Abstract 1435: Large Scale Validation of Novel Genetic Loci For Coronary Artery Disease in 26,000 Subjects
A combined analysis of two genome-wide association studies has recently identified 7 genomic loci affecting risk of coronary artery disease (CAD). We therefore aimed to examine the contribution of these 7 loci (1p13.3, 1q41, 2q36.3, 6q25.1, 9p21, 10q11.21 and 15q22.33) to CAD risk through replication in a pooled sample.
Methods: We examined a total of 26,001 individuals from nine case-control studies. Single nucleotide polymorphisms (SNPs) from the 7 genomic regions were genotyped in 13,218 CAD cases and in 12,783 controls. Association, subgroup and interaction analyses were performed to test the independent contribution of each locus to CAD risk.
Results: The locus on chromosome 9p21.3 was unique in that it showed an association in each of the 9 studies individually (SNP rs1333049, combined odds ratio (OR) =1.21 (95% CI (1.16–1.25), P-value=1.02x10−21). Evidence consistent with the findings from the genome-wide association studies, i.e. significant association with CAD risk for the same locus, was also obtained from pooled analysis for chromosomal loci 1p13.3 (rs599839, OR=1.13 (1.08–1.19), P=1.40x10−7), 1q41 (rs3008621, OR=1.09 (1.04–1.15), P=8.5x10−4), and 10q11.21 (rs501120, OR=1.10 (1.05–1.15), P=4.0x10−4). The associations with 6q25.1 (rs6922269, OR=1.05 (1.01–1.10); P=0.02) and 2q36.3 (rs2943634, OR=1.04 (1.00–1.08) were of borderline statistical significance. The chromosome 10q11.21 showed a gender interaction with a highly significant effect in women (OR=1.23 (1.13–1.31), P=1x10−5), but not in men (OR1.04 (0.96–1.10), P=NS). Otherwise, we found no evidence for heterogeneity across samples or sub-groups. The locus at 15q22.33 did not replicate.
Conclusion: This broad replication provides unprecedented evidence for association of at least 4 genetic loci with elevated risk for CAD. The findings provide a strong foundation for further investigation of these loci as genetic risk factors for CAD.