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Repeated replication and a prospective meta-analysis of the association between chromosome 9p21.3 and coronary artery disease.
- Source :
-
Circulation [Circulation] 2008 Apr 01; Vol. 117 (13), pp. 1675-84. Date of Electronic Publication: 2008 Mar 24. - Publication Year :
- 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.<br />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.<br />Conclusions: This broad replication provides unprecedented evidence for association between genetic variants at chromosome 9p21.3 and risk of CAD.
- Subjects :
- Aged
Case-Control Studies
Coronary Artery Disease epidemiology
Female
Genetic Markers genetics
Genotype
Humans
Male
Middle Aged
Prospective Studies
Risk Factors
Chromosomes, Human, Pair 9 genetics
Coronary Artery Disease genetics
Genetic Variation
Polymorphism, Single Nucleotide genetics
Repetitive Sequences, Nucleic Acid genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 117
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 18362232
- Full Text :
- https://doi.org/10.1161/CIRCULATIONAHA.107.730614