Abstract P3122: Rap1gap2 Fine-mapping For Causal Variants Of Prevalent Ischemic Heart Disease Among Diverse Postmenopausal Women From The Women’s Health Initiative

Abstract

Background: RAP1GAP2 is a GTP-ase activating protein that regulates secretion of dense granules from platelets at sites of endothelial damage, eliciting maximal platelet aggregation, a hallmark of ischemic events. Our published sex-stratified GWAS significantly associated RAP1GAP2 (Chr 17p13.3) variants with ischemic heart disease (IHD) case status and increased mortality risk among women but not men. We hypothesize that RAP1GAP2 genetic variation may demonstrate causal effects for the increased risk of IHD case status among postmenopausal women. Purpose: To fine-map RAP1GAP2 to identify causal markers for risk of IHD case status among racially and ethnically diverse postmenopausal women. Methods: We performed secondary analysis of 8,699 postmenopausal women from the Women’s Health Initiative (Observational cohort) who have publicly available genome-wide and densely imputed genotype data via NIH/dbGap (Affymetrix Affy 6.0). IHD case status was defined as prevalence of myocardial infarction, stroke, angina, congestive heart failure, peripheral arterial disease, or atherosclerotic interventional procedures at or prior to baseline; non-IHD controls were absent of all IHD criteria. PCA and Efficient Local Ancestry Inference (ELAI) were used to infer global and SNP-wise local ancestries. For each SNP, we performed SNP-wise logistic regression modeling, calibrating for the confounding effects of local and global ancestries and controlling for major cardiac risk factors, hormone replacement and cardiac medication exposure, IHD type (obstructive, nonobstructive), eGFR, education, income, and occupation. Results: Mean age 64.08 (±7.74) for a sample of 3,125 (36%) non-Hispanic Whites, 3,841 (44%) African Americans and 1,733 (20%) Hispanic Americans. We observed 1,932 IHD cases and 6,767 non-IHD controls. Novel PCA and ELAI uncovered strong spatial global population structure, varying ancestries, and ancestry-genotype correlations across genomic regions. Fine mapping analyses are underway and results will be available at time of presentation. Conclusions: Identifying sex- and ancestry-related causal genetic factors can serve as future targets for precision prevention of IHD among postmenopausal women.