Dataset Information

No association between FKBP5 gene methylation and acute and long-term cortisol output.

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.

SUBMITTER: Alexander N

PROVIDER: S-EPMC7266811 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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No association between FKBP5 gene methylation and acute and long-term cortisol output.

Alexander Nina N Alexander Nina N Kirschbaum Clemens C Stalder Tobias T Muehlhan Markus M Vogel Susanne S

Translational psychiatry 20200602 1

Prior studies identified DNA methylation (DNA<sub>M</sub>) 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 DNA<sub>M</sub> with both acute and chr ...[more]

PMID: 32488091

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Project description:Abstract Background: We have previously shown elevated cortisol levels during the day and a blunted cortisol awakening response (CAR) at the onset of psychosis. Although stressful events and childhood abuse have been suggested to possibly play a role in these abnormalities, the evidence behind this link remains inconsistent, and it has been suggested that these could be partly due to genetic predisposition. The aim of this study was to test interaction between history of childhood abuse and rs1360780 FKBP5 genotype on cortisol levels during the day and cortisol awakening response. Methods: Eighty-two first-episode psychosis patients and 53 controls were enrolled in the study. Saliva samples were collected at multiple time points during the day to measure diurnal cortisol levels and cortisol awakening response (CAR); DNA was extracted from blood or saliva samples and evaluated for a functional polymorphism at the rs1360780 locus in FKBP5. Information about presence of absence childhood physical or sexual abuse was collected using the Childhood Experience of Care and Abuse questionnaire. Univariate analyses were performed to test the effects of the interaction between presence of childhood abuse and FKBP5 genotype on cortisol measurements. Results: We found a significant interaction between history of childhood abuse and FKBP5 genotype on the CAR in first episode psychosis (F = 1.132, P = .01) but not in controls (P = .3). In particular patients with T allele (CT or TT) and history of childhood abuse had higher CAR than those with the same allele but without childhood abuse, while patients with CC genotype and history of childhood abuse had lower CAR than those with the same genotype but without childhood abuse. We also found a trend for interaction between history of childhood abuse and FKBP5 genotype on the cortisol levels during the day (F = 3.604, P = .06) in first episode psychosis but in controls (P = .3). In particular patients with T allele (CT or TT) and history of childhood abuse had higher diurnal cortisol levels than those with the same allele but without childhood abuse, while patients with CC genotype and history of childhood abuse had lower diurnal cortisol levels than those with the same genotype but without childhood abuse. Conclusion: Our findings suggest a role of interaction between childhood abuse and FKBP5 genotype in determining HPA axis abnormalities observed at the onset of psychosis.

Project description:Periodontitis, the leading cause of adult tooth loss, has been identified as an independent risk factor for cardiovascular disease (CVD). Studies suggest that periodontitis, like other CVD risk factors, shows the persistence of increased CVD risk even after mitigation. We hypothesized that periodontitis induces epigenetic changes in hematopoietic stem cells in the bone marrow (BM), and such changes persist after the clinical elimination of the disease and underlie the increased CVD risk. We used a BM transplant approach to simulate the clinical elimination of periodontitis and the persistence of the hypothesized epigenetic reprogramming. Using the low-density lipoprotein receptor knockout (LDLRo ) atherosclerosis mouse model, BM donor mice were fed a high-fat diet to induce atherosclerosis and orally inoculated with Porphyromonas gingivalis (Pg), a keystone periodontal pathogen; the second group was sham-inoculated. Naïve LDLR o mice were irradiated and transplanted with BM from one of the two donor groups. Recipients of BM from Pg-inoculated donors developed significantly more atherosclerosis, accompanied by cytokine/chemokines that suggested BM progenitor cell mobilization and were associated with atherosclerosis and/or PD. Using whole-genome bisulfite sequencing, 375 differentially methylated regions (DMRs) and global hypomethylation in recipients of BM from Pg-inoculated donors were observed. Some DMRs pointed to the involvement of enzymes with major roles in DNA methylation and demethylation. In validation assays, we found a significant increase in the activity of ten-eleven translocase-2 and a decrease in the activity of DNA methyltransferases. Plasma S-adenosylhomocysteine levels were significantly higher, and the S-adenosylmethionine to S-adenosylhomocysteine ratio was decreased, both of which have been associated with CVD. These changes may be related to increased oxidative stress as a result of Pg infection. These data suggest a novel and paradigm-shifting mechanism in the long-term association between periodontitis and atherosclerotic CVD.

Project description:Chronic exposure to cortisol is associated with cardiovascular, metabolic, and psychiatric disorders. Although cortisol can be readily measured from peripheral sources such as blood, urine, or saliva, multiple samplings spanning several days to weeks are necessary to reliably assess chronic cortisol exposure levels (referred to as cortisol load). Although cortisol levels in hair have been proposed as a measure of cortisol load, measurement is cumbersome and many people are not candidates due to short hair length and use of hair dyes. To date, there are no blood biomarkers that capture cortisol load. To identify a blood biomarker capable of integrating one-month cortisol exposure levels, 75 healthy participants provided 30+ days of awakening and bedtime saliva cortisol and completed psychosocial measures of anxiety, depression, and stress. Mean daily awakening and bedtime cortisol levels were then compared to CpG methylation levels, gene expression, and genotypes of the stress response gene FKBP5 obtained from blood drawn on the last day of the study. We found a correlation between FKBP5 methylation levels and mean 30+day awakening and bedtime cortisol levels (|r|≥0.32, p ≤ 0.006). We also observed a sex-specific correlation between bedtime cortisol levels and FKBP5 mRNA expression in female participants (r = 0.42, p = 0.005). Dividing the 30-day sampling period into four weekly bins showed that the correlations for both methylation and expression were not being driven by cortisol levels in the week preceding the blood draw. We also identified a female-specific association between FKBP5 mRNA expression and scores on the Beck Anxiety Inventory (r = 0.37, p = 0.013) and Beck Depression Inventory-II (r = 0.32, p = 0.033). Finally, DNA was genotyped at four SNPs, and variation in rs4713902 was shown to have an effect on FKBP5 expression under a codominant model (f = 3.41, p = 0.048) for females only. Our results suggest that blood FKBP5 DNA methylation and mRNA expression levels may be a useful marker for determining general or sex-specific 30-day cortisol load and justifies genome-wide approaches that can potentially identify additional cortisol markers with broader clinical utility.

Dataset Information

No association between FKBP5 gene methylation and acute and long-term cortisol output.

Publications

No association between FKBP5 gene methylation and acute and long-term cortisol output.

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