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

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=6.04x10(-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.

Figure 1

HapMap data (r²) of all SNPs of the chromosome 9 region (listed in online-only Data Supplement Table I) of Samani et al and the lead SNPs of McPherson et al and Helgadottir et al. The lead SNPs of former studies and the present study are marked.

Figure 2

Haplotypic ORs and 95% CIs associated with the ACAC haplotypes under the assumption of additive haplotype effects. Boxes indicate the relative sizes of the samples.

Figure 3

Heterozygous and homozygous ORs and 95% CIs under the assumption of an additive model. Boxes indicate the relative sizes of the samples. Effects were estimated from frequency tables presented on replication samples of the previously published studies (GerMIFS I: rs1333049; OHS-2, ARIC, CCHS, DHS, OHS-3: rs2383206; Iceland B, Atlanta, Philadelphia, Durham: rs107572786).