Mitochondrial gene variant contributing to coronary artery disease

Abstract

Genome‐wide association studies (GWAS) have identified genetic variants that are associated with the risk for coronary artery disease (CAD), but the functional significance of these loci has remained obscure. We identified a genetic variant associated with CAD risk that changes the sequence of a mitochondrial protease called paraplegin (SPG7) and confirmed this association by meta‐analysis of 14 GWAS including 22,000 CAD cases and 60,000 controls. The variant changes an arginine residue at position 688 to a glutamine residue in the protease domain of SPG7. Most mutations in SPG7 cause a loss of protease function leading to spastic paraplegia. Although the Gln688 variant was considered benign in terms of spastic paraplegia, we have evidence that it is in fact a protease gain‐of‐function variant. We observed a strong correlation between the presence of the variant allele and the level of mature active SPG7 in peripheral lymphocytes, as well in primary cultures of human aortic smooth muscles. Consistent with increased SPG7 protease activity, increased production of cytochrome c oxidase subunits, ATP synthesis, cell proliferation and ROS production were seen in cells stably expressing this variant. Our data suggest that this gain of function may also be detrimental to mitochondrial function with aging. Our study is the first to link a mitochondrial matrix AAA protease variant to the risk of CAD.(Supported by CIHR)