The following is a summary of “CpG Methylation Levels in HPA Axis Genes Predict Chronic Pain Outcomes Following Trauma Exposure,” published in the July 2023 issue of Pain by Branham et al.

Chronic post-traumatic musculoskeletal pain (CPTP) is a frequently observed consequence of traumatic stress exposure in the medical field. The etiology of CPTP needs to be fully comprehended regarding biological factors. However, existing evidence suggests that the hypothalamic-pituitary-adrenal (HPA) axis plays a pivotal role in its pathogenesis. Limited knowledge exists regarding the molecular mechanisms that underlie this association, including the involvement of epigenetic mechanisms. In this study, researchers evaluated the correlation between peritraumatic DNA methylation levels at 248 5′—C—phosphate—G—3′ (CpG) sites in genes related to the hypothalamic-pituitary-adrenal (HPA) axis (FKBP5, NR3C1, CRH, CRHR1, CRHR2, CRHBP, POMC) and the prediction of chronic post-traumatic pain (CPTP). Additionally, researchers investigated whether the identified methylation levels associated with CPTP impact the expression of these genes. Using participant samples and data from trauma survivors enrolled in longitudinal cohort studies (n = 290), researchers employed linear mixed modeling to evaluate the correlation between peritraumatic blood-based CpG methylation levels and CPTP (Chronic Post-Traumatic Pain).

About 66 (27%) of the 248 CpG sites evaluated in these models exhibited statistically significant predictive value for Chronic Pain and Traumatic Stress Symptoms (CPTP). Notably, the three most significantly associated CpG sites were identified within the POMC gene region, namely cg22900229 [β = .124, P < .001], cg16302441 [β = .443, P < .001], and cg01926269 [β = .130, P < .001]. Among the genes examined, both pro-opiomelanocortin (POMC) (z = 2.36, P = .018) and corticotropin-releasing hormone-binding protein (CRHBP) (z = 4.89, P < .001) exhibited an abundance of CpG sites that demonstrated a significant association with chronic pain and trauma-related psychopathology (CPTP). Additionally, pro-opiomelanocortin (POMC) expression showed an inverse correlation with methylation levels in a C-terminal peptide (CPTP)-dependent manner. Specifically, at 6 months with a Numeric Rating Scale (NRS) score less than 4, the correlation coefficient (r) was -0.59 with a P-value less than 0.001. 

Conversely, at 6 months with an NRS score greater than or equal to 4, the correlation coefficient was -0.18 with a p-value of 0.2312. Researchers’ findings indicate that the methylation of HPA axis genes, such as POMC and CRHBP, can predict the likelihood of developing and potentially contributing to vulnerability to Chronic Post-Traumatic Pain (CPTP). Peritraumatic blood levels of CpG methylation sites in hypothalamic-pituitary-adrenal (HPA) axis genes, specifically CpG sites in the pro-opiomelanocortin (POMC) gene, are indicative of the potential development of chronic post-traumatic psychopathology (CPTP). This data significantly enhances the researcher’s comprehension of epigenetic indicators and potential agents of CPTP, a prevalent, debilitating, and challenging-to-manage type of chronic pain.

Source: sciencedirect.com/science/article/pii/S1526590023003644