FKBP5 genotype-dependent DNA methylation and mRNA regulation after psychosocial stress in remitted depression and healthy controls.

BACKGROUND: Polymorphisms in the FK506 binding protein 5 (FKBP5) gene have been shown to influence glucocorticoid receptor sensitivity, stress response regulation, and depression risk in traumatized subjects, with most consistent findings reported for the functional variant rs1360780. In the present study, we investigated whether the FKBP5 polymorphism rs1360780 and lifetime history of major depression are associated with DNA methylation and FKBP5 gene expression after psychosocial stress. METHODS: A total of 116 individuals with a positive (n = 61) and negative (n = 55) lifetime history of major depression participated in the Trier Social Stress Test. We assessed plasma cortisol concentrations, FKBP5 mRNA expression, and CpG methylation of FKBP5 intron 7 in peripheral blood cells. RESULTS: Genotype-dependent plasma cortisol response to psychosocial stress exposure was observed in healthy controls, with the highest and longest-lasting cortisol increase in subjects with the TT genotype of the FKBP5 polymorphism rs1360780, and healthy controls carrying the T risk allele responded with a blunted FKBP5 mRNA expression after psychosocial stress. No genotype effects could be found in remitted depression. CONCLUSIONS: The FKBP5 rs1360780 polymorphism is associated with plasma cortisol and FKBP5 mRNA expression after psychosocial stress in healthy controls but not in remitted depression. Preliminary results of the DNA methylation analysis suggest that epigenetic modifications could be involved.

Increased HPA axis response to psychosocial stress in remitted depression: the influence of coping style.

The aim of the study was to examine the modulating effects of coping style on the response to psychosocial stress in remitted major depression (MD) and healthy controls. Thirty-three participants with a lifetime history of MD, who were in remission, and 32 age- and gender-matched healthy controls were recruited from a longitudinal-epidemiological study, in which the presence or absence of mental disorders was prospectively ascertained. Participants (aged 30-41 years) underwent two consecutive Trier Social Stress Tests (TSSTs). Subjects with a lifetime history of MD showed larger plasma ACTH and cortisol concentrations in response to both TSSTs, confirming a disturbed hypothalamic-pituitary-adrenal (HPA) axis regulation. Moreover, the MD group reported less positive, adaptive coping strategies and more negative, maladaptive strategies than the control group. The amount of negative coping predicted the size of the plasma cortisol response in the combined group. Our results demonstrate the importance of psychological coping strategies for the investigation of HPA axis response in depression.