION-CARDIOVASCULAR GENETICS Knowles, J. W., Assimes, T. L., Kiernan, M., Pavlovic, A., Goldstein, B. A., Yank, V., McConnell, M. V., Absher, D., Bustamante, C., Ashley, E. A., Ioannidis, J. P. 2012; 5 (3): 368-376

  View details for DOI 10.1161/CIRCGENETICS.112.962746

  View details for PubMedID 22715281

• The Evolution and Refinement of Traditional Risk Factors for Cardiovascular Disease CARDIOLOGY IN REVIEW deGoma, E. M., Knowles, J. W., Angeli, F., Budoff, M. J., Rader, D. J. 2012; 20 (3): 118-129

  Abstract

  Traditional risk factors for cardiovascular disease such as systemic hypertension and hypercholesterolemia, all described more than half a century ago, are relatively few in number. Efforts to expand the epidemiologic canon have met with limited success because of the high hurdle of causality. Fortunately, another solution to current deficiencies in risk assessment-in particular, the underestimation of risk both before and after initiation of pharmacotherapy-may exist. Parallel to the investigation of novel biomarkers, such as high-sensitivity C-reactive protein, ongoing research has yielded improved metrics of known causative conditions. This evolution of traditional risk factors, heralded by measures such as ambulatory blood pressure, central hemodynamics, low density lipoprotein particle concentration, genetic testing, and "vascular age," may better address the detection gap in cardiovascular disease.

  View details for DOI 10.1097/CRD.0b013e318239b924

  View details for Web of Science ID 000302772500004

  View details for PubMedID 22183062

  View details for PubMedCentralID PMC3310946

• Use and overuse of left ventriculography AMERICAN HEART JOURNAL Witteles, R. M., Knowles, J. W., Perez, M., Morris, W. M., Spettell, C. M., Brennan, T. A., Heidenreich, P. A. 2012; 163 (4): 617-?

  Abstract

  Left ventriculography provided the first imaging of left ventricular function and was historically performed as part of coronary angiography despite a small but significant risk of complications. Because modern noninvasive imaging techniques are more accurate and carry smaller risks, the routine use of left ventriculography is of questionable utility. We sought to analyze the frequency that left ventriculography was performed during coronary angiography in patients with and without a recent alternative assessment of left ventricular function.We performed a retrospective analysis of insurance claims data from the Aetna health care benefits database including all adults who underwent coronary angiography in 2007. The primary outcome was the concomitant use of left ventriculography during coronary angiography.Of 96,235 patients who underwent coronary angiography, left ventriculography was performed in 78,705 (81.8%). Use of left ventriculography was high in all subgroups, with greatest use in younger patients, those with a diagnosis of coronary disease, and those in the Southern United States. In the population who had undergone a very recent ejection fraction assessment by another modality (within 30 days) and who had had no intervening diagnosis of new heart failure, myocardial infarction, hypotension, or shock (37,149 patients), left ventriculography was performed in 32,798 patients (88%)-a rate higher than in the overall cohort.Left ventriculography was performed in most coronary angiography cases and often when an alternative imaging modality had been recently completed. New clinical practice guidelines should be considered to decrease the overuse of this invasive test.

  View details for DOI 10.1016/j.ahj.2011.12.018

  View details for PubMedID 22520528

• Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies LANCET Sarwar, N., Butterworth, A. S., Freitag, D. F., Gregson, J., Willeit, P., Gorman, D. N., Gao, P., Saleheen, D., Rendon, A., Nelson, C. P., Braund, P. S., Hall, A. S., Chasman, D. I., Tybjaerg-Hansen, A., Chambers, J. C., Benjamin, E. J., Franks, P. W., Clarke, R., Wilde, A. A., Trip, M. D., Steri, M., Witteman, J. C., Qi, L., van der Schoot, C. E., de Faire, U., Erdmann, J., Stringham, H. M., Koenig, W., Rader, D. J., Melzer, D., Reich, D., Psaty, B. M., Kleber, M. E., Panagiotakos, D. B., Willeit, J., Wennberg, P., Woodward, M., Adamovic, S., Rimm, E. B., Meade, T. W., Gillum, R. F., Shaffer, J. A., Hofman, A., Onat, A., Sundstrom, J., Wassertheil-Smoller, S., Mellstrom, D., Gallacher, J., Cushman, M., Tracy, R. P., Kauhanen, J., Karlsson, M., Salonen, J. T., Wilhelmsen, L., Amouyel, P., Cantin, B., Best, L. G., Ben-Shlomo, Y., Manson, J. E., Davey-Smith, G., de Bakker, P. I., O'Donnell, C. J., Wilson, J. F., Wilson, A. G., Assimes, T. L., Jansson, J., Ohlsson, C., Tivesten, A., Ljunggren, O., Reilly, M. P., Hamsten, A., Ingelsson, E., Cambien, F., Hung, J., Thomas, G. N., Boehnke, M., Schunkert, H., Asselbergs, F. W., Kastelein, J. J., Gudnason, V., Salomaa, V., Harris, T. B., Kooner, J. S., Allin, K. H., Nordestgaard, B. G., Hopewell, J. C., Goodall, A. H., Ridker, P. M., Holm, H., Watkins, H., Ouwehand, W. H., Samani, N. J., Kaptoge, S., Di Angelantonio, E., Harari, O., Danesh, J. 2012; 379 (9822): 1205-1213

  Abstract

  Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling.In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125,222 participants. We also compared the frequency of Asp358Ala in 51,441 patients with coronary heart disease and in 136,226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6.The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4-38·2) and of interleukin 6 by 14·6% (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9-9·1) and of fibrinogen by 1·0% (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes.Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.

  View details for DOI 10.1016/S0140-6736(11)61931-4

  View details for Web of Science ID 000302230400033

  View details for PubMedID 22421339

• Personalized Medicine and Cardiovascular Disease: From Genome to Bedside CURRENT CARDIOVASCULAR RISK REPORTS Pan, S., Dewey, F. E., Perez, M. V., Knowles, J. W., Chen, R., Butte, A. J., Ashley, E. A. 2011; 5 (6): 542–51

  View details for DOI 10.1007/s12170-011-0202-4

  View details for Web of Science ID 000219926300009

• Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma NATURE GENETICS Chambers, J. C., Zhang, W., Sehmi, J., Li, X., Wass, M. N., Van der Harst, P., Holm, H., Sanna, S., Kavousi, M., Baumeister, S. E., Coin, L. J., Deng, G., Gieger, C., Heard-Costa, N. L., Hottenga, J., Kuehnel, B., Kumar, V., Lagou, V., Liang, L., Luan, J., Vidal, P., Leach, I., O'Reilly, P. F., Peden, J. F., Rahmioglu, N., Soininen, P., Speliotes, E. K., Yuan, X., Thorleifsson, G., Alizadeh, B. Z., Atwood, L. D., Borecki, I. B., Brown, M. J., Charoen, P., Cucca, F., Das, D., de Geus, E. C., Dixon, A. L., Doering, A., Ehret, G., Eyjolfsson, G. I., Farrall, M., Forouhi, N. G., Friedrich, N., Goessling, W., Gudbjartsson, D. F., Harris, T. B., Hartikainen, A., Heath, S., Hirschfield, G. M., Hofman, A., Homuth, G., Hyppoenen, E., Janssen, H. A., Johnson, T., Kangas, A. J., Kema, I. P., Kuehn, J. P., Lai, S., Lathrop, M., Lerch, M. M., Li, Y., Liang, T., Lin, J., Loos, R. F., Martin, N. G., Moffatt, M. F., Montgomery, G. W., Munroe, P. B., Musunuru, K., Nakamura, Y., O'Donnell, C. J., Olafsson, I., Penninx, B. W., Pouta, A., Prins, B. P., Prokopenko, I., Puls, R., Ruokonen, A., Savolainen, M. J., Schlessinger, D., Schouten, J. L., Seedorf, U., Sen-Chowdhry, S., Siminovitch, K. A., Smit, J. H., Spector, T. D., Tan, W., Teslovich, T. M., Tukiainen, T., Uitterlinden, A. G., Van der Klauw, M. M., Vasan, R. S., Wallace, C., Wallaschofski, H., Wichmann, H., Willemsen, G., Wuertz, P., Xu, C., Yerges-Armstrong, L. M., Abecasis, G. R., Ahmadi, K. R., Boomsma, D. I., Caulfield, M., Cookson, W. O., van Duijn, C. M., Froguel, P., Matsuda, K., McCarthy, M. I., Meisinger, C., Mooser, V., Pietilainen, K. H., Schumann, G., Snieder, H., Sternberg, M. E., Stolk, R. P., Thomas, H. C., Thorsteinsdottir, U., Uda, M., Waeber, G., Wareham, N. J., Waterworth, D. M., Watkins, H., Whitfield, J. B., Witteman, J. M., Wolffenbuttel, B. R., Fox, C. S., Ala-Korpela, M., Stefansson, K., Vollenweider, P., Voelzke, H., Schadt, E. E., Scott, J., Jarvelin, M., Elliott, P., Kooner, J. S., Alcohol Genome-wide Assoc AlcGen, Diabet Genetics Replication, Genetic Invest Anthropometric, Global Lipids Genetics Consortium, Genetics Liver Dis GOLD Consortium, Int Consortium Blood Pressure ICBP, Meta-Anal Glucose Insulin-Related 2011; 43 (11): 1131–38

  Abstract

  Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.

  View details for DOI 10.1038/ng.970

  View details for Web of Science ID 000296584000019

  View details for PubMedID 22001757

  View details for PubMedCentralID PMC3482372

• Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes DIABETES Strawbridge, R. J., Dupuis, J., Prokopenko, I., Barker, A., Ahlqvist, E., Rybin, D., Petrie, J. R., Travers, M. E., Bouatia-Naji, N., Dimas, A. S., Nica, A., Wheeler, E., Chen, H., Voight, B. F., Taneera, J., Kanoni, S., Peden, J. F., Turrini, F., Gustafsson, S., Zabena, C., Almgren, P., Barker, D. J., Barnes, D., Dennison, E. M., Eriksson, J. G., Eriksson, P., Eury, E., Folkersen, L., Fox, C. S., Frayling, T. M., Goel, A., Gu, H. F., Horikoshi, M., Isomaa, B., Jackson, A. U., Jameson, K. A., Kajantie, E., Kerr-Conte, J., Kuulasmaa, T., Kuusisto, J., Loos, R. J., Luan, J., Makrilakis, K., Manning, A. K., Teresa Martinez-Larrad, M., Narisu, N., Mannila, M. N., Ohrvik, J., Osmond, C., Pascoe, L., Payne, F., Sayer, A. A., Sennblad, B., Silveira, A., Stancakova, A., Stirrups, K., Swift, A. J., Syvanen, A., Tuomi, T., van 't Hooft, F. M., Walker, M., Weedon, M. N., Xie, W., Zethelius, B., Ongen, H., Malarstig, A., Hopewell, J. C., Saleheen, D., Chambers, J., Parish, S., Danesh, J., Kooner, J., Ostenson, C., Lind, L., Cooper, C. C., Serrano-Rios, M., Ferrannini, E., Forsen, T. J., Clarke, R., Franzosi, M. G., Seedorf, U., Watkins, H., Froguel, P., Johnson, P., Deloukas, P., Collins, F. S., Laakso, M., Dermitzakis, E. T., Boehnke, M., McCarthy, M. I., Wareham, N. J., Groop, L., Pattou, F., Gloyn, A. L., Dedoussis, G. V., Lyssenko, V., Meigs, J. B., Barroso, I., Watanabe, R. M., Ingelsson, E., Langenberg, C., Hamsten, A., Florez, J. C. 2011; 60 (10): 2624-2634

  Abstract

  Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

  View details for DOI 10.2337/db11-0415

  View details for Web of Science ID 000295998700022

  View details for PubMedID 21873549

  View details for PubMedCentralID PMC3178302

• Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence PLOS GENETICS Dewey, F. E., Chen, R., Cordero, S. P., Ormond, K. E., Caleshu, C., Karczewski, K. J., Whirl-Carrillo, M., Wheeler, M. T., Dudley, J. T., Byrnes, J. K., Cornejo, O. E., Knowles, J. W., Woon, M., Sangkuhl, K., Gong, L., Thorn, C. F., Hebert, J. M., Capriotti, E., David, S. P., Pavlovic, A., West, A., Thakuria, J. V., Ball, M. P., Zaranek, A. W., Rehm, H. L., Church, G. M., West, J. S., Bustamante, C. D., Snyder, M., Altman, R. B., Klein, T. E., Butte, A. J., Ashley, E. A. 2011; 7 (9)

  Abstract

  Whole-genome sequencing harbors unprecedented potential for characterization of individual and family genetic variation. Here, we develop a novel synthetic human reference sequence that is ethnically concordant and use it for the analysis of genomes from a nuclear family with history of familial thrombophilia. We demonstrate that the use of the major allele reference sequence results in improved genotype accuracy for disease-associated variant loci. We infer recombination sites to the lowest median resolution demonstrated to date (< 1,000 base pairs). We use family inheritance state analysis to control sequencing error and inform family-wide haplotype phasing, allowing quantification of genome-wide compound heterozygosity. We develop a sequence-based methodology for Human Leukocyte Antigen typing that contributes to disease risk prediction. Finally, we advance methods for analysis of disease and pharmacogenomic risk across the coding and non-coding genome that incorporate phased variant data. We show these methods are capable of identifying multigenic risk for inherited thrombophilia and informing the appropriate pharmacological therapy. These ethnicity-specific, family-based approaches to interpretation of genetic variation are emblematic of the next generation of genetic risk assessment using whole-genome sequencing.

  View details for DOI 10.1371/journal.pgen.1002280

  View details for PubMedID 21935354

• Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease PLOS GENETICS Butterworth, A. S., Braund, P. S., Farrall, M., Hardwick, R. J., Saleheen, D., Peden, J. F., Soranzo, N., Chambers, J. C., Sivapalaratnam, S., Kleber, M. E., Keating, B., Qasim, A., Klopp, N., Erdmann, J., Assimes, T. L., Ball, S. G., Balmforth, A. J., Barnes, T. A., Basart, H., Baumert, J., Bezzina, C. R., Boerwinkle, E., Boehm, B. O., Brocheton, J., Bugert, P., Cambien, F., Clarke, R., Codd, V., Collins, R., Couper, D., Cupples, L. A., De Jong, J. S., Diemert, P., Ejebe, K., Elbers, C. C., Elliott, P., Fornage, M., Franzosi, M., Frossard, P., Garner, S., Goel, A., Goodall, A. H., Hengstenberg, C., Hunt, S. E., Kastelein, J. J., Klungel, O. H., Klueter, H., Koch, K., Koenig, I. R., Kooner, A. S., Laaksonen, R., Lathrop, M., Li, M., Liu, K., McPherson, R., Musameh, M. D., Musani, S., Nelson, C. P., O'Donnell, C. J., Ongen, H., Papanicolaou, G., Peters, A., Peters, B. J., Potter, S., Psaty, B. M., Qu, L., Rader, D. J., Rasheed, A., Rice, C., Scott, J., Seedorf, U., Sehmi, J. S., Sotoodehnia, N., Stark, K., Stephens, J., van der Schoot, C. E., van der Schouw, Y. T., Thorsteinsdottir, U., Tomaszewski, M., van der Harst, P., Vasan, R. S., Wilde, A. A., Willenborg, C., Winkelmann, B. R., Zaidi, M., Zhang, W., Ziegler, A., de Bakker, P. I., Koenig, W., Maerz, W., Trip, M. D., Reilly, M. P., Kathiresan, S., Schunkert, H., Hamsten, A., Hall, A. S., Kooner, J. S., Thompson, S. G., Thompson, J. R., Deloukas, P., Ouwehand, W. H., Watkins, H., Danesh, J., Samani, N. J. 2011; 7 (9)

  Abstract

  Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.

  View details for DOI 10.1371/journal.pgen.1002260

  View details for Web of Science ID 000295419100015

• OVERUSE OF LEFT VENTRICULOGRAPHY 60th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC) / I2 Summit / ACCF/Herman K. Gold Young Investigator's Award in Molecular and Cellular Cardiology Witteles, R., Knowles, J. W., Perez, M., Morris, W. H., Spettell, C. M., Brennan, T. A., Heidenreich, P. A. ELSEVIER SCIENCE INC. 2011: E1289–E1289

  View details for Web of Science ID 000291695101292

• Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease NATURE GENETICS Schunkert, H., Koenig, I. R., Kathiresan, S., Reilly, M. P., Assimes, T. L., Holm, H., Preuss, M., Stewart, A. F., Barbalic, M., Gieger, C., Absher, D., Aherrahrou, Z., Allayee, H., Altshuler, D., Anand, S. S., Andersen, K., Anderson, J. L., Ardissino, D., Ball, S. G., Balmforth, A. J., Barnes, T. A., Becker, D. M., Becker, L. C., Berger, K., Bis, J. C., Boekholdt, S. M., Boerwinkle, E., Braund, P. S., Brown, M. J., Burnett, M. S., Buysschaert, I., Carlquist, J. F., Chen, L., Cichon, S., Codd, V., Davies, R. W., Dedoussis, G., Dehghan, A., Demissie, S., Devaney, J. M., Diemert, P., Do, R., Doering, A., Eifert, S., El Mokhtari, N. E., Ellis, S. G., Elosua, R., Engert, J. C., Epstein, S. E., de Faire, U., Fischer, M., Folsom, A. R., Freyer, J., Gigante, B., Girelli, D., Gretarsdottir, S., Gudnason, V., Gulcher, J. R., Halperin, E., Hammond, N., Hazen, S. L., Hofman, A., Horne, B. D., Illig, T., Iribarren, C., Jones, G. T., Jukema, J. W., Kaiser, M. A., Kaplan, L. M., Kastelein, J. J., Khaw, K., Knowles, J. W., Kolovou, G., Kong, A., Laaksonen, R., Lambrechts, D., Leander, K., Lettre, G., Li, M., Lieb, W., Loley, C., Lotery, A. J., Mannucci, P. M., Maouche, S., Martinelli, N., McKeown, P. P., Meisinger, C., Meitinger, T., Melander, O., Merlini, P. A., Mooser, V., Morgan, T., Muehleisen, T. W., Muhlestein, J. B., Muenzel, T., Musunuru, K., Nahrstaedt, J., Nelson, C. P., Noethen, M. M., Olivieri, O., Patel, R. S., Patterson, C. C., Peters, A., Peyvandi, F., Qu, L., Quyyumi, A. A., Rader, D. J., Rallidis, L. S., Rice, C., Rosendaal, F. R., Rubin, D., Salomaa, V., Sampietro, M. L., Sandhu, M. S., Schadt, E., Schaefer, A., Schillert, A., Schreiber, S., Schrezenmeir, J., Schwartz, S. M., Siscovick, D. S., Sivananthan, M., Sivapalaratnam, S., Smith, A., Smith, T. B., Snoep, J. D., Soranzo, N., Spertus, J. A., Stark, K., Stirrups, K., Stoll, M., Tang, W. H., Tennstedt, S., Thorgeirsson, G., Thorleifsson, G., Tomaszewski, M., Uitterlinden, A. G., van Rij, A. M., Voight, B. F., Wareham, N. J., Wells, G. A., Wichmann, H., Wild, P. S., Willenborg, C., Witteman, J. C., Wright, B. J., Ye, S., Zeller, T., Ziegler, A., Cambien, F., Goodall, A. H., Cupples, L. A., Quertermous, T., Maerz, W., Hengstenberg, C., Blankenberg, S., Ouwehand, W. H., Hall, A. S., Deloukas, P., Thompson, J. R., Stefansson, K., Roberts, R., Thorsteinsdottir, U., O'Donnell, C. J., McPherson, R., Erdmann, J., Samani, N. J. 2011; 43 (4): 333-U153

  Abstract

  We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 × 10⁻⁸ and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.

  View details for DOI 10.1038/ng.784

  View details for Web of Science ID 000288903700013

  View details for PubMedID 21378990

  View details for PubMedCentralID PMC3119261

• A Bivariate Genome-Wide Approach to Metabolic Syndrome STAMPEED Consortium DIABETES Kraja, A. T., Vaidya, D., Pankow, J. S., Goodarzi, M. O., Assimes, T. L., Kullo, I. J., Sovio, U., Mathias, R. A., Sun, Y. V., Franceschini, N., Absher, D., Li, G., Zhang, Q., Feitosa, M. F., Glazer, N. L., Haritunians, T., Hartikainen, A., Knowles, J. W., North, K. E., Iribarren, C., Kral, B., Yanek, L., O'Reilly, P. F., McCarthy, M. I., Jaquish, C., Couper, D. J., Chakravarti, A., Psaty, B. M., Becker, L. C., Province, M. A., Boerwinkle, E., Quertermous, T., Palotie, L., Jarvelin, M., Becker, D. M., Kardia, S. L., Rotter, J. I., Chen, Y. I., Borecki, I. B. 2011; 60 (4): 1329-1339

  Abstract

  OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.

  View details for DOI 10.2337/db10-1011

  View details for Web of Science ID 000289496100029

  View details for PubMedID 21386085

  View details for PubMedCentralID PMC3064107

• Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits PLOS GENETICS Speliotes, E. K., Yerges-Armstrong, L. M., Wu, J., Hernaez, R., Kim, L. J., Palmer, C. D., Gudnason, V., Eiriksdottir, G., Garcia, M. E., Launer, L. J., Nalls, M. A., Clark, J. M., Mitchell, B. D., Shuldiner, A. R., Butler, J. L., Tomas, M., Hoffmann, U., Hwang, S., Massaro, J. M., O'Donnell, C. J., Sahani, D. V., Salomaa, V., Schadt, E. E., Schwartz, S. M., Siscovick, D. S., Voight, B. F., Carr, J. J., Feitosa, M. F., Harris, T. B., Fox, C. S., Smith, A. V., Kao, W. H., Hirschhorn, J. N., Borecki, I. B. 2011; 7 (3)

  Abstract

  Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10(-8)) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.

  View details for DOI 10.1371/journal.pgen.1001324

  View details for Web of Science ID 000288996600006

  View details for PubMedID 21423719

• Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies LANCET Reilly, M. P., Li, M., He, J., Ferguson, J. F., Stylianou, I. M., Mehta, N. N., Burnett, M. S., Devaney, J. M., Knouff, C. W., Thompson, J. R., Horne, B. D., Stewart, A. F., Assimes, T. L., Wild, P. S., Allayee, H., Nitschke, P. L., Patel, R. S., Martinelli, N., Girelli, D., Quyyumi, A. A., Anderson, J. L., Erdmann, J., Hall, A. S., Schunkert, H., Quertermous, T., Blankenberg, S., Hazen, S. L., Roberts, R., Kathiresan, S., Samani, N. J., Epstein, S. E., Rader, D. J. 2011; 377 (9763): 383-392

  Abstract

  We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis.We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12,393) with those who did not (controls, n=7383). To identify loci that predispose to myocardial infarction, we compared patients who had angiographic CAD and myocardial infarction (n=5783) with those who had angiographic CAD but no myocardial infarction (n=3644).In the comparison of patients with angiographic CAD versus controls, we identified a novel locus, ADAMTS7 (p=4·98×10(-13)). In the comparison of patients with angiographic CAD who had myocardial infarction versus those with angiographic CAD but no myocardial infarction, we identified a novel association at the ABO locus (p=7·62×10(-9)). The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction.Our findings indicate that specific genetic predispositions promote the development of coronary atherosclerosis whereas others lead to myocardial infarction in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalised risk assessment and used in the development of novel therapies for CAD.The PennCath and MedStar studies were supported by the Cardiovascular Institute of the University of Pennsylvania, by the MedStar Health Research Institute at Washington Hospital Center and by a research grant from GlaxoSmithKline. The funding and support for the other cohorts contributing to the paper are described in the webappendix.

  View details for DOI 10.1016/S0140-6736(10)61996-4

  View details for Web of Science ID 000287337000028

  View details for PubMedID 21239051

• Lack of Association Between the Trp719Arg Polymorphism in Kinesin-Like Protein-6 and Coronary Artery Disease in 19 Case-Control Studies JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Assimes, T. L., Holm, H., Kathiresan, S., Reilly, M. P., Thorleifsson, G., Voight, B. F., Erdmann, J., Willenborg, C., Vaidya, D., Xie, C., Patterson, C. C., Morgan, T. M., Burnett, M. S., Li, M., Hlatky, M. A., Knowles, J. W., Thompson, J. R., Absher, D., Iribarren, C., Go, A., Fortmann, S. P., Sidney, S., Risch, N., Tang, H., Myers, R. M., Berger, K., Stoll, M., Shah, S. H., Thorgeirsson, G., Andersen, K., Havulinna, A. S., Herrera, J. E., Faraday, N., Kim, Y., Kral, B. G., Mathias, R. A., Ruczinski, I., Suktitipat, B., Wilson, A. F., Yanek, L. R., Becker, L. C., Linsel-Nitschke, P., Lieb, W., Koenig, I. R., Hengstenberg, C., Fischer, M., Stark, K., Reinhard, W., Winogradow, J., Grassl, M., Grosshennig, A., Preuss, M., Schreiber, S., Wichmann, H., Meisinger, C., Yee, J., Friedlander, Y., Do, R., Meigs, J. B., Williams, G., Nathan, D. M., MacRae, C. A., Qu, L., Wilensky, R. L., Matthai, W. H., Qasim, A. N., Hakonarson, H., Pichard, A. D., Kent, K. M., Satler, L., Lindsay, J. M., Waksman, R., Knouff, C. W., Waterworth, D. M., Walker, M. C., Mooser, V. E., Marrugat, J., Lucas, G., Subirana, I., Sala, J., Ramos, R., Martinelli, N., Olivieri, O., Trabetti, E., Malerba, G., Pignatti, P. F., Guiducci, C., Mirel, D., Parkin, M., Hirschhorn, J. N., Asselta, R., Duga, S., Musunuru, K., Daly, M. J., Purcell, S., Eifert, S., Braund, P. S., Wright, B. J., Balmforth, A. J., Ball, S. G., Ouwehand, W. H., Deloukas, P., Scholz, M., Cambien, F., Huge, A., Scheffold, T., Salomaa, V., Girelli, D., Granger, C. B., Peltonen, L., McKeown, P. P., Altshuler, D., Melander, O., Devaney, J. M., Epstein, S. E., Rader, D. J., Elosua, R., Engert, J. C., Anand, S. S., Hall, A. S., Ziegler, A., O'Donnell, C. J., Spertus, J. A., Siscovick, D., Schwartz, S. M., Becker, D., Thorsteinsdottir, U., Stefansson, K., Schunkert, H., Samani, N. J., Quertermous, T. 2010; 56 (19): 1552-1563

  Abstract

  We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD).Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers.The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports.A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of ≥2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups.The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.

  View details for DOI 10.1016/j.jacc.2010.06.022

  View details for PubMedID 20933357

• Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index NATURE GENETICS Speliotes, E. K., Willer, C. J., Berndt, S. I., Monda, K. L., Thorleifsson, G., Jackson, A. U., Allen, H. L., Lindgren, C. M., Luan, J., Maegi, R., Randall, J. C., Vedantam, S., Winkler, T. W., Qi, L., Workalemahu, T., Heid, I. M., Steinthorsdottir, V., Stringham, H. M., Weedon, M. N., Wheeler, E., Wood, A. R., Ferreira, T., Weyant, R. J., Segre, A. V., Estrada, K., Liang, L., Nemesh, J., Park, J., Gustafsson, S., Kilpelaenen, T. O., Yang, J., Bouatia-Naji, N., Esko, T., Feitosa, M. F., Kutalik, Z., Mangino, M., Raychaudhuri, S., Scherag, A., Smith, A. V., Welch, R., Zhao, J. H., Aben, K. K., Absher, D. M., Amin, N., Dixon, A. L., Fisher, E., Glazer, N. L., Goddard, M. E., Heard-Costa, N. L., Hoesel, V., Hottenga, J., Johansson, A., Johnson, T., Ketkar, S., Lamina, C., Li, S., Moffatt, M. F., Myers, R. H., Narisu, N., Perry, J. R., Peters, M. J., Preuss, M., Ripatti, S., Rivadeneira, F., Sandholt, C., Scott, L. J., Timpson, N. J., Tyrer, J. P., van Wingerden, S., Watanabe, R. M., White, C. C., Wiklund, F., Barlassina, C., Chasman, D. I., Cooper, M. N., Jansson, J., Lawrence, R. W., Pellikka, N., Prokopenko, I., Shi, J., Thiering, E., Alavere, H., Alibrandi, M. T., Almgren, P., Arnold, A. M., Aspelund, T., Atwood, L. D., Balkau, B., Balmforth, A. J., Bennett, A. J., Ben-Shlomo, Y., Bergman, R. N., Bergmann, S., Biebermann, H., Blakemore, A. I., Boes, T., Bonnycastle, L. L., Bornstein, S. R., Brown, M. J., Buchanan, T. A., Busonero, F., Campbell, H., Cappuccio, F. P., Cavalcanti-Proenca, C., Chen, Y. I., Chen, C., Chines, P. S., Clarke, R., Coin, L., Connell, J., Day, I. N., den Heijer, M., Duan, J., Ebrahim, S., Elliott, P., Elosua, R., Eiriksdottir, G., Erdos, M. R., Eriksson, J. G., Facheris, M. F., Felix, S. B., Fischer-Posovszky, P., Folsom, A. R., Friedrich, N., Freimer, N. B., Fu, M., Gaget, S., Gejman, P. V., Geus, E. J., Gieger, C., Gjesing, A. P., Goel, A., Goyette, P., Grallert, H., Graessler, J., Greenawalt, D. M., Groves, C. J., Gudnason, V., Guiducci, C., Hartikainen, A., Hassanali, N., Hall, A. S., Havulinna, A. S., Hayward, C., Heath, A. C., Hengstenberg, C., Hicks, A. A., Hinney, A., Hofman, A., Homuth, G., Hui, J., Igl, W., Iribarren, C., Isomaa, B., Jacobs, K. B., Jarick, I., Jewell, E., John, U., Jorgensen, T., Jousilahti, P., Jula, A., Kaakinen, M., Kajantie, E., Kaplan, L. M., Kathiresan, S., Kettunen, J., Kinnunen, L., Knowles, J. W., Kolcic, I., Koenig, I. R., Koskinen, S., Kovacs, P., Kuusisto, J., Kraft, P., Kvaloy, K., Laitinen, J., Lantieri, O., Lanzani, C., Launer, L. J., Lecoeur, C., Lehtimaeki, T., Lettre, G., Liu, J., Lokki, M., Lorentzon, M., Luben, R. N., Ludwig, B., Manunta, P., Marek, D., Marre, M., Martin, N. G., McArdle, W. L., McCarthy, A., McKnight, B., Meitinger, T., Melander, O., Meyre, D., Midthjell, K., Montgomery, G. W., Morken, M. A., Morris, A. P., Mulic, R., Ngwa, J. S., Nelis, M., Neville, M. J., Nyholt, D. R., O'Donnell, C. J., O'Rahilly, S., Ong, K. K., Oostra, B., Pare, G., Parker, A. N., Perola, M., Pichler, I., Pietilaeinen, K. H., Platou, C. G., Polasek, O., Pouta, A., Rafelt, S., Raitakari, O., Rayner, N. W., Ridderstrale, M., Rief, W., Ruokonen, A., Robertson, N. R., Rzehak, P., Salomaa, V., Sanders, A. R., Sandhu, M. S., Sanna, S., Saramies, J., Savolainen, M. J., Scherag, S., Schipf, S., Schreiber, S., Schunkert, H., Silander, K., Sinisalo, J., Siscovick, D. S., Smit, J. H., Soranzo, N., Sovio, U., Stephens, J., Surakka, I., Swift, A. J., Tammesoo, M., Tardif, J., Teder-Laving, M., Teslovich, T. M., Thompson, J. R., Thomson, B., Toenjes, A., Tuomi, T., van Meurs, J. B., van Ommen, G., Vatin, V., Viikari, J., Visvikis-Siest, S., Vitart, V., Vogel, C. I., Voight, B. F., Waite, L. L., Wallaschofski, H., Walters, G. B., Widen, E., Wiegand, S., Wild, S. H., Willemsen, G., Witte, D. R., Witteman, J. C., Xu, J., Zhang, Q., Zgaga, L., Ziegler, A., Zitting, P., Beilby, J. P., Farooqi, I. S., Hebebrand, J., Huikuri, H. V., James, A. L., Kaehoenen, M., Levinson, D. F., Macciardi, F., Nieminen, M. S., Ohlsson, C., Palmer, L. J., Ridker, P. M., Stumvoll, M., Beckmann, J. S., Boeing, H., Boerwinkle, E., Boomsma, D. I., Caulfield, M. J., Chanock, S. J., Collins, F. S., Cupples, L. A., Smith, G. D., Erdmann, J., Froguel, P., Greonberg, H., Gyllensten, U., Hall, P., Hansen, T., Harris, T. B., Hattersley, A. T., Hayes, R. B., Heinrich, J., Hu, F. B., Hveem, K., Illig, T., Jarvelin, M., Kaprio, J., Karpe, F., Khaw, K., Kiemeney, L. A., Krude, H., Laakso, M., Lawlor, D. A., Metspalu, A., Munroe, P. B., Ouwehand, W. H., Pedersen, O., Penninx, B. W., Peters, A., Pramstaller, P. P., Quertermous, T., Reinehr, T., Rissanen, A., Rudan, I., Samani, N. J., Schwarz, P. E., Shuldiner, A. R., Spector, T. D., Tuomilehto, J., Uda, M., Uitterlinden, A., Valle, T. T., Wabitsch, M., Waeber, G., Wareham, N. J., Watkins, H., Wilson, J. F., Wright, A. F., Zillikens, M. C., Chatterjee, N., McCarroll, S. A., Purcell, S., Schadt, E. E., Visscher, P. M., Assimes, T. L., Borecki, I. B., Deloukas, P., Fox, C. S., Groop, L. C., Haritunians, T., Hunter, D. J., Kaplan, R. C., Mohlke, K. L., O'Connell, J. R., Peltonen, L., Schlessinger, D., Strachan, D. P., van Duijn, C. M., Wichmann, H., Frayling, T. M., Thorsteinsdottir, U., Abecasis, G. R., Barroso, I., Boehnke, M., Stefansson, K., North, K. E., McCarthy, M. I., Hirschhorn, J. N., Ingelsson, E., Loos, R. J. 2010; 42 (11): 937-U53

  Abstract

  Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

  View details for DOI 10.1038/ng.686

  View details for Web of Science ID 000283540500010

  View details for PubMedID 20935630

• Hundreds of variants clustered in genomic loci and biological pathways affect human height NATURE Allen, H. L., Estrada, K., Lettre, G., Berndt, S. I., Weedon, M. N., Rivadeneira, F., Willer, C. J., Jackson, A. U., Vedantam, S., Raychaudhuri, S., Ferreira, T., Wood, A. R., Weyant, R. J., Segre, A. V., Speliotes, E. K., Wheeler, E., Soranzo, N., Park, J., Yang, J., Gudbjartsson, D., Heard-Costa, N. L., Randall, J. C., Qi, L., Smith, A. V., Maegi, R., Pastinen, T., Liang, L., Heid, I. M., Luan, J., Thorleifsson, G., Winkler, T. W., Goddard, M. E., Lo, K. S., Palmer, C., Workalemahu, T., Aulchenko, Y. S., Johansson, A., Zillikens, M. C., Feitosa, M. F., Esko, T., Johnson, T., Ketkar, S., Kraft, P., Mangino, M., Prokopenko, I., Absher, D., Albrecht, E., Ernst, F., Glazer, N. L., Hayward, C., Hottenga, J., Jacobs, K. B., Knowles, J. W., Kutalik, Z., Monda, K. L., Polasek, O., Preuss, M., Rayner, N. W., Robertson, N. R., Steinthorsdottir, V., Tyrer, J. P., Voight, B. F., Wiklund, F., Xu, J., Zhao, J. H., Nyholt, D. R., Pellikka, N., Perola, M., Perry, J. R., Surakka, I., Tammesoo, M., Altmaier, E. L., Amin, N., Aspelund, T., Bhangale, T., Boucher, G., Chasman, D. I., Chen, C., Coin, L., Cooper, M. N., Dixon, A. L., Gibson, Q., Grundberg, E., Hao, K., Junttila, M. J., Kaplan, L. M., Kettunen, J., Koenig, I. R., Kwan, T., Lawrence, R. W., Levinson, D. F., Lorentzon, M., McKnight, B., Morris, A. P., Mueller, M., Ngwa, J. S., Purcell, S., Rafelt, S., Salem, R. M., Salvi, E., Sanna, S., Shi, J., Sovio, U., Thompson, J. R., Turchin, M. C., Vandenput, L., Verlaan, D. J., Vitart, V., White, C. C., Ziegler, A., Almgren, P., Balmforth, A. J., Campbell, H., Citterio, L., de Grandi, A., Dominiczak, A., Duan, J., Elliott, P., Elosua, R., Eriksson, J. G., Freimer, N. B., Geus, E. J., Glorioso, N., Haiqing, S., Hartikainen, A., Havulinna, A. S., Hicks, A. A., Hui, J., Igl, W., Illig, T., Jula, A., Kajantie, E., Kilpelaeinen, T. O., Koiranen, M., Kolcic, I., Koskinen, S., Kovacs, P., Laitinen, J., Liu, J., Lokki, M., Marusic, A., Maschio, A., Meitinger, T., Mulas, A., Pare, G., Parker, A. N., Peden, J. F., Petersmann, A., Pichler, I., Pietilainen, K. H., Pouta, A., Riddertrale, M., Rotter, J. I., Sambrook, J. G., Sanders, A. R., Schmidt, C. O., Sinisalo, J., Smit, J. H., Stringham, H. M., Walters, G. B., Widen, E., Wild, S. H., Willemsen, G., Zagato, L., Zgaga, L., Zitting, P., Alavere, H., Farrall, M., McArdle, W. L., Nelis, M., Peters, M. J., Ripatti, S., vVan Meurs, J. B., Aben, K. K., Ardlie, K. G., Beckmann, J. S., Beilby, J. P., Bergman, R. N., Bergmann, S., Collins, F. S., Cusi, D., den Heijer, M., Eiriksdottir, G., Gejman, P. V., Hall, A. S., Hamsten, A., Huikuri, H. V., Iribarren, C., Kahonen, M., Kaprio, J., Kathiresan, S., Kiemeney, L., Kocher, T., Launer, L. J., Lehtimaki, T., Melander, O., Mosley, T. H., Musk, A. W., Nieminen, M. S., O'Donnell, C. J., Ohlsson, C., Oostra, B., Palmer, L. J., Raitakari, O., Ridker, P. M., Rioux, J. D., Rissanen, A., Rivolta, C., Schunkert, H., Shuldiner, A. R., Siscovick, D. S., Stumvoll, M., Toenjes, A., Tuomilehto, J., van Ommen, G., Viikari, J., Heath, A. C., Martin, N. G., Montgomery, G. W., Province, M. A., Kayser, M., Arnold, A. M., Atwood, L. D., Boerwinkle, E., Chanock, S. J., Deloukas, P., Gieger, C., Gronberg, H., Hall, P., Hattersley, A. T., Hengstenberg, C., Hoffman, W., Lathrop, G. M., Salomaa, V., Schreiber, S., Uda, M., Waterworth, D., Wright, A. F., Assimes, T. L., Barroso, I., Hofman, A., Mohlke, K. L., Boomsma, D. I., Caulfield, M. J., Cupples, L. A., Erdmann, J., Fox, C. S., Gudnason, V., Gyllensten, U., Harris, T. B., Hayes, R. B., Jarvelin, M., Mooser, V., Munroe, P. B., Ouwehand, W. H., Penninx, B. W., Pramstaller, P. P., Quertermous, T., Rudan, I., Samani, N. J., Spector, T. D., Voelzke, H., Watkins, H., Wilson, J. F., Groop, L. C., Haritunians, T., Hu, F. B., Kaplan, R. C., Metspalu, A., North, K. E., Schlessinger, D., Wareham, N. J., Hunter, D. J., O'Connell, J. R., Strachan, D. P., Schadt, H., Thorsteinsdottir, U., Peltonen, L., Uitterlinden, A. G., Visscher, P. M., Chatterjee, N., Loos, R. J., Boehnke, M., McCarthy, M. I., Ingelsson, E., Lindgren, C. M., Abecasis, G. R., Stefansson, K., Frayling, T. M., Hirschhorn, J. N. 2010; 467 (7317): 832-838

  Abstract

  Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

  View details for DOI 10.1038/nature09410

  View details for Web of Science ID 000282898700065

  View details for PubMedID 20881960

• Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans 59th Annual Meeting of the American-Society-of-Human-Genetics Ingelsson, E., Langenberg, C., Hivert, M., Prokopenko, I., Lyssenko, V., Dupuis, J., Maegi, R., Sharp, S., Jackson, A. U., Assimes, T. L., Shrader, P., Knowles, J. W., Zethelius, B., Abbasi, F. A., Bergman, R. N., Bergmann, A., Berne, C., Boehnke, M., Bonnycastle, L. L., Bornstein, S. R., Buchanan, T. A., Bumpstead, S. J., Boettcher, Y., Chines, P., Collins, F. S., Cooper, C. C., Dennison, E. M., Erdos, M. R., Ferrannini, E., Fox, C. S., Graessler, J., Hao, K., Isomaa, B., Jameson, K. A., Kovacs, P., Kuusisto, J., Laakso, M., Ladenval, C., Mohlke, K. L., Morken, M. A., Narisu, N., Nathan, D. M., Pascoe, L., Payne, F., Petrie, J. R., Sayer, A. A., Schwarz, P. E., Scott, L. J., Stringham, H. M., Stumvoll, M., Swift, A. J., Syvanen, A., Tuomi, T., Tuomilehto, J., Tonjes, A., Valle, T. T., Williams, G. H., Lind, L., Barroso, I., Quertermous, T., Walker, M., Wareham, N. J., Meigs, J. B., McCarthy, M. I., Groop, L., Watanabe, R. M., Florez, J. C. AMER DIABETES ASSOC. 2010: 1266–75

  Abstract

  OBJECTIVE Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 x 10(-71)). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.

  View details for DOI 10.2337/DB09-1568

  View details for Web of Science ID 000277554700019

  View details for PubMedID 20185807

  View details for PubMedCentralID PMC2857908

• Genome-wide meta-analyses identify multiple loci associated with smoking behavior NATURE GENETICS Furberg, H., Kim, Y., Dackor, J., Boerwinkle, E., Franceschini, N., Ardissino, D., Bernardinelli, L., Mannucci, P. M., Mauri, F., Merlini, P. A., Absher, D., Assimes, T. L., Fortmann, S. P., Iribarren, C., Knowles, J. W., Quertermous, T., Ferrucci, L., Tanaka, T., Bis, J. C., Furberg, C. D., Haritunians, T., McKnight, B., Psaty, B. M., Taylor, K. D., Thacker, E. L., Almgren, P., Groop, L., Ladenvall, C., Boehnke, M., Jackson, A. U., Mohlke, K. L., Stringham, H. M., Tuomilehto, J., Benjamin, E. J., Hwang, S., Levy, D., Preis, S. R., Vasan, R. S., Duan, J., Gejman, P. V., Levinson, D. F., Sanders, A. R., Shi, J., Lips, E. H., McKay, J. D., Agudo, A., Barzan, L., Bencko, V., Benhamou, S., Castellsague, X., Canova, C., Conway, D. I., Fabianova, E., Foretova, L., Janout, V., Healy, C. M., Holcatova, I., Kjaerheim, K., Lagiou, P., Lissowska, J., Lowry, R., Macfarlane, T. V., Mates, D., Richiardi, L., Rudnai, P., Szeszenia-Dabrowska, N., Zaridze, D., Znaor, A., Lathrop, M., Brennan, P., Bandinelli, S., Frayling, T. M., Guralnik, J. M., Milaneschi, Y., Perry, J. R., Altshuler, D., Elosua, R., Kathiresan, S., Lucas, G., Melander, O., O'Donnell, C. J., Salomaa, V., Schwartz, S. M., Voight, B. F., Penninx, B. W., Smit, J. H., Vogelzangs, N., Boomsma, D. I., de Geus, E. J., Vink, J. M., Willemsen, G., Chanock, S. J., Gu, F., Hankinson, S. E., Hunter, D. J., Hofman, A., Tiemeier, H., Uitterlinden, A. G., van Duijn, C. M., Walter, S., Chasman, D. I., Everett, B. M., Pare, G., Ridker, P. M., Li, M. D., Maes, H. H., Audrain-McGovern, J., Posthuma, D., Thornton, L. M., Lerman, C., Kaprio, J., Rose, J. E., Ioannidis, J. P., Kraft, P., Lin, D., Sullivan, P. F. 2010; 42 (5): 441-U134

  Abstract

  Consistent but indirect evidence has implicated genetic factors in smoking behavior. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], beta = 1.03, standard error (s.e.) = 0.053, P = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], beta = 0.367, s.e. = 0.059, P = 5.7 x 10(-10); and rs1028936[A], beta = 0.446, s.e. = 0.074, P = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], beta = 0.333, s.e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.

  View details for DOI 10.1038/ng.571

  View details for Web of Science ID 000277179500017

  View details for PubMedID 20418890

  View details for PubMedCentralID PMC2914600

• Clinical assessment incorporating a personal genome LANCET Ashley, E. A., Butte, A. J., Wheeler, M. T., Chen, R., Klein, T. E., Dewey, F. E., Dudley, J. T., Ormond, K. E., Pavlovic, A., Morgan, A. A., Pushkarev, D., Neff, N. F., Hudgins, L., Gong, L., Hodges, L. M., Berlin, D. S., Thorn, C. F., Sangkuhl, K., Hebert, J. M., Woon, M., Sagreiya, H., Whaley, R., Knowles, J. W., Chou, M. F., Thakuria, J. V., Rosenbaum, A. M., Zaranek, A. W., Church, G. M., Greely, H. T., Quake, S. R., Altman, R. B. 2010; 375 (9725): 1525-1535

  Abstract

  The cost of genomic information has fallen steeply, but the clinical translation of genetic risk estimates remains unclear. We aimed to undertake an integrated analysis of a complete human genome in a clinical context.We assessed a patient with a family history of vascular disease and early sudden death. Clinical assessment included analysis of this patient's full genome sequence, risk prediction for coronary artery disease, screening for causes of sudden cardiac death, and genetic counselling. Genetic analysis included the development of novel methods for the integration of whole genome and clinical risk. Disease and risk analysis focused on prediction of genetic risk of variants associated with mendelian disease, recognised drug responses, and pathogenicity for novel variants. We queried disease-specific mutation databases and pharmacogenomics databases to identify genes and mutations with known associations with disease and drug response. We estimated post-test probabilities of disease by applying likelihood ratios derived from integration of multiple common variants to age-appropriate and sex-appropriate pre-test probabilities. We also accounted for gene-environment interactions and conditionally dependent risks.Analysis of 2.6 million single nucleotide polymorphisms and 752 copy number variations showed increased genetic risk for myocardial infarction, type 2 diabetes, and some cancers. We discovered rare variants in three genes that are clinically associated with sudden cardiac death-TMEM43, DSP, and MYBPC3. A variant in LPA was consistent with a family history of coronary artery disease. The patient had a heterozygous null mutation in CYP2C19 suggesting probable clopidogrel resistance, several variants associated with a positive response to lipid-lowering therapy, and variants in CYP4F2 and VKORC1 that suggest he might have a low initial dosing requirement for warfarin. Many variants of uncertain importance were reported.Although challenges remain, our results suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients.National Institute of General Medical Sciences; National Heart, Lung And Blood Institute; National Human Genome Research Institute; Howard Hughes Medical Institute; National Library of Medicine, Lucile Packard Foundation for Children's Health; Hewlett Packard Foundation; Breetwor Family Foundation.

  View details for Web of Science ID 000277655100025

  View details for PubMedID 20435227

• Characterizing the admixed African ancestry of African Americans GENOME BIOLOGY Zakharia, F., Basu, A., Absher, D., Assimes, T. L., Go, A. S., Hlatky, M. A., Iribarren, C., Knowles, J. W., Li, J., Narasimhan, B., Sidney, S., Southwick, A., Myers, R. M., Quertermous, T., Risch, N., Tang, H. 2009; 10 (12)

  Abstract

  Accurate, high-throughput genotyping allows the fine characterization of genetic ancestry. Here we applied recently developed statistical and computational techniques to the question of African ancestry in African Americans by using data on more than 450,000 single-nucleotide polymorphisms (SNPs) genotyped in 94 Africans of diverse geographic origins included in the HGDP, as well as 136 African Americans and 38 European Americans participating in the Atherosclerotic Disease Vascular Function and Genetic Epidemiology (ADVANCE) study. To focus on African ancestry, we reduced the data to include only those genotypes in each African American determined statistically to be African in origin.From cluster analysis, we found that all the African Americans are admixed in their African components of ancestry, with the majority contributions being from West and West-Central Africa, and only modest variation in these African-ancestry proportions among individuals. Furthermore, by principal components analysis, we found little evidence of genetic structure within the African component of ancestry in African Americans.These results are consistent with historic mating patterns among African Americans that are largely uncorrelated to African ancestral origins, and they cast doubt on the general utility of mtDNA or Y-chromosome markers alone to delineate the full African ancestry of African Americans. Our results also indicate that the genetic architecture of African Americans is distinct from that of Africans, and that the greatest source of potential genetic stratification bias in case-control studies of African Americans derives from the proportion of European ancestry.

  View details for DOI 10.1186/gb-2009-10-12-r141

  View details for Web of Science ID 000274289000011

  View details for PubMedID 20025784

  View details for PubMedCentralID PMC2812948

• Susceptibility locus for clinical and subclinical coronary artery disease at chromosome 9p21 in the multi-ethnic ADVANCE study HUMAN MOLECULAR GENETICS Assimes, T. L., Knowles, J. W., Basu, A., Iribarren, C., Southwick, A., Tang, H., Absher, D., Li, J., Fair, J. M., Rubin, G. D., Sidney, S., Fortmann, S. P., Go, A. S., Hlatky, M. A., Myers, R. M., Risch, N., Quertermous, T. 2008; 17 (15): 2320-2328

  Abstract

  A susceptibility locus for coronary artery disease (CAD) at chromosome 9p21 has recently been reported, which may influence the age of onset of CAD. We sought to replicate these findings among white subjects and to examine whether these results are consistent with other racial/ethnic groups by genotyping three single nucleotide polymorphisms (SNPs) in the risk interval in the Atherosclerotic Disease, Vascular Function, and Genetic Epidemiology (ADVANCE) study. One or more of these SNPs was associated with clinical CAD in whites, U.S. Hispanics and U.S. East Asians. None of the SNPs were associated with CAD in African Americans although the power to detect an odds ratio (OR) in this group equivalent to that seen in whites was only 24-30%. ORs were higher in Hispanics and East Asians and lower in African Americans, but in all groups the 95% confidence intervals overlapped with ORs observed in whites. High-risk alleles were also associated with increased coronary artery calcification in controls and the magnitude of these associations by racial/ethnic group closely mirrored the magnitude observed for clinical CAD. Unexpectedly, we noted significant genotype frequency differences between male and female cases (P = 0.003-0.05). Consequently, men tended towards a recessive and women tended towards a dominant mode of inheritance. Finally, an effect of genotype on the age of onset of CAD was detected but only in men carrying two versus one or no copy of the high-risk allele and presenting with CAD at age >50 years. Further investigations in other populations are needed to confirm or refute our findings.

  View details for DOI 10.1093/hmg/ddn132

  View details for Web of Science ID 000257788300007

  View details for PubMedID 18443000

  View details for PubMedCentralID PMC2733811

• A near null variant of 12/15-LOX encoded by a novel SNP in ALOX15 and the risk of coronary artery disease ATHEROSCLEROSIS Assimes, T. L., Knowles, J. W., Priest, J. R., Basu, A., Borchert, A., Volcik, K. A., Grove, M. L., Tabor, H. K., Southwick, A., Tabibiazar, R., Sidney, S., Boerwinkle, E., Go, A. S., Iribarren, C., Hlatky, M. A., Fortmann, S. P., Myers, R. M., Kuhn, H., Riseh, N., Quertermous, T. 2008; 198 (1): 136-144

  Abstract

  Murine genetic models suggest that function of the 12/15-LOX enzyme promotes atherosclerosis. We tested the hypothesis that exonic and/or promoter single nucleotide polymorphisms (SNPs) in the human 12/15-LOX gene (ALOX15) alter the risk of symptomatic coronary artery disease (CAD).We resequenced ALOX15 and then genotyped a common promoter and a less common novel coding SNP (T560M) in 1809 subjects with CAD and 1734 controls from Kaiser Permanente including a subset of participants of the Coronary Artery Risk Development in Young Adults study. We found no association between the promoter SNP and the risk of CAD. However, heterozygote carriers of the 560M allele had an increased risk of CAD (adjusted OR, 1.62; P=0.02) compared to non-carriers. In vitro studies demonstrated a 20-fold reduction in the catalytic activity of 560M when compared to 560T. We then genotyped T560M in 12,974 participants of the Atherosclerosis Risk in Communities study and similarly found that heterozygote carriers had an increased risk of CAD compared to non-carriers (adjusted HR, 1.31; P=0.06). In both population studies, homozygote carriers were rare and associated with a non-significant decreased risk of CAD compared to non-carriers (adjusted OR, 0.55; P=0.63 and HR, 0.93; P=0.9).A coding SNP in ALOX15 (T560M) results in a near null variant of human 12/15-LOX. Assuming a co-dominant mode of inheritance, this variant does not protect against CAD. Assuming a recessive mode of inheritance, the effect of this mutation remains unclear, but is unlikely to provide a protective effect to the degree suggested by mouse knockout studies.

  View details for DOI 10.1016/j.atheroscierosis.2007.09.003

  View details for Web of Science ID 000255491800016

  View details for PubMedID 17959182

  View details for PubMedCentralID PMC2440699

• Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease HUMAN GENETICS Assimes, T. L., Knowles, J. W., Priest, J. R., Basu, A., Volcik, K. A., Southwick, A., Tabor, H. K., Hartiala, J., Allayee, H., Grove, M. L., Tabibiazar, R., Sidney, S., Fortmann, S. P., Go, A., Hlatky, M., Iribarren, C., Boerwinkle, E., Myers, R., Risch, N., Quertermous, T. 2008; 123 (4): 399-408

  Abstract

  Recent human genetic studies suggest that allelic variants of leukotriene pathway genes influence the risk of clinical and subclinical atherosclerosis. We sequenced the promoter, exonic, and splice site regions of ALOX5 and ALOX5AP and then genotyped 7 SNPs in ALOX5 and 6 SNPs in ALOX5AP in 1,552 cases with clinically significant coronary artery disease (CAD) and 1,583 controls from Kaiser Permanente including a subset of participants of the coronary artery risk development in young adults study. A nominally significant association was detected between a promoter SNP in ALOX5 (rs12762303) and CAD in our subset of white/European subjects (adjusted odds ratio per minor allele, log-additive model, 1.32; P = 0.002). In this race/ethnic group, rs12762303 has a minor allele frequency of 15% and is tightly linked to variation at the SP1 variable tandem repeat promoter polymorphism. However, the association between CAD and rs12762303 could not be reproduced in the atherosclerosis risk in communities study (hazard rate ratio per minor allele; 1.08, P = 0.1). Assuming a recessive mode of inheritance, the association was not significant in either population study but our power to detect modest effects was limited. No significant associations were observed between all other SNPs and the risk of CAD. Overall, our findings do not support a link between common allelic variation in or near ALOX5 or ALOX5AP and the risk of CAD. However, additional studies are needed to exclude modest effects of promoter variation in ALOX5 on the risk of CAD assuming a recessive mode of inheritance.

  View details for DOI 10.1007/s00439-008-0489-5

  View details for Web of Science ID 000254959600008

  View details for PubMedID 18369664

• Failure to replicate an association of SNPs in the oxidized LDL receptor gene (OLRI) with CAD BMC MEDICAL GENETICS Knowles, J. W., Assimes, T. L., Boerwinkle, E., Fortmann, S. P., Go, A., Grove, M. L., Hlatky, M., Iribarren, C., Li, J., Myers, R., Risch, N., Sidney, S., Southwick, A., Volcik, K. A., Quertermous, T. 2008; 9

  Abstract

  The lectin-like oxidized LDL receptor LOX-1 (encoded by OLR1) is believed to play a key role in atherogenesis and some reports suggest an association of OLR1 polymorphisms with myocardial infarction (MI). We tested whether single nucleotide polymorphisms (SNPs) in OLR1 are associated with clinically significant CAD in the Atherosclerotic Disease, VAscular FuNction, & Geneti C Epidemiology (ADVANCE) study.ADVANCE is a population-based case-control study of subjects receiving care within Kaiser Permanente of Northern California including a subset of participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study. We first resequenced the promoter, exonic, and splice site regions of OLR1 and then genotyped four single nucleotide polymorphisms (SNPs), including a non-synonymous SNP (rs11053646, Lys167Asn) as well as an intronic SNP (rs3736232) previously associated with CAD.In 1,809 cases with clinical CAD and 1,734 controls, the minor allele of the coding SNP was nominally associated with a lower odds ratio (OR) of CAD across all ethnic groups studied (minimally adjusted OR 0.8, P = 0.007; fully adjusted OR 0.8, P = 0.01). The intronic SNP was nominally associated with an increased risk of CAD (minimally adjusted OR 1.12, p = 0.03; fully adjusted OR 1.13, P = 0.03). However, these associations were not replicated in over 13,200 individuals (including 1,470 cases) in the Atherosclerosis Risk in Communities (ARIC) study.Our results do not support the presence of an association between selected common SNPs in OLR1 and the risk of clinical CAD.

  View details for DOI 10.1186/1471-2350-9-23

  View details for Web of Science ID 000255652400001

  View details for PubMedID 18384690

  View details for PubMedCentralID PMC2322963

• Pharmacogenetics of Heart Failure: Evidence, Opportunities, and Challenges for Cardiovascular Pharmacogenomics JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH Wheeler, M. T., Ho, M., Knowles, J. W., Pavlovic, A., Ashley, E. A. 2008; 1 (1): 25-36

  Abstract

  Heart failure is a significant medical problem affecting more than five million people in the USA alone. Although clinical trials of pharmacological agents have demonstrated significant reductions in the relative risk of mortality across populations, absolute mortality remains high. In addition, individual variation in response is great. Some of this variation may be explained by genetic polymorphism. In this paper, we review the key studies to date in heart failure pharmacogenetics, setting this against a background of recent progress in the genetics of warfarin metabolism. Several polymorphisms that have supporting molecular and clinical data in the heart failure literature are reviewed, among them the beta1-adrenergic receptor variant Arg389Gly and the angiotensin converting enzyme gene insertion/deletion polymorphism. These variants and others are responsible for a fraction of the total variation seen in the treatment response to heart failure. With the dawn of the genomic age, further pharmacogenetic and new pharmacogenomic studies will advance our ability to tailor the treatment of heart failure.

  View details for DOI 10.1007/s12265-007-9007-8

  View details for Web of Science ID 000207734400008

  View details for PubMedID 20559955

• Association of polymorphisms in platelet and hemostasis system genes with acute myocardial infarction AMERICAN HEART JOURNAL Knowles, J. W., Wang, H., Itakura, H., Southwick, A., Myers, R. M., Iribarren, C., Fortmann, S. P., Go, A. S., Quertermous, T., Hlatky, M. A. 2007; 154 (6): 1052-1058

  Abstract

  Genetic polymorphisms may affect the balance between coagulation and fibrinolysis and thereby affect individual vulnerability to acute myocardial infarction (MI) among patients with underlying coronary atherosclerosis.We enrolled 1375 patients with an initial clinical presentation of coronary disease. We genotyped 49 single nucleotide polymorphisms (SNPs) in 9 coagulation system genes and compared patients who had an initial acute MI with patients who presented with stable exertional angina.An SNP in CD36 (rs3211956) was significantly (P = .04) more common among patients who presented with acute MI (minor allele frequency 10.5%) than patients with stable exertional angina (minor allele frequency 8.0%). This association became marginally significant, however, after adjustment for conventional cardiac risk factors in an additive genetic model (odds ratio 1.34, CI 1.00-1.88, P = .053). An SNP in ITGB3 (Leu59Pro, rs5918) was slightly, but not significantly (P = .083), more common among patients with acute MI (minor allele frequency 14.5%) than among patients with stable exertional angina (minor allele frequency 12.0%). Two linked SNPs in THBD (Ala473Val, rs1042579; and rs3176123) were slightly, but not significantly (P = .079 and 0.052, respectively), less common among patients with acute MI (minor allele frequency 16.1%) than among patients with stable exertional angina (18.7% and 19.0%, respectively).Four SNPs in platelet glycoprotein and hemostatic genes were nominally associated with acute MI rather than stable exertional angina as the initial clinical presentation of coronary artery disease. These findings are suggestive but require independent confirmation in larger studies.

  View details for DOI 10.1016/j.ahj.2007.05.021

  View details for PubMedID 18035074

• Genetic susceptibility to peripheral arterial disease: A dark corner in vascular biology ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Knowles, J. W., Assimes, T. L., Li, J., Quertermous, T., Cooke, J. P. 2007; 27 (10): 2068-2078

  Abstract

  Peripheral arterial disease (PAD) is characterized by reduced blood flow to the limbs, usually as a consequence of atherosclerosis, and affects approximately 12 million Americans. It is a common cause of cardiovascular morbidity and an independent predictor of cardiovascular mortality. Similar to other atherosclerotic diseases, such as coronary artery disease, PAD is the result of the complex interplay between injurious environmental stimuli and genetic predisposing factors of the host. Genetic susceptibility to PAD is likely contributed by sequence variants in multiple genes, each with modest effects. Although many of these variants probably alter susceptibility both to PAD and to coronary artery disease, it is likely that there exists a set of variants specifically to alter susceptibility to PAD. Despite the prevalence of PAD and its high societal burden, relatively little is known about such genetic variants. This review summarizes our limited present knowledge and gives an overview of recent, more powerful approaches to elucidating the genetic basis of PAD. We discuss the advantages and limitations of genetic studies and highlight the need for collaborative networks of PAD investigators for shedding light on this dark corner of vascular biology.

  View details for DOI 10.1161/01.ATV.0000282199.66398.8c

  View details for Web of Science ID 000249587000002

  View details for PubMedID 17656669

  View details for PubMedCentralID PMC4321902

• A case of complete heart block reverting to normal sinus rhythm after treatment for cardiac invasive Burkitt's lymphoma ANNALS OF HEMATOLOGY Knowles, J. W., Elliott, A. B., Brody, J. 2007; 86 (9): 687-690

  View details for DOI 10.1007/s00277-007-0290-x

  View details for Web of Science ID 000248580400011

  View details for PubMedID 17410366

• Cardiac hypertrophy and sudden death in mice with a genetically clamped renin transgene PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Caron, K. M., James, L. R., Kim, H. S., Knowles, J., Uhlir, R., Mao, L., Hagaman, J. R., Cascio, W., Rockman, H., Smithies, O. 2004; 101 (9): 3106-3111

  Abstract

  Several mouse models have already proved valuable for investigating hypertrophic responses to cardiac stress. Here, we characterize one caused by a well defined single copy transgene, RenTgMK, that genetically clamps plasma renin and thence angiotensin II at high levels. All of the transgenic males develop concentric cardiac hypertrophy with fibrosis but without dilatation. Over half die suddenly aged 6-8 months. Telemetry showed disturbances in diurnal rhythms a few days before death and, later, electrocardiographic disturbances comparable to those in humans with congestive heart failure. Expression of seven hypertrophy-related genes in this and two categorically different models (lack of atrial natriuretic peptide receptor A; overexpression of calsequestrin) were compared. Statistical analyses show that ventricular expressions of the genes coding for atrial natriuretic peptide, beta myosin heavy chain, medium chain acyl-CoA dehydrogenase, and adrenomedullin correlate equally well with the degree of hypertrophy, although their ranges of expression are, respectively, 50-, 30-, 10-, and 3-fold.

  View details for DOI 10.1073/pnas.0307333101

  View details for Web of Science ID 000220065300082

  View details for PubMedID 14978280

• Increased atherosclerosis and smooth muscle cell hypertrophy in natriuretic peptide receptor A(-/-) apolipoprotein E-/- mice ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Alexander, M. R., Knowles, J. W., Nishikimi, T., Maeda, N. 2003; 23 (6): 1077-1082

  Abstract

  Natriuretic peptide signaling is important in the regulation of blood pressure as well as in the growth of multiple cell types. To examine the role of natriuretic peptide signaling in atherosclerosis, we crossbred mice that lack natriuretic peptide receptor A (NPRA; Npr1-/-) with atherosclerosis-prone mice that lack apolipoprotein E (apoE; Apoe-/-).Doubly deficient Npr1-/-Apoe-/- mice have increased blood pressure relative to Npr1+/+Apoe-/- mice (118+/-4 mm Hg compared with 108+/-2 mm Hg, P<0.05) that is coincident with a 64% greater atherosclerotic lesion size (P<0.005) and more advanced plaque morphology. Additionally, aortic medial thickness is increased by 52% in Npr1-/-Apoe-/- mice relative to Npr1+/+Apoe-/- mice (P<0.0001). Npr1-/-Apoe-/- mice also have significantly greater cardiac mass (9.0+/-0.3 mg/g body weight) than either Npr1+/+Apoe-/- mice (5.8+/-0.2 mg/g) or Npr1-/-Apoe+/+ mice (7.1+/-0.2 mg/g), suggesting that the lack of both NPRA and apoE synergistically enhances cardiac hypertrophy.These data provide evidence that NPR1 is an atherosclerosis susceptibility locus and represents a potential link between atherosclerosis and cardiac hypertrophy. Our results also suggest roles for Npr1 as well as Apoe in regulation of hypertrophic cell growth.

  View details for DOI 10.1161/01.ATV.0000071702.45741.2E

  View details for Web of Science ID 000183527900025

  View details for PubMedID 12702516

• Common variations in noncoding regions of the human natriuretic peptide receptor A gene have quantitative effects HUMAN GENETICS Knowles, J. W., Erickson, L. M., Guy, V. K., Sigel, C. S., Wilder, J. C., Maeda, N. 2003; 112 (1): 62-70

  Abstract

  Genetic susceptibility to common conditions, such as essential hypertension and cardiac hypertrophy, is probably determined by various combinations of small quantitative changes in the expression of many genes. NPR1, coding for natriuretic peptide receptor A (NPRA), is a potential candidate, because NPRA mediates natriuretic, diuretic, and vasorelaxing actions of the nariuretic peptides, and because genetically determined quantitative changes in the expression of this gene affect blood pressure and heart weight in a dose-dependent manner in mice. To determine whether there are common quantitative variants in human NPR1, we have sequenced the entire human NPR1 gene and identified 10 polymorphic sites in its non-coding sequence by using DNA from 34 unrelated human individuals. Five of the sites are single nucleotide polymorphisms; the remaining five are length polymorphisms, including a highly variable complex dinucleotide repeat in intron 19. There are three common haplotypes 5' to this dinucleotide repeat and three 3' to it, but the 5' haplotypes and 3' haplotypes appear to be randomly associated. Transient expression analysis in cultured cells of reporter plasmids with the proximal promoter sequences of NPR1 and its 3' untranslated regions showed that these polymorphisms have functional effects. We conclude that common NPR1 alleles can alter expression of the gene as much as two-fold and could therefore significantly affect genetic risks for essential hypertension and cardiac hypertrophy in humans.

  View details for DOI 10.1007/s00439-002-0834-z

  View details for Web of Science ID 000180552400010

  View details for PubMedID 12483301

• Ventricular expression of natriuretic peptides in Npr1(-/-) mice with cardiac hypertrophy and fibrosis AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Ellmers, L. J., Knowles, J. W., Kim, H. S., Smithies, O., Maeda, N., Cameron, V. A. 2002; 283 (2): H707-H714

  Abstract

  Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones that regulate blood pressure and volume, and exert their biological actions via the natriuretic peptide receptor-A gene (Npr1). Mice lacking Npr1 (Npr(-/-)) have marked cardiac hypertrophy and fibrosis disproportionate to their increased blood pressure. This study examined the relationships between ANP and BNP gene expression, immunoreactivity and fibrosis in cardiac tissue, circulating ANP levels, and ANP and BNP mRNA during embryogenesis in Npr1(-/-) mice. Disruption of the Npr1 signaling pathway resulted in augmented ANP and BNP gene and ANP protein expression in the cardiac ventricles, most pronounced for ANP mRNA in females [414 +/- 57 in Npr1(-/-) ng/mg and 124 +/- 25 ng/mg in wild-type (WT) by Taqman assay, P < 0.001]. This increased expression was highly correlated to the degree of cardiac hypertrophy and was localized to the left ventricle (LV) inner free wall and to areas of ventricular fibrosis. In contrast, plasma ANP was significantly greater than WT in male but not female Npr1(-/-) mice. Increased ANP and BNP gene expression was observed in Npr1(-/-) embryos from 16 days of gestation. Our study suggests that cardiac ventricular expression of ANP and BNP is more closely associated with local hypertrophy and fibrosis than either systemic blood pressure or circulating ANP levels.

  View details for DOI 10.1152/ajpheart.00677.2001

  View details for Web of Science ID 000176880500031

  View details for PubMedID 12124219

• Interactions between endothelial nitric oxide synthase and sex hormones in vascular protection in mice JOURNAL OF CLINICAL INVESTIGATION Hodgin, J. B., Knowles, J. W., Kim, H. S., Smithies, O., Maeda, N. 2002; 109 (4): 541-548

  Abstract

  The vasculoprotective effects of sex hormones, particularly estrogens, have been attributed to their ability to increase the bioavailability of nitric oxide through activation of endothelial nitric oxide synthase (eNOS). To dissect the relative contribution in vivo of eNOS, sex hormones, and their interaction in two complex vascular phenotypes, hypertension and atherosclerosis, we used mice doubly deficient in eNOS and apoE (nnee) or lacking only apoE (NNee). Females and males were gonadectomized at 1 month of age and implanted either with control pellets or pellets releasing 17beta-estradiol (E2). Hormonally intact nnee mice have elevated blood pressure (BP) and increased atherosclerosis compared with NNee mice, but on removal of gonads, BP and atherosclerosis decreased significantly in nnee mice but not in NNee mice. Three months of treatment with exogenous E2 dramatically reduced atherosclerosis and significantly lowered BP in both NNee and nnee mice compared with animals treated with control pellets. Thus exogenous E2 has strong BP-lowering and atheroprotective effects in apoE-deficient mice, but eNOS is not essential for either effect. Endogenous sex hormones, on the other hand, cause significant damage to the vasculature in the absence of eNOS, but these effects are overridden by interactions between eNOS and sex hormones.

  View details for DOI 10.1172/JC1200214066

  View details for Web of Science ID 000173965900016

  View details for PubMedID 11854327

• Evidence for a novel natriuretic peptide receptor that prefers brain natriuretic peptide over atrial natriuretic peptide BIOCHEMICAL JOURNAL Goy, M. F., Oliver, P. M., Purdy, K. E., Knowles, J. W., Fox, J. E., Mohler, P. J., Qian, X., Smithies, O., Maeda, N. 2001; 358: 379-387

  Abstract

  Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) exert their physiological actions by binding to natriuretic peptide receptor A (NPRA), a receptor guanylate cyclase (rGC) that synthesizes cGMP in response to both ligands. The family of rGCs is rapidly expanding, and it is plausible that there might be additional, as yet undiscovered, rGCs whose function is to provide alternative signalling pathways for one or both of these peptides, particularly given the low affinity of NPRA for BNP. We have investigated this hypothesis, using a genetically modified (knockout) mouse in which the gene encoding NPRA has been disrupted. Enzyme assays and NPRA-specific Western blots performed on tissues from wild-type mice demonstrate that ANP-activated cGMP synthesis provides a good index of NPRA protein expression, which ranges from maximal in adrenal gland, lung, kidney, and testis to minimal in heart and colon. In contrast, immunoreactive NPRA is not detectable in tissues isolated from NPRA knockout animals and ANP- and BNP-stimulatable GC activities are markedly reduced in all mutant tissues. However, testis and adrenal gland retain statistically significant, high-affinity responses to BNP. This residual response to BNP cannot be accounted for by natriuretic peptide receptor B, or any other known mammalian rGC, suggesting the presence of a novel receptor in these tissues that prefers BNP over ANP.

  View details for Web of Science ID 000170877900012

  View details for PubMedID 11513736

• Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice JOURNAL OF CLINICAL INVESTIGATION Knowles, J. W., Esposito, G., Mao, L., Hagaman, J. R., Fox, J. E., Smithies, O., Rockman, H. A., Maeda, N. 2001; 107 (8): 975-984

  Abstract

  Mice lacking natriuretic peptide receptor A (NPRA) have marked cardiac hypertrophy and chamber dilatation disproportionate to their increased blood pressure (BP), suggesting, in support of previous in vitro data, that the NPRA system moderates the cardiac response to hypertrophic stimuli. Here, we have followed the changes in cardiac function in response to altered mechanical load on the heart of NPRA-null mice (Npr1-/-). Chronic treatment with either enalapril, furosemide, hydralazine, or losartan were all effective in reducing and maintaining BP at normal levels without affecting heart weight/body weight. In the reverse direction, we used transverse aortic constriction (TAC) to induce pressure overload. In the Npr1-/- mice, TAC resulted in a 15-fold increase in atrial natriuretic peptide (ANP) expression, a 55% increase in left ventricular weight/body weight (LV/BW), dilatation of the LV, and significant decline in cardiac function. In contrast, banded Npr1+/+ mice showed only a threefold increase in ANP expression, an 11% increase in LV/BW, a 0.2 mm decrease in LV end diastolic dimension, and no change in fractional shortening. The activation of mitogen-activated protein kinases that occurs in response to TAC did not differ in the Npr1+/+ and Npr1-/- mice. Taken together, these results suggest that the NPRA system has direct antihypertrophic actions in the heart, independent of its role in BP control.

  View details for Web of Science ID 000168152000009

  View details for PubMedID 11306601

• Genetic modifiers of atherosclerosis in mice ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Knowles, J. W., Maeda, N. 2000; 20 (11): 2336-2345

  Abstract

  Atherosclerosis is a complex, multifactorial disease with both genetic and environmental determinants. Experimental investigation of the effects of these determinants on the development and progression of atherosclerosis has been greatly facilitated by the use of targeted mouse models of the disease, particularly those resulting from the absence of functional genes for apolipoprotein E or the low density lipoprotein receptor (LDLR). This review focuses on the influence on atherosclerosis of combining apoE or LDLR deficiencies with factors affecting atherogenesis, including (1) inflammatory processes, (2) glucose metabolism, (3) blood pressure, and (4) coagulation and fibrinolysis. We also discuss the general problem of using the mouse to test the effects on atherogenesis of human polymorphic variations and future ways of enhancing the usefulness of these mouse models.

  View details for Web of Science ID 000165306600002

  View details for PubMedID 11073835

• Enhanced atherosclerosis and kidney dysfunction in eNOS(-)/(-)Apo(-)/(-) mice are ameliorated by enalapril treatment JOURNAL OF CLINICAL INVESTIGATION Knowles, J. W., Reddick, R. L., Jennette, J. C., Shesely, E. G., Smithies, O., Maeda, N. 2000; 105 (4): 451-458

  Abstract

  Hypertension and atherosclerosis are each important causes of morbidity and mortality in the developed world. We have investigated the interaction between these conditions by breeding mice that are atherosclerotic due to lack of apolipoprotein (apo) E with mice that are hypertensive due to lack of endothelial nitric oxide synthase (eNOS). The doubly deficient mice (nnee) have higher blood pressure (BP) and increased atherosclerotic lesion size but no change in plasma lipoprotein profiles compared with normotensive but atherosclerotic (NNee) mice. The nnee mice also develop kidney damage, evidenced by increased plasma creatinine, decreased kidney weight/body weight ratio, and glomerular lipid deposition and calcification. Enalapril treatment abolishes the deleterious effects of eNOS deficiency on BP, atherosclerosis, and kidney dysfunction in nnee mice. In striking contrast, a genetic lack of inducible NOS, which does not affect BP, has no effect on the development of atherosclerotic lesions in Apoe(-/-) mice. We also observed a positive relationship between BP and size of atherosclerotic lesions These results suggest that the atherogenic effects of eNOS deficiency can be partially explained by an increase in BP and reemphasize the importance of controlling hypertension in preventing atherosclerosis.

  View details for Web of Science ID 000085446700008

  View details for PubMedID 10683374

• Low salt intake down-regulates the guanylin signaling pathway in rat distal colon GASTROENTEROLOGY Li, Z. P., Knowles, J. W., Goyeau, D., Prabhakar, S., Short, D. B., Perkins, A. G., Goy, M. F. 1996; 111 (6): 1714-1721

  Abstract

  Guanylin, an endogenous gastrointestinal peptide, causes the translocation of NaCl from interstitial fluid to the intestinal lumen. The aim of this study was to examine whether changes in dietary salt intake lead to compensatory changes in expression of the guanylin signaling pathway.Rats received low-, normal-, or high-sodium diets for 1 week. Colonic guanylin expression was evaluated by Western and Northern blotting, rates of guanylin secretion by measuring biologically active guanylin released into the medium from colon explants, and expression of the guanylin receptor (C-type guanylate cyclase) by Northern blotting and bioassay.By every criterion, the low-salt diet reduced expression of guanylin to 30%-40% of the level found in control animals. Guanylin receptor expression was also decreased, although less dramatically and with a lower statistical significance. For both guanylin and guanylin receptor, the high-salt diet had no significant effect on expression.The data support the hypothesis that the guanylin pathway is down-regulated as an adaptive response to salt restriction.

  View details for Web of Science ID A1996VW29200039

  View details for PubMedID 8942754