Abstract 2070: Identification of SPG7 as a Novel Risk Locus for Coronary Artery Disease by Genome-wide Association
We have carried out a genome-wide association study (GWAS) for coronary artery disease (CAD) comparing 1542 patients with early onset (mean age 49) angiographically-defined CAD to 1455 elderly (mean age 75) asymptomatic controls identified 384 other single nucleotide polymorphisms (SNPs) that also associate with CAD. Since most of these SNPs occur in intergenic regions or within introns of known genes, we extended our analysis to include linked nonsynonymous coding SNPs that are not present on the commercial SNP microarrays. We identified a common SNP (MAF 0.19) that results in the substitution of glutamine for arginine at position 688 of the mitochondrial protease paraplegin encoded by SPG7. Imputation based on HapMap linkage disequilibrium using the program, Impute, failed to predict that this variant should be more strongly associated with CAD. However, PCR genotyping showed that Arg688Gln SNP was more highly associated with risk for CAD (p=9.8×10 – 6) than the SNP on the array (p=4.5×10 – 4). We have since replicated the association of the SPG7 Gln688 variant with coronary artery disease in collaboration with several large independent sample populations of CAD cases and controls. The Arg688Gln variant lies in a region of SPG7 sequence that is highly conserved throughout evolution and thus is likely to influence SPG7 function. SPG7 performs an essential proofreading function eliminating misfolded protein in the mitochondrial matrix. Epitope-tagged proteins for the common and the Arg688Gln variant forms of SPG7 show identical localization to mitochondria, suggesting that CAD risk may relate to prolonged susceptibility to atherogenic signals, such as apoptosis induced by oxidized lipoproteins. Ongoing studies are addressing this hypothesis.