Deciphering the Behavioral and Genetic Architecture of Cardiovascular Disease in Polycystic Ovary Syndrome - PROJECT SUMMARY. Polycystic ovary syndrome (PCOS) is a common, complex metabolic and reproductive disorder affecting approximately 1 in 5 reproductive-age females globally. PCOS increases the risk of cardiovascular disease (CVD)—including myocardial infarction, coronary artery disease, and stroke—yet current guidelines lack conclusive PCOS-specific evidence to guide risk stratification, precision prevention, or treatment. In the US alone, annual healthcare costs related to PCOS exceed $15 billion (2023), excluding the long-term CVD burden. Genetic predisposition to PCOS contributes to cardiometabolic abnormalities in undiagnosed females and males, but its role in CVD risk remains poorly characterized. Although behavior-genetic interactions in CVD risk are generally established, longitudinal studies that integrate these risk factors among females with PCOS and undiagnosed females and males with a genetic predisposition to PCOS are still scarce. Without elucidating how behavioral and genetic factors contribute to CVD risk in PCOS, prevention efforts will remain generalized, missing opportunities to target millions. Using harmonized, validated behavioral, genomic and phenotypic data from large prospective cohorts—Nurses' Health Studies (NHS, NHS II), Health Professionals Follow-up Study, Black Women's Health Study, UK Biobank, and NIH All of Us Research Program—I will address these gaps with 3 Specific Aims. In Aim 1, I will compare the magnitude and direction of longitudinal associations between behavioral risk factors—poor diet, physical activity, sleep, smoking, and obesity—and CVD risk among females with and without PCOS. In Aim 2, I will evaluate the longitudinal associations between genetic predisposition to PCOS and CVD risk (1) among females with PCOS, (2) among females without PCOS, and (3) among males. In Aim 3, I will assess the extent to which healthy behavioral factors modify the relationship between genetic predisposition to PCOS and CVD risk (1) among females with and without PCOS and (2) among males. If successful, this proposal will generate first-of-its-kind evidence on the etiopathogenesis of PCOS- related CVD and whether PCOS-specific behavioral-genetic risk patterns justify precision prevention or whether existing CVD frameworks suffice. In either case, the findings will directly inform clinical guidelines and population- level prevention efforts, advancing cardiovascular health in this understudied high-risk population. These findings will also lay the foundation for developing a PCOS-informed model to enhance CVD risk identification, stratification, and management. This proposal aligns with NHLBI's Strategic Vision Objectives 3 and 7, Division of Cardiovascular Sciences' Implementation Plan Objective 3, and Goals 1-4 of the NIH Strategic Plan for Nutrition Research. The proposed training and mentored research will equip me with complementary knowledge and skills in cardiovascular and behavioral epidemiology, statistical genetics, multi-ancestry data integration, and predictive modeling—supporting my goal to become an independent, interdisciplinary investigator advancing precision medicine for complex metabolic and reproductive diseases and traits.
