Repeated replication and a prospective meta-analysis of the association between chromosome 9p21.3 and coronary artery disease

被引：302

作者：

Schunkert, Heribert ^{[1
]}

Goetz, Anika ^{[1
,2
]}

Braund, Peter ^{[3
]}

McGinnis, Ralph ^{[5
]}

Tregouet, David-Alexandre ^{[8
,9
]}

Mangino, Massimo ^{[3
]}

Linsel-Nitschke, Patrick ^{[1
]}

Cambien, Francois ^{[8
,9
]}

Hengstenberg, Christian ^{[10
]}

Stark, Klaus ^{[10
]}

Blankenberg, Stefan ^{[11
]}

Tiret, Laurence ^{[8
,9
]}

Ducimetiere, Pierre ^{[12
]}

Keniry, Andrew ^{[5
]}

Ghori, Mohammed J. R. ^{[5
]}

Schreiber, Stefan ^{[13
]}

El Mokhtari, Nour Eddine ^{[13
]}

Hall, Alistair S. ^{[14
]}

Dixon, Richard J. ^{[3
]}

Goodall, Alison H. ^{[3
]}

Liptau, Henrike ^{[1
]}

Pollard, Helen ^{[3
]}

Schwarz, Daniel F. ^{[2
]}

Hothorn, Ludwig A. ^{[15
]}

Wichmann, H. -Erich ^{[16
,17
]}

Koenig, Inke R. ^{[2
]}

Fischer, Marcus ^{[10
]}

Meisinger, Christa ^{[16
]}

Ouwehand, Willem ^{[6
,7
]}

Deloukas, Panos ^{[5
]}

Thompson, John R. ^{[4
]}

Erdmann, Jeanette ^{[1
]}

Ziegler, Andreas ^{[2
]}

Samani, Nilesh J. ^{[3
]}

机构：

[1] Univ Lubeck, Med Klin 2, Lubeck, Germany

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

[3] Univ Leicester, Dept Cardiovasc Sci, Glenfield Hosp, Clin Sci Wing, Leicester LE3 9QP, Leics, England

[4] Univ Leicester, Dept Hlth Sci & Genet, Glenfield Hosp, Clin Sci Wing, Leicester LE3 9QP, Leics, England

[5] Wellcome Trust Sanger Inst, Hinxton, England

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

[7] Cambridge Ctr, Natl Hlth Serv Blood & Transplant, Cambridge, England

[8] INSERM, Paris, France

[9] Univ Paris 06, Paris, France

[10] Univ Regensburg, Klin & Poliklin Innere Med 2, Regensburg, Germany

[11] Johannes Gutenberg Univ Mainz, Med Klin 2, Mainz, Germany

[12] Univ Paris Sud 9, INSERM, Unite 780, Villejuif, France

[13] UK SH, Inst Klin Mol Biol, Kiel, Germany

[14] Univ Leeds, Fac Med & Hlth, Leeds Inst Genet & Therapeut, C Net Grp, Leeds, W Yorkshire, England

[15] Leibniz Univ Hannover, Inst Biostat, Hannover, Germany

[16] Deutsches Forschungszentrum Umwelt & Gesundheit, Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany

[17] Univ Munich, Inst Med Informat & Biometry & Epidemiol, Munich, Germany

来源：

CIRCULATION | 2008年 / 117卷 / 13期

基金：

英国惠康基金;

关键词：

chromosomes; coronary disease; genetics; meta-analysis; myocardial infarction; risk factors;

D O I：

10.1161/CIRCULATIONAHA.107.730614

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background - Recently, genome-wide association studies identified variants on chromosome 9p21.3 as affecting the risk of coronary artery disease (CAD). We investigated the association of this locus with CAD in 7 case-control studies and undertook a meta-analysis. Methods and Results - A single-nucleotide polymorphism (SNP), rs1333049, representing the 9p21.3 locus, was genotyped in 7 case-control studies involving a total of 4645 patients with myocardial infarction or CAD and 5177 controls. The mode of inheritance was determined. In addition, in 5 of the 7 studies, we genotyped 3 additional SNPs to assess a risk-associated haplotype (ACAC). Finally, a meta-analysis of the present data and previously published samples was conducted. A limited fine mapping of the locus was performed. The risk allele (C) of the lead SNP, rs1333049, was uniformly associated with CAD in each study (P < 0.05). In a pooled analysis, the odds ratio per copy of the risk allele was 1.29 (95% confidence interval, 1.22 to 1.37; P = 0.0001). Haplotype analysis further suggested that this effect was not homogeneous across the haplotypic background (test for interaction, P = 0.0079). An autosomal-additive mode of inheritance best explained the underlying association. The meta-analysis of the rs1333049 SNP in 12 004 cases and 28 949 controls increased the overall level of evidence for association with CAD to P = 6.04 x 10(-10) (odds ratio, 1.24; 95% confidence interval, 1.20 to 1.29). Genotyping of 31 additional SNPs in the region identified several with a highly significant association with CAD, but none had predictive information beyond that of the rs1333049 SNP. Conclusion - This broad replication provides unprecedented evidence for association between genetic variants at chromosome 9p21.3 and risk of CAD.

引用

页码：1675 / 1684

页数：10

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