Background: FK506-binding protein 5 (FKBP5) binds to glucocorticoid receptors and modulates glucocorticoid sensitivity. The FKBP5 gene has been implicated in the dysregulation of human stress responses, contributing to the risk and treatment response of stress-related disorders. The present study examined whether epigenetic changes in FKBP5 are associated with chronic post-traumatic stress disorder (PTSD) status in the context of FKBP5 genetic variation (rs1360780 polymorphism) among male veterans exposed to combat trauma.
Methods: Korean male veterans who served on active duty during the Vietnam War were categorized into 2 groups: with PTSD (n = 123) and without PTSD (n = 116). The genotype of FKBP5 rs1360780 and DNA methylation levels of two CpG sites at the FKBP5 intron 7 region were assessed in peripheral blood. Analysis of covariance was performed to examine main and interaction effects of PTSD status and FKBP5 genotype on FKBP5 DNA methylation level, with age, trauma levels, and alcohol use as covariates.
Results: A significant main effect of FKBP5 rs1360780 and PTSD and an interaction effect between genotype and PTSD status were found on mean FKBP5 DNA methylation level. The T allele of rs1360780 was associated with lower FKBP5 methylation level. In addition, the PTSD group showed significantly higher methylation than did the non-PTSD group among veterans carrying the risk T allele (n = 96), while no group difference was observed on methylation levels among veterans with the CC genotype (n = 143). Among veterans carrying the T allele, FKBP5 methylation levels were positively correlated with the severity of PTSD symptoms.
Conclusions: The present study demonstrated different FKBP5 methylation levels in PTSD depending on FKBP5 genetic variation among veterans exposed to combat trauma. The present finding suggests that the genetic and epigenetic modulation of FKBP5 is involved in the pathophysiology of PTSD. Further longitudinal research involving people exposed to trauma is required to understand causal relationships of FKBP5 in the development and recovery of PTSD.
Keywords: DNA methylation; Epigenetics; FKBP5; Genetics; HPA axis; Post-traumatic stress disorder.
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