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

被引：189

作者：

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, Stavroula ^{[6
]}

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, He ^{[27
]}

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, Erik ^{[40
]}

Kruppa, Jochen ^{[41
]}

Mahajan, Anubha ^{[31
]}

Scott, Robert A. ^{[42
]}

Willenborg, Christina ^{[3
]}

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, Nicola ^{[48
]}

Denny, Josh C. ^{[21
,49
]}

Shaffer, Christian ^{[21
]}

El-Mokhtari, Nour Eddine ^{[50
]}

Franke, Andre ^{[51
]}

Heilmann, Stefanie ^{[52
,53
]}

Hengstenberg, Christian ^{[10
,11
]}

Hoffmann, Per ^{[52
,53
,54
]}

Holmen, Oddgeir L. ^{[55
,56
]}

机构：

[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

来源：

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY | 2017年 / 69卷 / 07期

关键词：

cholesteryl ester transfer protein; expression quantitative trait loci; genetics; genome-wide association; single nucleotide polymorphism; GENOME-WIDE ASSOCIATION; ABDOMINAL AORTIC-ANEURYSM; SCAVENGER RECEPTOR; PHOSPHOLIPASE A(2); CETP MASS; SR-BI; METAANALYSIS; VARIANT; RISK; SUSCEPTIBILITY;

D O I：

10.1016/j.jacc.2016.11.056

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

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.

引用

页码：823 / 836

页数：14

共 44 条

[11] Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk [J].

Ehret, Georg B. ;

Munroe, Patricia B. ;

Rice, Kenneth M. ;

Bochud, Murielle ;

Johnson, Andrew D. ;

Chasman, Daniel I. ;

Smith, Albert V. ;

Tobin, Martin D. ;

Verwoert, Germaine C. ;

Hwang, Shih-Jen ;

Pihur, Vasyl ;

Vollenweider, Peter ;

O'Reilly, Paul F. ;

Amin, Najaf ;

Bragg-Gresham, Jennifer L. ;

Teumer, Alexander ;

Glazer, Nicole L. ;

Launer, Lenore ;

Zhao, Jing Hua ;

Aulchenko, Yurii ;

Heath, Simon ;

Sober, Siim ;

Parsa, Afshin ;

Luan, Jian'an ;

Arora, Pankaj ;

Dehghan, Abbas ;

Zhang, Feng ;

Lucas, Gavin ;

Hicks, Andrew A. ;

Jackson, Anne U. ;

Peden, John F. ;

Tanaka, Toshiko ;

Wild, Sarah H. ;

Rudan, Igor ;

Igl, Wilmar ;

Milaneschi, Yuri ;

Parker, Alex N. ;

Fava, Cristiano ;

Chambers, John C. ;

Fox, Ervin R. ;

Kumari, Meena ;

Go, Min Jin ;

van der Harst, Pim ;

Kao, Wen Hong Linda ;

Sjogren, Marketa ;

Vinay, D. G. ;

Alexander, Myriam ;

Tabara, Yasuharu ;

Shaw-Hawkins, Sue ;

Whincup, Peter H. .

NATURE, 2011, 478 (7367) :103-109

[12] GRASP v2.0: an update on the Genome-Wide Repository of Associations between SNPs and phenotypes [J].

Eicher, John D. ;

Landowski, Christa ;

Stackhouse, Brian ;

Sloan, Arielle ;

Chen, Wenjie ;

Jensen, Nicole ;

Lien, Ju-Ping ;

Leslie, Richard ;

Johnson, Andrew D. .

NUCLEIC ACIDS RESEARCH, 2015, 43 (D1) :D799-D804

[13] Genetic and epigenetic fine mapping of causal autoimmune disease variants [J].

Farh, Kyle Kai-How ;

Marson, Alexander ;

Zhu, Jiang ;

Kleinewietfeld, Markus ;

Housley, William J. ;

Beik, Samantha ;

Shoresh, Noam ;

Whitton, Holly ;

Ryan, Russell J. H. ;

Shishkin, Alexander A. ;

Hatan, Meital ;

Carrasco-Alfonso, Marlene J. ;

Mayer, Dita ;

Luckey, C. John ;

Patsopoulos, Nikolaos A. ;

De Jager, Philip L. ;

Kuchroo, Vijay K. ;

Epstein, Charles B. ;

Daly, Mark J. ;

Hafler, David A. ;

Bernstein, Bradley E. .

NATURE, 2015, 518 (7539) :337-343

[14] The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm [J].

Helgadottir, Anna ;

Thorleifsson, Gudmar ;

Magnusson, Kristinn P. ;

Gretarsdottir, Solveig ;

Steinthorsdottir, Valgerdur ;

Manolescu, Andrei ;

Jones, Gregory T. ;

Rinkel, Gabriel J. E. ;

Blankensteijn, Jan D. ;

Ronkainen, Antti ;

Jaaskelainen, Juha E. ;

Kyo, Yoshiki ;

Lenk, Guy M. ;

Sakalihasan, Natzi ;

Kostulas, Konstantinos ;

Gottsater, Anders ;

Flex, Andrea ;

Stefansson, Hreinn ;

Hansen, Torben ;

Andersen, Gitte ;

Weinsheimer, Shantel ;

Borch-Johnsen, Knut ;

Jorgensen, Torben ;

Shah, Svati H. ;

Quyyumi, Arshed A. ;

Granger, Christopher B. ;

Reilly, Muredach P. ;

Austin, Harland ;

Levey, Allan I. ;

Vaccarino, Viola ;

Palsdottir, Ebba ;

Walters, G. Bragi ;

Jonsdottir, Thorbjorg ;

Snorradottir, Steinunn ;

Magnusdottir, Dana ;

Gudmundsson, Gudmundur ;

Ferrell, Robert E. ;

Sveinbjornsdottir, Sigurlaug ;

Hernesniemi, Juha ;

Niemela, Mika ;

Limet, Raymond ;

Andersen, Karl ;

Sigurdsson, Gunnar ;

Benediktsson, Rafn ;

Verhoeven, Eric L. G. ;

Teijink, Joep A. W. ;

Grobbee, Diederick E. ;

Rader, Daniel J. ;

Collier, David A. ;

Pedersen, Oluf .

NATURE GENETICS, 2008, 40 (02) :217-224

[15] Mendelian randomization of blood lipids for coronary heart disease [J].

Holmes, Michael V. ;

Asselbergs, Folkert W. ;

Palmer, Tom M. ;

Drenos, Fotios ;

Lanktree, Matthew B. ;

Nelson, Christopher P. ;

Dale, Caroline E. ;

Padmanabhan, Sandosh ;

Finan, Chris ;

Swerdlow, Daniel I. ;

Tragante, Vinicius ;

van Iperen, Erik P. A. ;

Sivapalaratnam, Suthesh ;

Shah, Sonia ;

Elbers, Clara C. ;

Shah, Tina ;

Engmann, Jorgen ;

Giambartolomei, Claudia ;

White, Jon ;

Zabaneh, Delilah ;

Sofat, Reecha ;

McLachlan, Stela ;

Doevendans, Pieter A. ;

Balmforth, Anthony J. ;

Hall, Alistair S. ;

North, Kari E. ;

Almoguera, Berta ;

Hoogeveen, Ron C. ;

Cushman, Mary ;

Fornage, Myriam ;

Patel, Sanjay R. ;

Redline, Susan ;

Siscovick, David S. ;

Tsai, Michael Y. ;

Karczewski, Konrad J. ;

Hofker, Marten H. ;

Verschuren, W. Monique ;

Bots, Michiel L. ;

van der Schouw, Yvonne T. ;

Melander, Olle ;

Dominiczak, Anna F. ;

Morris, Richard ;

Ben-Shlomo, Yoav ;

Price, Jackie ;

Kumari, Meena ;

Baumert, Jens ;

Peters, Annette ;

Thorand, Barbara ;

Koenig, Wolfgang ;

Gaunt, Tom R. .

EUROPEAN HEART JOURNAL, 2015, 36 (09) :539-+

[16] Mendelian randomization studies in coronary artery disease [J].

Jansen, Henning ;

Samani, Nilesh J. ;

Schunkert, Heribert .

EUROPEAN HEART JOURNAL, 2014, 35 (29) :1917-+

[17] SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap [J].

Johnson, Andrew D. ;

Handsaker, Robert E. ;

Pulit, Sara L. ;

Nizzari, Marcia M. ;

O'Donnell, Christopher J. ;

de Bakker, Paul I. W. .

BIOINFORMATICS, 2008, 24 (24) :2938-2939

[18] Haplotype analysis of the CETP gene:: not TaqIB, but the closely linked-629C→A polymorphism and a novel promoter variant are independently associated with CETP concentration [J].

Klerkx, AHEM ;

Tanck, MWT ;

Kastelein, JJP ;

Molhuizen, HOF ;

Jukema, JW ;

Zwinderman, AH ;

Kuivenhoven, JA .

HUMAN MOLECULAR GENETICS, 2003, 12 (02) :111-123

[19] Gene transfer and hepatic overexpression of the HDL receptor SR-BI reduces atherosclerosis in the cholesterol-fed LDL receptor-deficient mouse [J].

Kozarsky, KF ;

Donahee, MH ;

Glick, JM ;

Krieger, M ;

Rader, DJ .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2000, 20 (03) :721-727

[20] Meta-analysis and imputation refines the association of 15q25 with smoking quantity [J].

Liu, Jason Z. ;

Tozzi, Federica ;

Waterworth, Dawn M. ;

Pillai, Sreekumar G. ;

Muglia, Pierandrea ;

Middleton, Lefkos ;

Berrettini, Wade ;

Knouff, Christopher W. ;

Yuan, Xin ;

Waeber, Gerard ;

Vollenweider, Peter ;

Preisig, Martin ;

Wareham, Nicholas J. ;

Zhao, Jing Hua ;

Loos, Ruth J. F. ;

Barroso, Ines ;

Khaw, Kay-Tee ;

Grundy, Scott ;

Barter, Philip ;

Mahley, Robert ;

Kesaniemi, Antero ;

McPherson, Ruth ;

Vincent, John B. ;

Strauss, John ;

Kennedy, James L. ;

Farmer, Anne ;

McGuffin, Peter ;

Day, Richard ;

Matthews, Keith ;

Bakke, Per ;

Gulsvik, Amund ;

Lucae, Susanne ;

Ising, Marcus ;

Brueckl, Tanja ;

Horstmann, Sonja ;

Wichmann, H-Erich ;

Rawal, Rajesh ;

Dahmen, Norbert ;

Lamina, Claudia ;

Polasek, Ozren ;

Zgaga, Lina ;

Huffman, Jennifer ;

Campbell, Susan ;

Kooner, Jaspal ;

Chambers, John C. ;

Burnett, Mary Susan ;

Devaney, Joseph M. ;

Pichard, Augusto D. ;

Kent, Kenneth M. ;

Satler, Lowell .

NATURE GENETICS, 2010, 42 (05) :436-U75

← 1 2 3 4 5 →