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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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© 2022 Published by Elsevier Inc.
