PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of death in the United States with high morbidity, including poor quality of life and respiratory exacerbations leading to hospitalization and increased mortality. There are no disease modifying drugs for COPD. Low-income individuals are disproportionately affected by COPD and have significantly worse health outcomes compared to those with higher income. Our team, and others, found that increased exposure to social environmental stressors is associated with worse COPD respiratory symptoms and quality of life, independent of chronologic age, education, BMI, and smoking history. However, strategies to reduce social/behavioral risk factors have, to date, been inefficient. Thus, complementary strategies to reduce the burden of disease are needed; biologic mechanisms, e.g. epigenetics, that could be intervened upon, could provide a promising alternative strategy. Strong parallel lines of evidence support epigenetic involvement in the biologic response to social stress exposures and for COPD pathogenesis. Both individual loci and the epigenetic aging pathway are implicated. Our preliminary results further support DNA methylation (DNAm; a type of epigenetic data) is related to both worse COPD outcomes and increased social stress exposure, in a low-income population. Despite this evidence, no studies have rigorously examined DNAm in the context of both social stressors and COPD outcomes. Therefore, this ESI-led proposal tests the hypothesis that social environment stressors contribute to worsened COPD respiratory and quality of life outcomes through epigenetic mechanisms, including in the epigenetic aging pathway and at individual (non-aging) loci. We leverage two existing COPD studies that collected unified measures of social stressors, from across the lifespan, COPD health outcomes, as well as blood and induced sputum biosamples with suitable prevalence and variability in exposures and outcomes. In Aim 1, we test for accelerated epigenetic aging mechanisms in social stress effects on COPD health outcomes. In Aim 2, we test for DNA methylation mechanisms at a targeted set of loci (previously associated with COPD, socioeconomic position, or social stressors). For each aim, blood and induced sputum DNAm will be tested in parallel, and results compared across specimen types to further inform mechanism/biomarker utility. Social stress exposures to be tested include past adverse childhood experience and recent violence, discrimination, and perceived stress as well as a composite index of stress. COPD outcomes to be tested include impact of COPD on health and life quality (via SGRQ and CAT score) and respiratory symptom severity (via mMRC and exacerbation frequency). Aim 3 will relate DNAm findings from Aims 1-2 to induced sputum gene expression levels to identify downstream functional gene expression changes. Our results can provide new DNA and/or RNA biologic targets tha...