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 interventions to close the health disparities
gap. Finally, given the shared etiologic mechanisms, these findings have broader applicability to other
autoimmune diseases.