Epigenomic landscape of individual- and neighborhood-level social disadvantages and cardiovascular health disparity

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ABSTRACT As cardiovascular disease (CVD) remains the leading cause of death and disproportionately affects Black communities in the U.S., there is an urgent need to address cardiovascular racial disparities. Individual-level social determinants of health (iSDH; e.g., poverty and education) and neighborhood-level SDH (nSDH) have been linked to CVD risk factors, as well as subclinical and clinical outcomes. Exposure to SDH may start from young age and accumulate over the lifespan. However, most studies on SDH and CVD have focused on either older adults or the elderly, while racial disparity studies have focused on self-reported race. Longitudinal studies of SDH from young age that also consider genetic ancestry in relation to CVD racial disparity are urgently needed. Furthermore, current indices to measure SDH do not take specific health outcomes into account and thus provide limited information for these outcomes. The underlying biological mechanisms between SDH and CVD remain largely unknown. Epigenetic markers have been associated with social disadvantages and CVD outcomes, and epigenetic processes represent a potential biological mediator between SDH and CVD racial disparity. However, most prior studies are cross-sectional and limited to one or two time points and/or use samples collected after disease development. These limitations hinder us from studying the dynamic nature of epigenomic biomarkers and their temporal and/or mediating role on the process from SDH exposure to subclinical CVD at middle age, and then into clinical CVD later in life. In the proposed study, we address these gaps using a social epigenetic approach to understand the impact of the individual- and neighborhood-level SDH on DNA methylation markers and the mediating/temporal role of SDH-associated DNA methylation markers in CVD development and disparity. We are uniquely poised to conduct this study because we can leverage existing resources from the Coronary Artery Risk Development in Young Adults (CARDIA) Study. CARDIA is a community-based biracial cohort of individuals enrolled at ages 18–30 years from four large U.S. cities with large variations in social disadvantages, currently followed every 5 years for >35 years. Specifically, we propose (1) to develop iSDH and nSDH indices, and trajectories specific to subclinical CVD; (2) to identify SDH-associated DNAm biomarkers and examine their roles in CVD risk and disparity using TOPMed ready-to-use longitudinal epigenomic data; (3) to examine genetic roles in SDH-associated DNAm biomarkers in relation to CVD risk and disparity using TOPMed ready-to-use WGS data; and (4) to validate our findings in other TOPMed cohorts, and deploy a user-friendly web application. By evaluating multiple modifiable risk factors of CVD related to SDH, the findings from this highly time- and cost- effective study will be invaluable for targeting high-need populations, tailoring interventions at the individual and neighborhood levels, and distributing resources to tackle social disadvantages in the U.S. and worldwide.