Abstract 3568: Genomic Convergence Identified CAPG and VAMP8 as Candidate Genes for CAD
Background: By combining genetic linkage evidence with a microarray expression study (genomic convergence), we prioritized capping protein, gelsolin-like (CAPG) and vesicle-associated membrane protein 8 (VAMP8) as candidate genes for coronary artery disease (CAD). The two genes reside within 200 kilobases on chromosome 2p11.2. A previous genome-wide study found association at single nucleotide polymorphism (SNP) rs1010 in VAMP8 with myocardial infarction (MI). We sought to thoroughly evaluate associations in the two genes with CAD.
Methods: Tagging and coding SNPs were examined in multiple independent datasets, including a family-based dataset (N=2954), a White case-control dataset (N=982), and an African-American case-control dataset (N=250). Stratified analyses on the MI subphenotype and gender were performed to further characterize associations. Stepwise logistic regression was implemented to identify independent association. Allele-specific gene expression was evaluated in 92 human aortas.
Results: VAMP8 SNP rs3731828 was the most significant result, with association in both Whites (p=0.008, OR=1.4) and African-Americans (p=0.007, OR=2.3), and highly significant in the joint analysis of both ethnic groups (p=0.0001, OR=1.6). In addition, the risk allele of rs3731828 was correlated with higher VAMP8 gene expression in aortas (p=0.05). One SNP in CAPG and the previously reported VAMP8 SNP rs1010 were associated with CAD in at least two datasets (p<0.05). No MI or gender specific associations were found in either gene.
Conclusions: Genomic convergence is an effective strategy in identifying genes for complex diseases, such as CAD. We provided additional genetic evidence supporting CAPG and VAMP8 as CAD susceptibility genes, with the VAMP8 displaying stronger association. Importantly, our data suggest that the VAMP8’s genetic effect is not constrained by subgroups represented by ethnicity, MI subphenotype, or gender. Furthermore, we are the first to show that rs3731828 mediates allele-specific VAMP8 expression in arterial wall, which provides a plausible molecular mechanism for the strong and consistent genetic risk conferred by the SNP.