337 Gain-of-function variant in the mitochondrial protein SPG7 associated with increased risk of coronary artery disease

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In a genome-wide association study (GWAS), we identified a genetic variant associated with coronary artery disease (CAD) risk that changes the sequence of a mitochondrial protease called paraplegin (SPG7). We 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 the protease domain cause a loss of SPG7 protease function leading to spastic paraplegia (hence the name), a neurodegenerative disorder characterized by progressive weakness and spasticity of the lower limbs due to degeneration of corticospinal axons. Here, we sought to understand how this variant might contribute to CAD. Using peripheral lymphocytes from patients with CAD, as well primary cultures of human aortic smooth muscle cells, genotyped for the SPG7 variant, we tested what effect the variant has on SPG7 protease activity and mitochondrial function. We observed a strong correlation (P = 1.23x10-7) between the presence of the variant allele and the level of mature proteolytically active SPG7. Consistent with increased SPG7 protease activity, cells stably expressing the CAD risk variant of SPG7 had increased production of cytochrome c oxidase subunits (COX1,3, and 4), elevated ATP synthesis and ROS production. In addition, cellular proliferation was elevated in these cells, consistent with a pro-atherogenic phenotype. Our study is the first to link a mitochondrial matrix AAA protease gain-of-function variant to an increased risk of CAD.