Abstract 15054: Genome Wide Association Study of Coronary Microvascular Disease Assessed by Cardiac Perfusion Positron Emission Tomography

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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. However, little is known about the pathogenesis, and there are no directed therapies for CMVD. Perfusion cardiac PET allows for the quantitative assessment of myocardial blood flow (MBF) at rest and stress and MBF reserve (MBFR) and represents the most clinical advanced non-invasive imaging modality for CMVD. Hypothesis: Here we perform the first genome-wide association study (GWAS) for CMVD using cardiac PET MBF parameters. Methods: Rest and stress MBF and MBFR were measured using Rubidium-82 cardiac perfusion PET stress tests which were obtained as part of routine clinical care. We performed a GWAS in 383 samples of European (EUR) and 539 samples of African ancestry (AFR) in the Penn Medicine Biobank using MBF values and REGENIE software. Models were adjusted for age, sex, age 2 , age x sex, 5 principal components, and batch corresponding to phenotype extraction. Additionally fine mapping was performed for loci with P-value < 1e-05 using implementation of SuSiE in the polyfun package by integrating gene expression and functional annotations from heart ventricular, atrium, aorta, and coronary artery tissues in the EpiMap database. Results: We identified 10 variants in AFR ancestry for MBFR at p-value < 5e-7. Among the top hits, our results identified novel signals in variants mapping to LOC105374051, UNC13A, RPL21P130, ATP6V0A2, CCSER1, and MDFI , among others. We also identified 4 variants in AFR and 1 in EUR for rest MBF and 3 variants in AFR and 1 in EUR for stress MBF phenotypes, including loci near ARHGAP18 and ARHGAP22 . Fine mapping identified 4 loci in AFR for MBFR including NRP1, ERC1, RN7SKP148, and SCL15A4 . In sex-stratified analyses, we found that variants were more strongly associated with PET-derived MBF phenotypes in AFR women than in AFR men and in EUR men relative to EUR women. Conclusions: Our study identified several variants associated with perfusion PET MBF parameters in populations of EUR and AFR ancestry, some of which represent putative CMVD loci. This work yields novel insights into mechanisms of CMVD.