Abstract 126: Genome Wide Association Study in the Million Veteran Program Identifies a Novel Role for Thrombosis in the Pathogenesis of Peripheral Artery Disease

Abstract

Introduction: PAD is a leading cause of cardiovascular morbidity and mortality. Previously published GWAS have been limited by small sample sizes and have only identified 3 genome-wide significant (P<5x10 -8 ) risk loci to date. Hypothesis: DNA sequence variants affecting multiple biological pathways are associated with PAD risk. Methods: Using electronic health record data, we identified individuals with and without clinical PAD from the 353,323 Million Veteran Program (MVP) participants genotyped on a customized Affymetrix Biobank array. We tested 32 million genotyped and imputed DNA variants for association with clinical PAD separately in participants of European (EUR), African (AFR), and Hispanic (HIS) ancestry using logistic regression models controlling for age, sex and population structure, and then performed trans-ethnic meta-analysis. The results were replicated with data from the UK Biobank. Results: We identified 31,307 individuals (24,009 EUR, 5,373 AFR, 1,925 HIS) with, and 211,753 individuals without, PAD. Following meta-analysis and replication, there were 19 genome-wide significant risk loci associated with PAD. We replicated a known association at 9p21 (P=4.3 x10 -39 ), and identified several novel loci associated with PAD that were previously known to be associated with atherosclerosis ( LPA , HDAC9 ), diabetes ( TCF7L2 ), lipid levels ( LPL , CELSR2 ), and tobacco use ( CHRNA3 ). We also identified a novel association with PAD for the Factor V Leiden (FVL) mutation (OR 1.20, P=1.6x10 -12 ), which remained significant after controlling for venous thromboembolism (OR 1.10, P=8.7x10 -4 ). Sensitivity analysis demonstrated FVL is associated with increasing risk estimates for PAD severity (claudication OR 1.19, P=0.0012; rest pain OR 1.41, P=0.004; tissue loss OR 1.57, P=7x10 -9 ). Conclusions: Using the MVP, we assembled the largest reported cohort of individuals with clinical PAD and genetic data worldwide. Our data replicate known causal risk factors and identify a novel association for FVL and its putative role for thrombosis in the development of clinical PAD.