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. 2023 Sep-Oct;24(7):578-586.
doi: 10.1080/15622975.2023.2177342. Epub 2023 Mar 13.

Promoter methylation of the glucocorticoid receptor following trauma may be associated with subsequent development of PTSD

Lior Carmi  1   2 , Joseph Zohar  1   3 , Alzbeta Juven-Wetzler  1 , Frank Desarnaud  4 , Louri Makotkine  4 , Linda M Bierer  4 , Hagit Cohen  5 , Rachel Yehuda  4
Affiliations

Promoter methylation of the glucocorticoid receptor following trauma may be associated with subsequent development of PTSD

Lior Carmi et al. World J Biol Psychiatry. 2023 Sep-Oct.

Abstract

Objectives: The ability to identify persons at elevated risk for post-traumatic stress disorder (PTSD) soon after exposure to trauma, could aid clinical decision-making and treatment. In this study, we explored whether cytosine methylation of the 1 F promoter of the NR3C1 (glucocorticoid receptor [GR]) gene obtained immediately following a trauma could predict PTSD.

Methods: Our sample comprised 52 trauma survivors (28 women, 24 men), presenting to the Emergency Department (ED) within six hours of a traumatic event and followed for 13 months. Blood samples were taken at intake (n = 42) and again at the end of the study (13 months later, n = 27) to determine NR3C1-1F promoter methylation as well as plasma levels of cortisol, adrenocorticotropic-hormone (ACTH), and neuropeptide-Y (NPY).

Results: At the 13-month follow-up, participants who met the PTSD criteria (n = 4) showed significantly lower NR3C1-1F promoter sum percent methylation compared to the non-PTSD group (n = 38). Further, NR3C1-1F methylation at ED intake was inversely correlated with PTSD severity 13 months later, indicating that lower NR3C1-1F promoter methylation in the immediate aftermath of trauma was associated with the development of PTSD.

Conclusion: To the extent that reduced promoter methylation is associated with greater GR expression and responsivity, this finding is consistent with the hypothalamic-pituitary-adrenal dysregulation previously described for PTSD.

Trial registration: ClinicalTrials.gov NCT00855270.

Keywords: DNA cytosine methylation; cortisol; emergency department; glucocorticoid receptor; posttraumatic stress disorder (PTSD).

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Conflict of interest statement

Declarations of interest: none

Figures

Figure 1:
Figure 1:. NR3C1-1F promoter methylation at the initial ED visit
(A) Sum percent methylation at each of the 39 cytosine-phosphate-guanine (CpG) sites of the NR3C1-1F promoter for samples obtained at the initial ED visit. Boxes represent the location of known or putative canonical (solid-lined box) and non-canonical (broken-lined box) NGFI-A–binding sites. (B) Sum percent methylation at the ED for participants with (n = 4) and without PTSD (n = 33) at 13 months. (C) Pearson’s correlation analysis between PTSD severity (CAPS total scores) at 13 months and NR3C1-1F promoter methylation at the ED for all subjects (n=37). Data are presented as mean ± SEM.
Figure 2.
Figure 2.
ACTH (log) levels at the ED for participants with PTSD (n = 3) and without PTSD (n = 38) at 13 months. Data are presented as mean ± SEM.
Figure 3.
Figure 3.
NR3C1-1F promoter methylation at 13-month follow-up: Pearson’s correlation between PTSD severity (CAPS scores) at 13-month follow-up and NR3C1-1F promoter methylation at 13 months, indicating a significant inverse association.
See this image and copyright information in PMC

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