Abstract
Prior studies identified DNA methylation (DNAM) changes in a regulatory region within the FK506 binding protein 5 (FKBP5) gene as a crucial mediator of long-term negative health outcomes following early adversity. A critical mechanism underlying this link, in turn, has been suggested to be epigenetically induced dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. The purpose of this study was thus to investigate associations of FKBP5 DNAM with both acute and chronic cortisol output. Two hundred adults with differential exposure to childhood trauma (CT) were underwent a laboratory stressor (Trier Social Stress Test) and provided salivary samples for the analysis of acute cortisol stress responses. In addition, hair cortisol concentrations were determined as a valid measure of integrated long-term cortisol levels. Whole blood samples were drawn for DNAM analyses of FKBP5 intron 7 via bisulfite pyrosequencing. In contrast to most prior work, only healthy participants were included in order to disentangle the effects of trauma exposure per se from those related to mental disorders. First, our findings did not reveal strong evidence for a robust effect of CT on FKBP5 intron 7 DNAM status, even if genetic predisposition (rs1360780 genotype) was taken into account. Second, FKBP5 DNAM levels were found to be unrelated to acute cortisol stress reactivity and long-term cortisol concentration in hair. The failure to demonstrate a significant association between CT and FKBP5 DNAM in an exclusively healthy sample could be interpreted as suggesting that individuals’ mental health status may be a critical modulator of previously observed effects.
Highlights
Adversity has been repeatedly linked with the epigenetic state of genes that regulate major stress response systems, thereby promoting vulnerability to stress-related mental disorders[1,2]
The different trauma groups did not differ in sex distribution, age, years in school, body mass index, or use of oral contraceptives (Table 1)
Axis related to epigenetic changes in FK506 binding protein 5 (FKBP5)
Summary
Adversity has been repeatedly linked with the epigenetic state of genes that regulate major stress response systems, thereby promoting vulnerability to stress-related mental disorders[1,2]. FKBP5 induction, most notably the rs1360780 T allele, induce GR resistance and impair negative feedback regulation of the HPA-axis[7]. This disruption in regulatory homeostasis results in chronically elevated glucocorticoid levels[3]. The rs1360780 T allele (along with other high-induction FKBP5 alleles) has been identified as a risk factor for mental disorders in a recent candidate gene based metaanalysis[9], in particular upon exposure to environmental adversity[7,10]. The latest genome-wide metaanalysis of depression could not replicate this finding[11]
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