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  • Title: Glucocorticoid receptor gene methylation moderates the association of childhood trauma and cortisol stress reactivity.
    Author: Alexander N, Kirschbaum C, Wankerl M, Stauch BJ, Stalder T, Steudte-Schmiedgen S, Muehlhan M, Miller R.
    Journal: Psychoneuroendocrinology; 2018 Apr; 90():68-75. PubMed ID: 29433075.
    Abstract:
    Exposure to childhood trauma (CT) has been linked to sustained dysregulations of major stress response systems, including findings of both exaggerated and attenuated hypothalamus-pituitary-adrenal (HPA) axis activity. Likewise, CT constitutes a common risk factor for a broad range of psychiatric conditions that involve distinct neuroendocrine profiles. In this study, we investigated the role of epigenetic variability in a stress-related gene as a potential mediator or moderator of such differential trajectories in CT survivors. For this, we screened adult volunteers for CT and recruited a healthy sample of 98 exposed (67 with mild-moderate, 31 with moderate-severe exposure) and 102 control individuals, with an equal number of males and females in each group. DNA methylation (DNAM) levels of the glucocorticoid receptor exon 1F promoter (NR3C1-1F) at functionally relevant sites were analyzed via bisulfite pyrosequencing from whole blood samples. Participants were exposed to a laboratory stressor (Trier Social Stress Test) to assess salivary cortisol stress responses. The major finding of this study indicates that DNAM in a biologically relevant region of NR3C1-1F moderates the specific direction of HPA-axis dysregulation (hypo- vs. hyperreactivity) in adults exposed to moderate-severe CT. Those trauma survivors with increased NR3C1-1F DNAM displayed, on average, 10.4 nmol/l (62.3%) higher peak cortisol levels in response to the TSST compared to those with low DNAM. In contrast, unexposed and mildly-moderately exposed individuals displayed moderately sized cortisol stress responses irrespective of NR3C1-1F DNAM. Contrary to some prior work, however, our data provides no evidence for a direct association of CT and NR3C1-1F DNAM status. According to this study, epigenetic changes of NR3C1-1F may provide a more in-depth understanding of the highly variable neuroendocrine and pathological sequelae of CT.
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