Details
| Original language | English |
|---|---|
| Pages (from-to) | 1675-1684 |
| Number of pages | 10 |
| Journal | CIRCULATION |
| Volume | 117 |
| Issue number | 13 |
| Publication status | Published - 1 Apr 2008 |
Abstract
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=6.04×10 (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.
Keywords
- Chromosomes, Coronary disease, Genetics, Meta-analysis, Myocardial infarction, Risk factors
ASJC Scopus subject areas
- Medicine(all)
- Cardiology and Cardiovascular Medicine
- Medicine(all)
- Physiology (medical)
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In: CIRCULATION, Vol. 117, No. 13, 01.04.2008, p. 1675-1684.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
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 - 2008/4/1
Y1 - 2008/4/1
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=6.04×10 (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.
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=6.04×10 (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.
KW - Chromosomes
KW - Coronary disease
KW - Genetics
KW - Meta-analysis
KW - Myocardial infarction
KW - Risk factors
UR - http://www.scopus.com/inward/record.url?scp=41649085340&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.107.730614
DO - 10.1161/CIRCULATIONAHA.107.730614
M3 - Article
C2 - 18362232
AN - SCOPUS:41649085340
VL - 117
SP - 1675
EP - 1684
JO - CIRCULATION
JF - CIRCULATION
SN - 0009-7322
IS - 13
ER -