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DNA Methylation Levels in Hypothalamic-pituitary-adrenal Axis Genes Predict Chronic Pain Outcomes Following Trauma Exposure

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      Chronic posttraumatic musculoskeletal pain (CPTP) is a common outcome of traumatic stress exposure. Biological factors that predict risk for and mediate the development of CPTP are poorly understood. Current evidence indicates that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis plays a substantial role in the development of CPTP. However, little is known about the molecular mechanisms that drive the association between HPA axis genes and CPTP, such as epigenetic regulatory mechanisms. In the current study, we assessed whether peritraumatic DNA methylation levels at 248 CG dinucleotides (CpG sites) in seven HPA axis genes (FKBP5, NR3C1, CRH, CRHR1, CRHR2, CRHBP, POMC) predicted CPTP and whether identified CPTP-associated methylation levels influenced mRNA expression of those genes. Using participant samples and data collected from multi-ethnic women and men enrolled into four longitudinal cohort studies of trauma survivors (n=290), we used repeated measures mixed modeling to assess the relationship between peritraumatic CpG levels and CPTP (assessed via 0-10 NRS six weeks, six months, and one year following trauma exposure). Sixty-six (27%) of the CpG sites assessed in these models were statistically significantly associated with CPTP. Both POMC (z = 2.36, p = 0.018) and CRHBP (z = 4.89, p < 0.001) were enriched in CpG sites significantly associated with CPTP. The three CpG sites that were most statistically significantly associated with CPTP originated from the POMC gene region (i.e. cg22900229 [β=0.124, p<0.001,], cg16302441 [β=0.443, p<0.001], cg01926269[β=0.130, p<0.001]). Further, mRNA expression in the POMC gene was inversely correlated with CpG methylation levels in a CPTP dependent manner (six-month NRS<4: r=-0.590959, p<0.001; six-month NRS≥4: r=-0.1780231, p=0.2312). Altogether our results suggest that CpG methylation of HPA axis genes such as POMC and CRHBP might contribute to vulnerability to CPTP. Further studies are needed to validate these findings. Grant support from National Institute of General Medical Sciences 1T32GM135128 R01NS118563 Rita Allen Award in Pain K01AR071504.
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