Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

被引：237

作者：

Howson, Joanna M. M. ^{[1
]}

Zhao, Wei ^{[2
]}

Barnes, Daniel R. ^{[1
]}

Ho, Weang-Kee ^{[1
,3
]}

Young, Robin ^{[1
,4
]}

Paul, Dirk S. ^{[1
]}

Waite, Lindsay L. ^{[5
]}

Freitag, Daniel F. ^{[1
]}

Fauman, Eric B. ^{[6
]}

Salfati, Elias L. ^{[7
,8
]}

Sun, Benjamin B. ^{[1
]}

Eicher, John D. ^{[9
,10
,11
]}

Johnson, Andrew D. ^{[9
,10
,11
]}

Sheu, Wayne H. H. ^{[12
,13
,14
]}

Nielsen, Sune F. ^{[15
]}

Lin, Wei-Yu ^{[1
,16
]}

Surendran, Praveen ^{[1
]}

Malarstig, Anders ^{[17
]}

Wilk, Jemma B. ^{[18
]}

Tybjaerg-Hansen, Anne ^{[19
,20
]}

Rasmussen, Katrine L. ^{[15
]}

Kamstrup, Pia R. ^{[15
]}

Deloukas, Panos ^{[21
,22
]}

Erdmann, Jeanette ^{[23
,24
,25
]}

Kathiresan, Sekar ^{[26
,27
]}

Samani, Nilesh J. ^{[28
,29
]}

Schunkert, Heribert ^{[30
,31
]}

Watkins, Hugh ^{[32
,33
]}

Do, Ron ^{[34
]}

Rader, Daniel J. ^{[35
,36
,37
]}

Johnson, Julie A. ^{[38
,42
]}

Hazen, Stanley L. ^{[39
]}

Quyyumi, Arshed A. ^{[40
]}

Spertus, John A. ^{[41
]}

Pepine, Carl J. ^{[43
]}

Franceschini, Nora ^{[44
]}

Justice, Anne ^{[44
]}

Reiner, Alex P. ^{[45
]}

Buyske, Steven ^{[46
]}

Hindorff, Lucia A. ^{[47
]}

Carty, Cara L. ^{[48
]}

North, Kari E. ^{[44
,49
]}

Kooperberg, Charles ^{[48
]}

Boerwinkle, Eric ^{[50
,51
]}

Young, Kristin ^{[44
]}

Graff, Mariaelisa ^{[44
]}

Peters, Ulrike ^{[48
]}

Absher, Devin ^{[5
]}

Hsiung, Chao A. ^{[52
]}

Lee, Wen-Jane ^{[53
]}

机构：

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

[2] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA

[3] Univ Nottingham, Dept Appl Math, Malaysia Campus, Semenyih, Malaysia

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

[5] HudsonAlpha Inst Biotechnol, Huntsville, AL USA

[6] Pfizer Worldwide Res & Dev, Cambridge, MA USA

[7] Stanford Univ, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA

[8] Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA

[9] NHLBI, Populat Sci Branch, Bldg 10, Bethesda, MD 20892 USA

[10] NHLBI, Framingham, MA USA

[11] Boston Univ Framingham Heart Study, Framingham, MA USA

[12] Taichung Vet Gen Hosp, Dept Internal Med, Div Endocrine & Metab, Taichung, Taiwan

[13] Natl Yang Ming Univ, Sch Med, Taipei, Taiwan

[14] Natl Def Med Ctr, Coll Med, Taipei, Taiwan

[15] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Copenhagen, Denmark

[16] Newcastle Univ, Northern Inst Canc Res, Newcastle Upon Tyne, Tyne & Wear, England

[17] Pfizer Worldwide Res & Dev, Stockholm, Sweden

[18] Pfizer Worldwide Res & Dev, Human Genet, Cambridge, MA USA

[19] Copenhagen Univ Hosp, Rigshosp, Dept Clin Biochem, Copenhagen, Denmark

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

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

[22] Queen Mary Univ London, Ctr Genom Hlth, London, England

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

[24] DZHK German Res Ctr Cardiovascr Res, Partner Site Hamburg Lubeck Kiel, Lubeck, Germany

[25] Univ Heart Ctr Lubeck, Lubeck, Germany

[26] Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA

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

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

[29] Glenfield Hosp, NIHR Leicester Biomed Res Ctr, Leicester, Leics, England

[30] Tech Univ Munich, Deutsches Herzzentrum Munchen, Munich, Germany

[31] DZHK German Ctr Cardiovascr Res, Partner Site Munich Heart Alliance, Munich, Germany

[32] Univ Oxford, Radcliffe Dept Med, Oxford, England

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

[34] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, Dept Genet & Genom Sci, New York, NY 10029 USA

[35] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA

[36] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA

[37] Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA

[38] Univ Florida, Coll Pharm, Gainesville, FL USA

[39] Lerner Res Inst, Dept Cellular & Mol Med, Cleveland, OH USA

[40] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA

[41] St Lukes Mid Amer Heart Inst, Kansas City, MO USA

[42] Univ Missouri, Dept Biomed & Hlth Informat, Kansas City, MO 64110 USA

[43] Univ Florida, Coll Med, Gainesville, FL USA

[44] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA

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

[46] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ USA

[47] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA

[48] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA

[49] Carolina Ctr Genome Sci, Chapel Hill, NC USA

[50] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA

来源：

NATURE GENETICS | 2017年 / 49卷 / 07期

基金：

英国医学研究理事会; 欧洲研究理事会;

关键词：

GENE-EXPRESSION; PROTEIN-C; ASSOCIATION ANALYSIS; CHROMATIN STATES; PLASMA-LEVELS; TRANS-EQTLS; METAANALYSIS; HAPTOGLOBIN; VARIANT; HEART;

D O I：

10.1038/ng.3874

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide1,2. Although 58 genomic regions have been associated with CAD thus far3-9, most of the heritability is unexplained9, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed metaanalysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 x 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p. Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with celltype- specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

引用

页码：1113 / +

页数：9

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