Abstract MP37: DNA Methylation of Leptin Mediates the Relationship Between Stress-Associated Inflammation and Insulin Resistance: Data from the Washington DC Cardiovascular Health and Needs Assessment

Introduction: Chronic psychosocial stressors are associated with inflammation and cardiovascular (CV) risk, including insulin resistance (IR); however, potential DNA methylation (DNAm) mediators between stress-related inflammation and IR are not known. Hypothesis: DNAm biomarkers mediate the relationship between stress-related inflammation and IR. Methods: Participants from the DC Cardiovascular Health and Needs Assessment (DC-CHNA) underwent phenotyping at the NIH Clinical Center. Homeostatic Model Assessment for Insulin Resistance was calculated using insulin and glucose values. Social isolation, loneliness, and depression were determined using validated surveys. IL-8 was measured using an ELISA-based method. Principal component DNAm-based surrogate markers of leptin, cystatin C, and plasminogen activator inhibitor-1 were calculated from DNAm data obtained from participants' buffy coat samples. We examined relationships of interest with regression models adjusted for atherosclerotic cardiovascular disease (ASCVD) risk score and body mass index (BMI). Mediation analysis was used to evaluate DNAm measures as possible mediators. Results: The DC-CHNA consisted of 60 African American participants (mean age 61±11 years, 93% female) with ASCVD risk. Social isolation (β=0.34, p=0.009) and depression (β=0.30, p=0.04) associated with IL-8. IL-8 then inversely associated with DNAm-based surrogate leptin levels and directly associated with IR; leptin DNAm mediated the IL-8-IR relationship ( Figure ). Conclusions: We show a relationship between stress-associated IL-8 and IR mediated by DNAm-based surrogate leptin levels. While relationships between inflammation, serum leptin, and IR are documented, the impact of chronic stress on leptin DNAm in the context of CV risk requires further investigation in larger, diverse cohorts. DNAm-based surrogate markers of plasma proteins, such as leptin, could serve as a marker for increased CV risk in populations disproportionately exposed to chronic stress.