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Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease.
Webb, Thomas R; Erdmann, Jeanette; Stirrups, Kathleen E; Stitziel, Nathan O; Masca, Nicholas G D; Jansen, Henning; Kanoni, Stavroula; Nelson, Christopher P; Ferrario, Paola G; König, Inke R; Eicher, John D; Johnson, Andrew D; Hamby, Stephen E; Betsholtz, Christer; Ruusalepp, Arno; Franzén, Oscar; Schadt, Eric E; Björkegren, Johan L M; Weeke, Peter E; Auer, Paul L; Schick, Ursula M; Lu, Yingchang; Zhang, He; Dube, Marie-Pierre; Goel, Anuj; Farrall, Martin; Peloso, Gina M; Won, Hong-Hee; Do, Ron; van Iperen, Erik; Kruppa, Jochen; Mahajan, Anubha; Scott, Robert A; Willenborg, Christina; Braund, Peter S; van Capelleveen, Julian C; Doney, Alex S F; Donnelly, Louise A; Asselta, Rosanna; Merlini, Pier A; Duga, Stefano; Marziliano, Nicola; Denny, Josh C; Shaffer, Christian; El-Mokhtari, Nour Eddine; Franke, Andre; Heilmann, Stefanie; Hengstenberg, Christian; Hoffmann, Per; Holmen, Oddgeir L.
Afiliação
  • Webb TR; Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
  • Erdmann J; Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany; DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany; University Heart Center Luebeck, Lübeck, Germany.
  • Stirrups KE; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom.
  • Stitziel NO; Cardiovascular Division, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri; Department of Genetics, Washington University School of Medicine, Saint Louis, Missouri; McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, Missouri.
  • Masca NG; Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
  • Jansen H; Deutsches Herzzentrum München, Technische Universität München, München, Germany; DZHK, Partner Site Munich Heart Alliance, Munich, Germany.
  • Kanoni S; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
  • Nelson CP; Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
  • Ferrario PG; DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany; Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany.
  • König IR; DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany; Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany.
  • Eicher JD; Center for Population Studies, National Heart, Lung, and Blood Institute, The Framingham Heart Study, Framingham, Massachusetts.
  • Johnson AD; Center for Population Studies, National Heart, Lung, and Blood Institute, The Framingham Heart Study, Framingham, Massachusetts.
  • Hamby SE; Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
  • Betsholtz C; Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden; Department of Medical Biochemistry and Biophysics, Vascular Biology Unit, Karolinska Institutet, Stockholm, Sweden.
  • Ruusalepp A; Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Tartu, Estonia; Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia; Clinical Gene Networks AB, Stockholm, Sweden.
  • Franzén O; Clinical Gene Networks AB, Stockholm, Sweden; Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
  • Schadt EE; Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
  • Björkegren JL; Department of Medical Biochemistry and Biophysics, Vascular Biology Unit, Karolinska Institutet, Stockholm, Sweden; Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Tartu, Estonia; Clinical Gene Networks AB, Stockholm, Sweden; Department of Genetics &
  • Weeke PE; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
  • Auer PL; School of Public Heath, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin.
  • Schick UM; Fred Hutchinson Cancer Research Center, Seattle, Washington; The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York.
  • Lu Y; The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York.
  • Zhang H; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan.
  • Dube MP; Université de Montréal, Faculté de médecine, Département de médecine, Montreal, Quebec, Canada; Montreal Heart Institute, Montreal, Quebec, Canada.
  • Goel A; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
  • Farrall M; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
  • Peloso GM; Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad In
  • Won HH; Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad In
  • Do R; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York; The Center for Statistical Genetics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; The Icahn Institute for Genomi
  • van Iperen E; Department of Biostatistics, Academic Medical Center, Amsterdam, the Netherlands.
  • Kruppa J; Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Hannover, Germany.
  • Mahajan A; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
  • Scott RA; MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom.
  • Willenborg C; Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.
  • Braund PS; Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
  • van Capelleveen JC; Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
  • Doney AS; Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Scotland, United Kingdom.
  • Donnelly LA; Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Scotland, United Kingdom.
  • Asselta R; Department of Biomedical Sciences, Humanitas University, Milan, Italy; Humanitas Clinical and Research Center, Milan, Italy.
  • Merlini PA; Niguarda Hospital, Milan, Italy.
  • Duga S; Department of Biomedical Sciences, Humanitas University, Milan, Italy; Humanitas Clinical and Research Center, Milan, Italy.
  • Marziliano N; Azienda Sanitaria Locale 3 San Francesco, Nuoro, Italy 3, Nuoro, Italy.
  • Denny JC; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Biomedical informatics, Vanderbilt University Medical Center, Nashville, Tennessee.
  • Shaffer C; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
  • El-Mokhtari NE; Klinik für Kardiologie, Pneumologie und Innere Medizin, Imland Klinik Rendsburg, Rendsburg, Germany.
  • Franke A; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
  • Heilmann S; Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
  • Hengstenberg C; McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, Missouri; Deutsches Herzzentrum München, Technische Universität München, München, Germany.
  • Hoffmann P; Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany; Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Holmen OL; HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway; St. Olav Hospital, Trondheim University Hospital, Trondheim, Norway.
J Am Coll Cardiol ; 69(7): 823-836, 2017 Feb 21.
Article em En | MEDLINE | ID: mdl-28209224
ABSTRACT

BACKGROUND:

Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits.

OBJECTIVES:

This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci.

METHODS:

In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs.

RESULTS:

We identified 6 new loci associated with CAD at genome-wide

significance:

on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10-4 with a range of other diseases/traits.

CONCLUSIONS:

We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença da Artéria Coronariana / Loci Gênicos / Pleiotropia Genética Tipo de estudo: Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male Idioma: En Revista: J Am Coll Cardiol Ano de publicação: 2017 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença da Artéria Coronariana / Loci Gênicos / Pleiotropia Genética Tipo de estudo: Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male Idioma: En Revista: J Am Coll Cardiol Ano de publicação: 2017 Tipo de documento: Article