Abstract 233: Genetic Evidence for Overlap in the Pathogenesis of Peripheral Artery Disease and Coronary Artery Disease

Introduction: Peripheral artery disease (PAD) is thought to share atherosclerotic biologic mechanisms and traditional risk factors with coronary artery disease (CAD). Although significant progress has been made in identifying genetic contributors to CAD, genetic factors underlying PAD remain largely uncharacterized. The aim of our study was to evaluate the shared genetic architecture between PAD and CAD. Hypothesis: DNA sequence variants associated with CAD risk are also associated with PAD. Methods: We analyzed the electronic health records from 239,621 U.S. Veterans of European ancestry with available imputed genetic data from the VA Million Veteran Program. Within this cohort we identified 16,364 participants with PAD, and 67,636 with CAD. We constructed additive weighted genetic risk scores (GRS) of 57 DNA sequence variants previously associated with CAD at genome-wide significance. We standardized the GRS to have a mean of zero and standard deviation (SD) of 1, and assessed the strength of its association with PAD through logistic regression. Models were adjusted for age, sex, and 7 principal components of ancestry. In a mediation analysis, we then included CAD status in the model to examine if these genetic associations remained significant after accounting for a CAD diagnosis. Results: The CAD GRS was significantly associated with clinical CAD [OR = 1.22 per SD increase in GRS, (95%CI: 1.21 -1.23, Z-Score = 44.5, P -16 )]. The CAD GRS was also significantly associated with PAD [OR = 1.12 per SD increase in GRS, (95%CI: 1.10-1.14, Z-Score = 14.5, P -16 )]. This magnitude of association was attenuated when further adjusting for CAD in the regression model but remained strongly significant [OR = 1.05 per SD increase in GRS, (95%CI: 1.03-1.07, Z-Score = 6.2, P = 5.6x10 -10 )]. Conclusions: In the largest single cohort of CAD and PAD cases worldwide, we found that a genetic risk score of DNA sequence variants associated with risk for CAD are also associated with risk of PAD, even after accounting for the presence of coronary atherosclerosis. These data suggest significant overlap in the mechanisms underlying development of atherosclerosis within both the peripheral and coronary arterial beds.