CpG methylation levels in HPA axis genes predict chronic pain outcomes following trauma exposure.

Mar 13, 2023

Experts: Erica M Branham,Samuel A McLean,Ishani Deliwala,Matthew C Mauck,Ying Zhao,Lauren A McKibben,Aaron Lee,Alex B Spencer,Anthony S Zannas,Megan Lechner,Teresa Danza,Marc-Anthony Velilla,Phyllis L Hendry,Claire Pearson,David A Peak,Jeffrey Jones,Niels K Rathlev,Sarah D Linnstaedt

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.
Copyright © 2023. Published by Elsevier Inc.

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ABOUT THE EXPERTS

Erica M Branham,Samuel A McLean,Ishani Deliwala,Matthew C Mauck,Ying Zhao,Lauren A McKibben,Aaron Lee,Alex B Spencer,Anthony S Zannas,Megan Lechner,Teresa Danza,Marc-Anthony Velilla,Phyllis L Hendry,Claire Pearson,David A Peak,Jeffrey Jones,Niels K Rathlev,Sarah D Linnstaedt

Erica M Branham

Institute for Trauma Recovery, University of North Carolina, Chapel Hill, NC, USA; Department of Anesthesiology, University of North Carolina, Chapel Hill, NC, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC, USA.

Samuel A McLean

Institute for Trauma Recovery, University of North Carolina, Chapel Hill, NC, USA; Department of Anesthesiology, University of North Carolina, Chapel Hill, NC, USA; Department of Emergency Medicine, University of North Carolina, Chapel Hill, NC, USA.

Ishani Deliwala

Institute for Trauma Recovery, University of North Carolina, Chapel Hill, NC, USA; Department of Anesthesiology, University of North Carolina, Chapel Hill, NC, USA.

Matthew C Mauck

Institute for Trauma Recovery, University of North Carolina, Chapel Hill, NC, USA; Department of Anesthesiology, University of North Carolina, Chapel Hill, NC, USA.

Ying Zhao

Institute for Trauma Recovery, University of North Carolina, Chapel Hill, NC, USA; Department of Anesthesiology, University of North Carolina, Chapel Hill, NC, USA.

Lauren A McKibben

Institute for Trauma Recovery, University of North Carolina, Chapel Hill, NC, USA; Department of Anesthesiology, University of North Carolina, Chapel Hill, NC, USA.

Aaron Lee

Institute for Trauma Recovery, University of North Carolina, Chapel Hill, NC, USA; Department of Anesthesiology, University of North Carolina, Chapel Hill, NC, USA.

Alex B Spencer

Institute for Trauma Recovery, University of North Carolina, Chapel Hill, NC, USA; Department of Anesthesiology, University of North Carolina, Chapel Hill, NC, USA.

Anthony S Zannas

Institute for Trauma Recovery, University of North Carolina, Chapel Hill, NC, USA; Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA; Carolina Stress Initiative, University of North Carolina, Chapel Hill, NC, USA.

Megan Lechner

Forensic Nursing Program, Memorial Health System, Colorado Springs, CO, USA.

Teresa Danza

Forensic Nursing Program, Albuquerque SANE Collaborative, Albuquerque, NM, USA.

Marc-Anthony Velilla

Department of Emergency Medicine, Sinai Grace Hospital, Detroit, MI, USA.

Phyllis L Hendry

Department of Emergency Medicine, University of Florida College of Medicine, Jacksonville, FL, USA.

Claire Pearson

Department of Emergency Medicine, Detroit Receiving, Detroit MI, USA.

David A Peak

Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA.

Jeffrey Jones

Department of Emergency Medicine, Spectrum Health Butterworth Campus, Grand Rapids, Michigan, USA.

Niels K Rathlev

Department of Emergency Medicine, University of Massachusetts Chan Medical School Baystate, Springfield, MA, USA.

Sarah D Linnstaedt

Institute for Trauma Recovery, University of North Carolina, Chapel Hill, NC, USA; Department of Anesthesiology, University of North Carolina, Chapel Hill, NC, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC, USA. Electronic address: sarah_linnstaedt@med.unc.edu.