CpG Methylation Levels in HPA Axis Genes Predict Chronic Pain Outcomes Following Trauma Exposure

Chronic post-traumatic musculoskeletal pain (CPTP) is a common outcome of traumatic stress exposure. Biological factors that influence the development of CPTP are poorly understood, though current evidence indicates that the hypothalamic-pituitary-adrenal (HPA) axis plays a critical role in its development. Little is known about molecular mechanisms underlying this association, including epigenetic mechanisms. Here, we assessed whether peritraumatic DNA methylation levels at 248 5'-C-phosphate-G-3' (CpG) sites in HPA axis genes (FKBP5, NR3C1, CRH, CRHR1, CRHR2, CRHBP, POMC) predict CPTP and whether identified CPTP-associated methylation levels influence expression of those genes. Using participant samples and data collected from trauma survivors enrolled into longitudinal cohort studies (n = 290), we used linear mixed modeling to assess the relationship between peritraumatic blood-based CpG methylation levels and CPTP. A total of 66 (27%) of the 248 CpG sites assessed in these models statistically significantly predicted CPTP, with the three most significantly associated CpG sites originating from the POMC gene region (ie, cg22900229 [13 = .124, P < .001], cg16302441 [13 = .443, P < .001], cg01926269 [13 = .130, P < .001]). Among the genes analyzed, both POMC (z = 2.36, P = .018) and CRHBP (z = 4.89, P < .001) were enriched in CpG sites significantly associated with CPTP. Further, POMC expression was inversely correlated with methylation levels in a CPTP-dependent manner (6-months NRS<4: r = -.59, P < .001; 6-months NRS & GE; 4: r = -.18, P = .2312). Our results suggest that methylation of HPA axis genes including POMC and CRHBP predict risk for and may contribute to vulnerability to CPTP. Perspective: Peritraumatic blood levels of CpG methylation sites in HPA axis genes, particularly CpG sites in the POMC gene, predict CPTP development. This data substantially advances our under-standing of epigenetic predictors and potential mediators of CPTP, a highly common, morbid, and hard-to-treat form of chronic pain.& COPY; 2023 by United States Association for the Study of Pain, Inc.