TY - CHAP
T1 - Repeated replication and a prospective meta-analysis of the association between chromosome 9p21.3 and coronary artery disease
AU - Schunkert, Heribert
AU - Götz, Anika
AU - Braund, Peter
AU - McGinnis, Ralph
AU - Tregouet, David Alexandre
AU - Mangino, Massimo
AU - Linsel-Nitschke, Patrick
AU - Cambien, Francois
AU - Hengstenberg, Christian
AU - Stark, Klaus
AU - Blankenberg, Stefan
AU - Tiret, Laurence
AU - Ducimetiere, Pierre
AU - Keniry, Andrew
AU - Ghori, Mohammed J.R.
AU - Schreiber, Stefan
AU - El Mokhtari, Nour Eddine
AU - Hall, Alistair S.
AU - Dixon, Richard J.
AU - Goodall, Alison H.
AU - Liptau, Henrike
AU - Pollard, Helen
AU - Schwarz, Daniel F.
AU - Hothorn, Ludwig A.
AU - Wichmann, H. Erich
AU - König, Inke R.
AU - Fischer, Marcus
AU - Meisinger, Christa
AU - Ouwehand, Willem
AU - Deloukas, Panos
AU - Thompson, John R.
AU - Erdmann, Jeanette
AU - Ziegler, Andreas
AU - Samani, Nilesh J.
PY - 2008/4
Y1 - 2008/4
N2 - 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=6.04x10(-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. CONCLUSIONS: This broad replication provides unprecedented evidence for association between genetic variants at chromosome 9p21.3 and risk of CAD.
AB - 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=6.04x10(-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. CONCLUSIONS: This broad replication provides unprecedented evidence for association between genetic variants at chromosome 9p21.3 and risk of CAD.
U2 - 10.1161/CIRCULATIONAHA.107.730614
DO - 10.1161/CIRCULATIONAHA.107.730614
M3 - Chapter
C2 - 18362232
SN - 1524-4539 (Electronic)\r0009-7322 (Linking)
T3 - Circulation
SP - 1675
EP - 1684
BT - Circulation
ER -
