A common allele on chromosome 9 associated with coronary heart disease

Abstract

Coronary heart disease (CHD) is a major cause of death in Western countries. We used genome-wide association scanning to identify a 58-kilobase interval on chromosome 9p21 that was consistently associated with CHD in six independent samples (more than 23,000 participants) from four Caucasian populations. This interval, which is located near the CDKN2A and CDKN2B genes, contains no annotated genes and is not associated with established CHD risk factors such as plasma lipoproteins, hypertension, or diabetes. Homozygotes for the risk allele make up 20 to 25% of Caucasians and have a approximately 30 to 40% increased risk of CHD.

Figures

Fig. 1

Study design for identification and validation of sequence variants associated with CHD. Assuming independence, the probability of any single SNP achieving a nominal significance level of 0.025 in all three studies with the associations being in the same direction was 3.9 × 10−6 (0.0253 × 0.52); thus, none of the 100,000 SNPs would be expected by chance to replicate consistently in all three comparisons.

Fig. 2

Fine mapping of the genomic interval on chromosome 9 associated with CHD. (A) SNPs spaced ~5 kb apart in the interval extending 175 kb upstream and downstream of rs10757274 and rs2383206 were assayed in 500 cases and 500 controls from the OHS population with GeneChip Human Mapping 500K Array Sets (Affymetrix, Santa Clara, CA). Bars represent P values (determined with χ2 tests) for differences in allele frequency between cases and controls. Arrowheads indicate rs10757274 and rs2383206. The asterisk represents rs518394. The risk interval is indicated with a gray box. The linkage disequilibrium map indicates pairwise r2 values. Blocks are shaded on a continuous scale, where white represents an r2 of 0 and black represents an r2 of 1. (B) Physical map of the region showing the location of the risk interval (gray box) relative to the noncoding RNA DQ485453 and adjacent genes CDKN2A, ARF, and CDKN2B. Arrowheads indicate rs10757274 and rs2383206, and the asterisk represents rs518394 [see (A)].