Highlights
- •Chronic musculoskeletal pain is common following traumatic stress exposure
- •CpG DNA methylation levels in seven HPA axis stress genes predict chronic pain in trauma survivors
- •CpG sites in POMC most strongly predict chronic pain and influence POMC mRNA levels
- •Epigenetic regulation of stress system gene function may contribute to chronic pain development
Abstract
Chronic posttraumatic 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 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. 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 (i.e. cg22900229 [β=0.124, p<0.001], cg16302441 [β=0.443, p<0.001], cg01926269
[β=0.130, p<0.001]). Among the genes analyzed, 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.
Further, POMC expression was inversely correlated with methylation levels in a CPTP-dependent manner
(six-month NRS<4: r=-0.59, p<0.001; six-month NRS≥4: r=-0.18, p=0.2312). 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 chronic posttraumatic musculoskeletal pain (CPTP) development. This
data substantially advances our understanding of epigenetic predictors and potential
mediators of CPTP, a highly common, morbid, and hard-to-treat form of chronic pain.
Key words
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Article info
Publication history
Accepted:
March 1,
2023
Received in revised form:
February 21,
2023
Received:
November 28,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Disclosures: Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Numbers R01AR060852 (McLean), R01AR064700 (McLean), R01NS118563 (Linnstaedt and McLean), and K01AR071504 (Linnstaedt). Additional funding was provided by the Rita Allen Foundation (Linnstaedt) and the Mayday Fund (Linnstaedt and McLean). Erica Branham was supported in part by a grant from the National Institute of General Medical Sciences under award T32GM135128. The content is solely the responsibility of the authors and does not necessarily represent the views of these funding agencies. We report no conflicts of interest.
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