Stratifying Coronary Artery Disease (CAD) GWAS Loci Using Cardiac Perfusion Positron Emission Tomography to Identify Loci for Coronary Microvascular Disease

Introduction: Coronary Microvascular Disease (CMVD), defined as disease of the coronary pre-arterioles, arterioles, and capillaries, accounts for 30-50% of the burden of Ischemic Heart Disease (IHD). CAD GWAS studies have identified more than 235 loci, however, the populations enrolled represent heterogeneous IHD with inclusion criteria that include ischemia without confirmation of obstructive CAD (Ischemia with non-obstructed Coronary Arteries). Hypothesis: We hypothesize that CAD GWAS studies are really IHD GWAS studies and a subset of patients enrolled have CMVD as the etiology of their ischemia. Thus several CAD GWAS loci may be CMVD loci. Here we use quantitative measures of myocardial blood flow (MBF) and MBF reserve (MBFR) from cardiac Perfusion PET studies to stratify known CAD loci for CMVD. Methods: We performed a genomic association study for 235 known CAD loci in 383 samples of European (EUR) and 539 samples of African ancestry (AFR) in the Penn Medicine Biobank using clinical Rubidium-82 PET using REGENIE software. Models were adjusted for age, sex, age 2 , age x sex, 5 principal components, and batch corresponding to phenotype extraction. We examined regions within 250kb of known CAD loci for association with PET-derived MBF and MBFR. Bonferroni corrected P-value < 2.13e-4 was considered significant. Results: We found 40 loci in patients of AFR ancestry and 11 CAD loci in patients of EUR ancestry that were significantly associated with MBFR, including several genes which are known to play a role in microvasculature function and angiogenesis (VEGFa, FLT1, and FGF1). Stress MBF values have been shown to reflect epicardial CAD. We found 28 loci in patients of AFR ancestry and 12 loci in patients of EUR ancestry which were significantly associated with stress MBF and are mostly distinct from loci associated with MBFR. One notable exception is PRDM16 which was highly significant in both phenotypes. Conclusions: Our study sub-stratified variants previously associated with CAD to identify those that may be involved in CMVD. Several genes known to be involved in microvasculature function (VEGFa, FLT1, and FGF1) were putative CMVD genes. PRDM16 was associated with stress MBF and MBFR. This work prioritizes CAD loci for further study of mechanisms of CMVD.