Abstract 14588: A Large-Scale Genome-Wide Association Study of Angiographically Determined Burden of Coronary Atherosclerosis in a Genetically Diverse Population

Abstract

Introduction: Few large-scale genome wide association studies (GWAS) of angiographically derived burden of coronary atherosclerosis have been reported to date. The yield of this approach relative to case-control GWAS of coronary artery disease (CAD) remains unclear. Methods: We used the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program, a national quality and safety organization for invasive cardiac procedures, to conduct the largest ever GWAS of burden of coronary atherosclerosis involving participants of the Million Veteran Program (MVP). Obstructive disease of a native major vessel was defined as the presence of at least one obstruction >50% of the luminal diameter, or a prior revascularization procedure, involving the main artery and/or its major branches. Non-obstructive disease was defined as one or more vessels having one or more obstructions of >20% but none more than 50%. We classified an individual’s extent of disease as normal, non-obstructive, one vessel, two vessel, or three vessel / left main CAD. GWAS was performed stratified by racial/ethnic group using linear regression in REGENIE, with age, sex, and genetic principal components as covariates. Stratified results were then combined through meta-analysis using GWAMA. Results: The extent of disease was quantified in 49,213 non-Hispanic White, 11,326 non-Hispanic Black, and 4,058 Hispanic MVP participants, a majority of which were subjects with clinical CAD. Forty-three loci reached genome wide significance including 27 among Whites, four among Blacks at SORT1 , LPL , COL4A2 , and LDLR , two among Hispanics at CDKN2B-AS1 and NRG4 , and an additional 13 through meta-analysis of all three strata. Two loci, HHEX and NRG4 , have not been previously established as susceptibility loci CAD. Conclusions: Large-scale GWAS of burden of coronary atherosclerosis complements discovery efforts of case-control GWAS of CAD. Despite substantially smaller sample sizes, this quantitative approach recapitulated many established loci for CAD, uncovered novel loci, and identified several known susceptibility loci in admixed Black and Hispanic populations. The latter required a remarkably larger sample size to achieve through GWAS of clinically defined events alone.