Abstract
Some individuals suffering from posttraumatic stress disorder (PTSD) exhibit lower basal salivary cortisol and higher glucocorticoid receptor (GR) sensitivity. Recent studies suggest that epigenetic mechanisms regulate the activity of cortisol and GR. As a means to combine and cross-validate those findings, we compared cortisol, GR expression and promoter methylation levels in peripheral T lymphocytes of healthy controls versus individuals endorsing a diagnosis of lifetime PTSD. Thirty subjects with lifetime (current or remitted) PTSD and 16 subjects never exposed to trauma were recruited. Salivary cortisol was collected at six time points over the course of a single weekday and analyzed utilizing a time-resolved fluorescence immunoassay. GR expression (GRtotal, 1B, 1C, 1F and 1H) was measured by quantitative RT-PCR. DNA methylation levels in human glucocorticoid receptor (hGR) 1B and 1C variant's promoter were quantified by epityper in T lymphocytes isolated by magnetic-assisted cell sorting. Individuals with lifetime PTSD have lower morning cortisol release, higher mRNA expression of hGRtotal, 1B, and 1C and lower overall methylation levels in hGR 1B and 1C promoters. Cortisol levels were inversely correlated with hGR 1B mRNA expression. Moreover, overall and CpG site-specific methylation levels were inversely correlated with hGRtotal and 1B mRNA expression. There was no difference between current and remitted PTSD across cortisol, GR expression mRNA and DNA methylation data. Traumatic events induce DNA methylation alterations in distinct promoters of hGR with transcriptional modifications that associate with hypoactive hypothalamus-pituitary-adrenal axis in individuals with PTSD. Our results also point toward an important role of hGR 1B variant in PTSD.
Highlights
Posttraumatic stress disorder (PTSD) is characterized by symptoms of intrusions, avoidance and hyperarousal following exposure to a traumatic event
Consistent with previous ficantly lower in the PTSD group compared with the controls for the time interval between 30 and 45 min post awakening
In this study, we investigated the HPA axis profile of individuals suffering from lifetime PTSD and healthy controls by measuring basal salivary cortisol levels, human glucocorticoid receptor (hGR) peripheral expression and CpG methylation states in T lymphocytes
Summary
Posttraumatic stress disorder (PTSD) is characterized by symptoms of intrusions, avoidance and hyperarousal following exposure to a traumatic event. The clinical manifestations of PTSD may reflect enduring changes in the stress-related neurobiological structures and systems.[8] changes in the activity of the hypothalamus-pituitary-adrenal (HPA) axis, the main stress regulatory system, are induced by exposure to severe stressors in animals and humans[9,10] and dysfunction of the HPA axis activity is a well-characterized feature in PTSD Such patients exhibit higher corticotropin releasing factor in the cerebrospinal fluid,[11,12] lower plasma and serum morning cortisol release,[13] higher glucocorticoid receptor (GR) expression in lymphocytes[14] and greater GR sensitivity.[15] In addition, recent studies have shown that life-events, at least early in life, can modify the chemical structure surrounding the genome and influence gene expression,[16] including GR expression.[17,18,19]
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