Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:69

Article

Webb, Thomas R.^1,2  Erdmann, Jeanette^3,4,5  Stirrups, Kathleen E.^6,7  Stitziel, Nathan O.^8,9,10  Masca, Nicholas G. D.^1,2  Jansen, Henning^11,12  Kanoni, Stavroula⁶  Nelson, Christopher P.^1,2  Ferrario, Paola G.^4,13  Koenig, Inke R.^4,13  Eicher, John D.¹⁴  Johnson, Andrew D.¹⁴  Hamby, Stephen E.^1,2  Betsholtz, Christer^15,16  Ruusalepp, Arno^17,18,19  Franzen, Oscar^19,20  Schadt, Eric E.²⁰  Bjoerkegren, Johan L. M.^16,17,19,20  Weeke, Peter E.^21,22  Auer, Paul L.²³  Schick, Ursula M.^24,25  Lu, Yingchang^25,26  Zhang, He²⁷  Dube, Marie-Pierre^28,29  Goel, Anuj^30,31  Farrall, Martin^30,31  Peloso, Gina M.^32,33,34,35  Won, Hong-Hee^{32,33,34,35,36}  Do, Ron^26,37,38,39  van Iperen, Erik⁴⁰  Kruppa, Jochen⁴¹  Mahajan, Anubha³¹  Scott, Robert A.⁴²  Willenborg, Christina³  Braund, Peter S.^1,2  van Capelleveen, Julian C.⁴³  Doney, Alex S. F.⁴⁴  Donnelly, Louise A.⁴⁴  Asselta, Rosanna^45,46  Merlini, Pier A.⁴⁷  Duga, Stefano^45,46  Marziliano, Nicola⁴⁸  Denny, Josh C.^21,49  Shaffer, Christian²¹  El-Mokhtari, Nour Eddine⁵⁰  Franke, Andre⁵¹  Heilmann, Stefanie^52,53  Hengstenberg, Christian^10,11  Hoffmann, Per^52,53,54  Holmen, Oddgeir L.^55,56  Hveem, Kristian^55,57  Jansson, Jan-Hakan⁵⁸  Joeckel, Karl-Heinz⁵⁹  Kessler, Thorsten^11,12  Kriebel, Jennifer^60,61,62  Laugwitz, Karl L.^12,63  Marouli, Eirini⁶  Martinelli, Nicola⁶⁴  McCarthy, Mark I.^31,65,66  Van Zuydam, Natalie R.⁶⁵  Meisinger, Christa⁶¹  Esko, Tonu^67,68,69,70  Mihailov, Evelin⁶⁷  Escher, Stefan A.⁷¹  Alver, Maris^67,72  Moebus, Susanne⁵⁹  Morris, Andrew D.⁷³  Virtamo, Jarma⁷⁴  Nikpay, Majid⁷⁵  Olivieri, Oliviero⁶⁴  Provost, Sylvie²⁹  AlQarawi, Alaa⁷⁶  Robertson, Neil R.^31,65  Akinsansya, Karen O.⁷⁷  Reilly, Dermot F.⁷⁷  Vogt, Thomas F.⁷⁷  Yin, Wu⁷⁷  Asselbergs, Folkert W.^78,79,80  Kooperberg, Charles²⁴  Jackson, Rebecca D.⁸¹  Stahl, Eli⁸²  Mueller-Nurasyid, Martina^12,83,84  Strauch, Konstantin^83,85  Varga, Tibor V.⁷¹  Waldenberger, Melanie^60,61  Zeng, Lingyao^11,12  Chowdhury, Rajiv⁸⁶  Salomaa, Veikko⁷⁴  Ford, Ian⁸⁷  Jukema, J. Wouter⁸⁸  Amouyel, Philippe⁸⁹  Nordestgaard, Borge G.^90,91  Ferrieres, Jean⁹²  Saleheen, Danish^93,94  Sattar, Naveed⁹⁵  Surendran, Praveen⁸⁵  Wagner, Aline⁹⁶  Young, Robin⁸⁶  Howson, Joanna M. M.⁸⁶  Butterworth, Adam S.^86,97  Danesh, John^86,97,98  Ardissino, Diego⁹⁹  Bottinger, Erwin P.²⁵  Erbel, Raimund⁵⁹  Franks, Paul W.^71,100,101  Girelli, Domenico⁶⁴  Hall, Alistair S.¹⁰²  Hovingh, G. Kees⁴³  Kastrati, Adnan¹¹  Lieb, Wolfgang¹⁰³  Meitinger, Thomas^12,104,105  Kraus, William E.^106,107  Shah, Svati H.^106,107  McPherson, Ruth⁷⁵  Orho-Melander, Marju¹⁰⁸  Melander, Olle¹⁰⁹  Metspalu, Andres^67,72  Palmer, Colin N. A.⁴⁴  Peters, Annette^12,61  Rader, Daniel J.^110,111  Reilly, Muredach P.^112,113  Loos, Ruth J. F.^25,26,114  Reiner, Alex P.^24,115  Roden, Dan M.^21,116  Tardif, Jean-Claude^28,29  Thompson, John R.^2,117  Wareham, Nicholas J.⁴²  Watkins, Hugh^30,31  Willer, Cristen J.^28,118,119  Samani, Nilesh J.^1,2  Schunkert, Heribert^11,12  Deloukas, Panos^6,76  Kathiresan, Sekar^32,33,34,120 

[1] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England

[2] Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England

[3] Univ Lubeck, Inst Cardiogenet, Lubeck, Germany

[4] DZHK German Res Ctr Cardiovasc Res, Lubeck, Germany

[5] Univ Heart Ctr Luebeck, Lubeck, Germany

[6] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England

[7] Univ Cambridge, Dept Haematol, Cambridge, England

[8] Washington Univ, Sch Med, Dept Med, Div Cardiovasc, St Louis, MO 63110 USA

[9] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA

[10] Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO USA

[11] Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany

[12] DZHK, Munich, Germany

[13] Univ Lubeck, Inst Med Biometrie & Stat, Lubeck, Germany

[14] NHLBI, Ctr Populat Studies, Framingham Heart Study, Framingham, MA USA

[15] Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden

[16] Karolinska Inst, Vasc Biol Unit, Dept Med Biochem & Biophys, Stockholm, Sweden

[17] Univ Tartu, Inst Biomed & Translat Med, Dept Physiol, Tartu, Estonia

[18] Tartu Univ Hosp, Dept Cardiac Surg, Tartu, Estonia

[19] Clin Gene Networks AB, Stockholm, Sweden

[20] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA

[21] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA

[22] Copenhagen Univ Hosp, Rigshosp, Dept Cardiol, Lab Mol Cardiol, Copenhagen, Denmark

[23] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA

[24] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA

[25] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA

[26] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA

[27] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA

[28] Univ Montreal, Fac Med, Dept Med, Montreal, PQ, Canada

[29] Montreal Heart Inst, Montreal, PQ, Canada

[30] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England

[31] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[32] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[33] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA

[34] Harvard Med Sch, Dept Med, Boston, MA USA

[35] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[36] Sungkyunkwan Univ, Samsung Med Ctr, Samsung Adv Inst Hlth Sci & Technol, Seoul, South Korea

[37] Icahn Sch Med Mt Sinai, Ctr Stat Genet, Dept Genet & Genom Sci, New York, NY 10029 USA

[38] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA

[39] Icahn Sch Med Mt Sinai, Zena & Michael Weiner Cardiovasc Inst, New York, NY 10029 USA

[40] Acad Med Ctr, Dept Biostat, Amsterdam, Netherlands

[41] Univ Vet Med Hannover, Inst Anim Breeding & Genet, Hannover, Germany

[42] Addenbrookes Hosp, MRC Epidemiol Unit, Inst Metab Sci, Cambridge, England

[43] Acad Med Ctr, Dept Vasc Med, Amsterdam, Netherlands

[44] Univ Dundee, Hosp & Med Sch, Med Res Inst, Dundee, Scotland

[45] Humanitas Univ, Dept Biomed Sci, Milan, Italy

[46] Humanitas Clin & Res Ctr, Milan, Italy

[47] Osped Niguarda Ca Granda, Milan, Italy

[48] Azienda Sanit Locale 3 San Francesco, Nuoro, Italy

[49] Vanderbilt Univ, Med Ctr, Dept Biomed informat, Nashville, TN USA

[50] Imland Klin Rendsburg, Klin Kardiol Pneumol & Innere Med, Rendsburg, Germany

[51] Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[52] Univ Bonn, Inst Human Genet, Bonn, Germany

[53] Univ Bonn, Dept Genom, Life & Brain Ctr, Bonn, Germany

[54] Univ Basel, Dept Biomed, Div Med Genet, Basel, Switzerland

[55] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, Levanger, Norway

[56] Trondheim Reg & Univ Hosp, St Olav Hosp, Trondheim, Norway

[57] Nord Trondelag Hlth Trust, Levanger Hosp, Dept Med, Levanger, Norway

[58] Umea Univ, Res Unit Skelleftea, Dept Publ Hlth & Clin Med, Umea, Sweden

[59] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany

[60] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany

[61] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany

[62] German Ctr Diabet Res, Neuherberg, Germany

[63] Tech Univ Munich, Klinikum Rechts Isar, Inst Med Klin & Poliklin, Munich, Germany

[64] Univ Verona, Sect Internal Med, Dept Med, Verona, Italy

[65] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[66] Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Old Rd Headington, Oxford, England

[67] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia

[68] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA

[69] Harvard Med Sch, Dept Genet, Boston, MA USA

[70] Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA USA

[71] Lund Univ, Dept Clin Sci, Ctr Diabet, Genet & Mol Epidemiol Unit, Malmo, Sweden

[72] Inst Mol & Cell Biol, Tartu, Estonia

[73] Univ Edinburgh, Sch Med, Sch Mol Genet & Populat Hlth Sci, Teviot Pl, Edinburgh, Midlothian, Scotland

[74] Natl Inst Hlth & Welf THL, Helsinki, Finland

[75] Univ Ottawa, Inst Heart, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada

[76] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence R, Jeddah, Saudi Arabia

[77] Merck Sharp & Dohme Ltd, Rahway, NJ USA

[78] UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands

[79] ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands

[80] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England

[81] Ohio State Univ, Dept Med, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA

[82] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA

[83] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, Neuherberg, Germany

[84] Ludwig Maximilians Univ Munchen, Dept Med 1, Univ Hosp Grosshadern, Munich, Germany

[85] Ludwig Maximilians Univ Munchen, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany

[86] Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge, England

[87] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland

[88] Leiden Univ, Med Ctr, Leiden & Interuniv Cardiol Inst Netherlands, Dept Cardiol, Utrecht, Netherlands

[89] Univ Lille, INSERM, CHU Lille, Inst Pasteur Lille,RID AGE U1167, Lille, France

[90] Copenhagen Univ Hosp & Med Sci, Copenhagen, Denmark

[91] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark

[92] Toulouse Univ, Sch Med, Toulouse, France

[93] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA

[94] Ctr Noncommunicable Dis, Karachi, Pakistan

[95] Univ Glasgow, Glasgow Cardiovasc Res Ctr, British Heart Fdn, Glasgow, Lanark, Scotland

[96] Univ Strasbourg, Dept Epidemiol & Publ Hlth, Strasbourg, France

[97] Univ Cambridge, Res Unit Donor Hlth & Genom, Natl Inst Hlth Res Blood & Transplant, Cambridge, England

[98] Wellcome Trust Sanger Inst, Cambridge, England

[99] Parma Univ Hosp, Parma, Italy

[100] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA

[101] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden

[102] Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Leeds, W Yorkshire, England

[103] Christian Albrechts Univ Kiel, Inst Epidemiol & Biobank Popgen, Kiel, Germany

[104] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, Neuherberg, Germany

[105] Tech Univ Munich, Inst Human Genet, Munich, Germany

[106] Duke Univ, Duke Mol Physiol Inst, Durham, NC USA

[107] Duke Univ, Dept Med, Div Cardiol, Durham, NC USA

[108] Lund Univ, Clin Res Ctr, Dept Clin Sci Malmo, Malmo, Sweden

[109] Lund Univ, Malmo Univ Hosp, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden

[110] Univ Penn, Dept Genet, Cardiovasc Inst, Philadelphia, PA 19104 USA

[111] Univ Penn, Inst Translat Med & Therapeut, Perelman Sch Med, Philadelphia, PA 19104 USA

[112] Columbia Univ, Dept Med, Div Cardiol, New York, NY USA

[113] Columbia Univ, Irving Inst Clin & Translat Res, New York, NY USA

[114] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA

[115] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[116] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

[117] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England

[118] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA

[119] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA

[120] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA

关键词: cholesteryl ester transfer protein;    expression quantitative trait loci;    genetics;    genome-wide association;    single nucleotide polymorphism;   

DOI  :  10.1016/j.jacc.2016.11.056

来源: Elsevier

【 摘 要 】

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 x 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. (C) 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

【 授权许可】

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