ABSTRACT Systemic lupus erythematosus (SLE, or lupus) is a prototypic autoimmune disease marked by a disproportionate prevalence and severity burden in women of African ancestry (AA). There is a critical need for efforts that identify the molecular mechanisms through which positive and negative social determinants of health contribute to the lupus health disparity, so that progress in improving disease outcomes can be made and the health disparities gap can be closed. This research project addresses the objectives of PAR-19-372 to “1) advance understanding of mechanisms by which social factors lead to epigenetic changes that affect minority health and health disparities, and 2) promote epigenetics research to better predict disease or resiliency among health disparity populations.” We are seeking to identify and characterize the epigenetic mechanisms by which positive and negative social experiences affect gene function and thereby influence SLE in AA women. We have previously shown that racial discrimination is associated with worse disease outcomes in AA women, while social support seems to have a positive impact. Multiple environmental exposures, including psychosocial factors, affect variation in DNA methylation. Despite their influence on SLE in AA women, it is not known how environmental experiences affect and operate through the individual epigenome to influence disease. We will test the following hypotheses in AA women: 1) exposure to adverse and protective social contexts is associated with epigenomic changes involving immune, inflammatory, and energy metabolism pathways, which in turn are associated with disease outcomes; and 2) social support compensates for the detrimental, independent effect of racial discrimination on SLE through epigenetic and gene regulatory mechanisms. We will leverage our existing registry and infrastructure, together with our community partnership, to accomplish this community-engaged integrative mechanistic study. We will enroll 300 AA women with SLE and 300 unaffected AA women, collect sociodemographic, medical, genotypic, leukocyte proportion, DNA methylation, and gene expression data, and use validated measures to assess life course racial discrimination and social support. We propose to: identify variation in DNA methylation (DNAm) associated with (a) exposure to racial discrimination, (b) exposure to social support, and (c) epigenetic age acceleration (Aim 1); to assess whether social DNAm sites affect gene expression (Aim 2); and identify the synergistic effects of social factors on DNAm changes on SLE and develop a social factors-DNAm predictive model for disease outcomes (Aim 3). This will be the first study investigating epigenetic mechanisms by which risk and resiliency factors affect gene function and lupus in AA women. These results will greatly expand the knowledge of how social factors affect gene function, disease outcomes, and health disparities, which might inform the development of effective ...