Abstract 3140: Genetic Variants Within the Oxidative Phosphorylation Pathway Influence Risk of Ischemic Stroke

Abstract

Background: Prior studies have shown an association between mutations within the oxidative phosphorylation (OXPHOS) pathway and familial ischemic stroke syndromes. We investigated whether common autosomal and mitochondrial genetic variants within OXPHOS genes were associated with sporadic ischemic stroke in case-control. Methods: This multicenter association study was performed using a discovery cohort of 1643 individuals and a validation cohort of 2432 individuals from sites participating in the International Stroke Genetics Consortium. We employed a gene-set enrichment analysis (GSEA) using all 95 genes structurally involved in OXPHOS to determine the probability that the OXPHOS gene-set harbored more variants associated with stroke than predicted by chance. We then constructed a genetic score consisting of common variants within these genes. This genetic score was developed in the discovery cohort, and then tested for association with ischemic stroke in the validation cohort. Results: GSEA identified an aggregate association between the OXPHOS gene-set and ischemic stroke (p = 0.012). Based on this result, we constructed and validated a genetic score which demonstrated an association between OXPHOS genetic variation and ischemic stroke (odds ratio (OR) = 1.17, p = 0.008). In order to further distill the association between OXPHOS and stroke, we developed and tested additional scores for each of the five OXPHOS respiratory complexes. This sub-analysis revealed an independent association between OXPHOS Complex I and ischemic stroke (OR = 1.06, p = 0.050). Conclusions: This pathway-based study, informed by GSEA, employing independent discovery and validation cohorts, establishes an association between common genetic variants within OXPHOS genes and ischemic stroke. Analysis of variants within each OXHPOS Complex suggests that Complex I mediates this effect. Further studies are needed to identify the individual variants which influence ischemic stroke risk. Such discoveries offer the promise of new therapeutic targets for the prevention and treatment of stroke.