Genetic Associations of Ischemic Heart Disease and Symptoms Among Diverse Postmenopausal Women

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Project Summary/Abstract Ischemic heart disease (IHD) is the most common cause of global mortality. Women in the U.S. are more likely than men to report “atypical” symptoms of IHD, have a mis- or undiagnosed heart attack, and experience delayed cardiac treatment. Current screening, diagnostic, and intervention protocols are based on research focused primarily on symptoms and physiologic profiles in men of European ancestry. As a result, women experience significant healthcare disparities related to major adverse cardiac events (MACE), including myocardial infarction, stroke, and death. The incidence of IHD and MACE in women is highest during the postmenopausal (post-MP) phase, when it surpasses that of age-matched men. Known risk factors fail to fully explain these sex-based IHD disparities. Genetic variation between the sexes has been implicated as a major reason for symptom and outcome differences, preceding all other known cardiac risk factors. Its mechanisms, however, are poorly understood. Women with African American (AA) ancestry and Hispanic women are at greater risk of poor outcomes, yet even less is known about their genetic risk factors. The PI has identified RAP1GAP2 as a strong candidate gene for sex-associated effects on women’s IHD outcomes. Her preliminary studies demonstrate 1) associations between certain RAP1GAP2 markers and IHD case status and mortality among women but not men, with variations in ancestry-specific alleles; and 2) trends in gene-expression differences by sex, IHD, and platelet activity. RAP1GAP2 is a major contributor to platelet activation. Platelet activity is an independent risk factor for heart disease, linking clotting with IHD development. The next logical step in this work is to fill in missing gene marker data across the full RAP1GAP2 gene in high-risk women, identifying causal associations with IHD outcomes (aka, gene fine-mapping) while accounting for genomic ancestry variation. This will poise our team for studies of mechanism and clinical application. The purpose of this R21 is to determine RAP1GAP2 causal gene markers indicative of female-associated cardiac health risks (Aim 1—time to first MACE occurrence; Aim 2—presence of “atypical” IHD symptoms) and test ancestry-moderation of gene effects on outcomes (Aim 3) using novel and rigorous statistical genetics methods. Our research team will harness existing biorepository data from three all-female cardiac studies that examined more than 17,000 post-MP women in the U.S. Guided by the NIH’s sex-as-a- biological-variable framework and symptom science model, we designed this study to address often-cited research limitations of statistical power and diversity. Rather than relying solely on social constructs of race, we will incorporate genomic ancestry markers to achieve Aims 1 and 2. Results will fill evidentiary gaps in the genetics underlying women’s IHD. Findings could lead to improved sex-based IHD evaluation, treatment, and outcomes for women, thereby reducing cardiac health disparities.