Project Summary Psychosocial stress has been repeatedly associated with immune dysregulation and increased risk for coronary heart disease (CHD), but the mechanisms underlying this association remain unclear. Our parent grant (R01HL163031) investigates this relationship by focusing on DNA methylation (DNAm), one of the critical epigenetic mechanisms and a proposed key link between environmental exposures and human health. Using multi-ancestry human cohorts participating in the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we identify stress-associated DNAm sites predictive of incident CHD. Employing human cell models, we further investigate the mechanistic role of these sites in immune cell function. The proposed research supplement seeks to expand this line of research by further investigating the relationship between discrimination stress and CHD, specifically in minoritized individuals, a population group that is subjected to a higher stress burden and is disproportionately affected by CHD. Leveraging the Jackson Heart Study, a cohort of African American or Black individuals with a wealth of longitudinal phenotypic and DNAm data, this project aims to investigate how stress in minoritized and disadvantaged populations influences the perpetuation of CHD disparities by pursuing two distinct but complementary specific aims: 1) Identify the genomic site-specific DNAm signatures associated with discrimination stress and CHD in Black individuals; and 2) mechanistically dissect how stress-driven DNAm signatures become established and shape immune cell function relevant to CHD in diverse donors. These aims will expand the scope of prior work examining cohorts of primarily European ancestry to include individuals with more diverse backgrounds and will also illuminate the relationship between discrimination stress and CHD outcomes. Dissecting the epigenetic mechanisms linking psychosocial stress with disease risk can create opportunities for novel predictive models and therapeutic targets to enhance personalized CHD prevention and treatment in high-risk minoritized populations.