SA57 - GENETIC AND EPIGENETIC INVOLVEMENT OF THE FKPB5 GENE IN POSTTRAUMATIC STRESS DISORDER AFTER COMBAT TRAUMA

Abstract

Background FK506 binding protein 5 (FKBP5) is a major regulatory protein of the HPA axis, which binds to the glucocorticoid receptors and modulate glucocorticoid sensitivity. The FKBP5 genes have been implicated in dysregulation of human stress responses, contributing to vulnerable phenotypes such as depression and anxiety. The present study aimed to investigate whether genetic and epigenetic factors of the FKBP5 are a predictive biomarker of Posttraumatic Stress Disorder (PTSD) among veterans exposed to combat. In addition, the influence of potentially associated factors, including combat exposure levels and alcohol problem, was examined in the pathophysiology of PTSD. Methods All subjects were Korean male veterans who served on active duty during the Vietnam War and the Combat Exposure Scale (CES) was used for assessing the level of wartime stressors experienced by combatants. Using the Clinician-Administered PTSD Scale (CAPS), combat veterans were grouped into those with (n=124) and without (n=120) PTSD. Three SNPs of the FKBP5 locus (rs9296158, rs1360780, and rs9470080) were genotyped with single base primer extension assay using the ABI PRISM SNaPShot Multiplex kit. DNA methylation levels at two CpG sites in the FKBP5 intron 7 region were quantified in the peripheral blood using the bisulfite pyrosequencing method. The effects of FKBP5 variants, the DNA methylation levels and clinical factors on the diagnosis of PTSD were tested using binary logistic regression analysis. Results Since a significant interaction effect between alcohol problem and FKBP5 variants was found for PTSD symptom, logistic regression analyses stratified by presence of alcohol problem were performed. Among combat-exposed individuals without alcohol problem, the risk allele of FKBP5 rs1360780, higher methylation levels at the FKBP5 CpG1 site, high combat exposure significantly predicted PTSD diagnosis in combat-exposed individuals (Model Summary: -2 Log likelihood=144.07, Nagelkerke R2=0.279; Overall percentage of correct classification resulting from the model=72.9%). In the logistic model among subjects with alcohol problem, the combat exposure level was an only significant predictor of PTSD status. Discussion The present study demonstrated the involvement of FKBP5 genetic variants and higher DNA methylation of the FKBP5 in PTSD status without alcohol problem. The present findings suggest that the external traumatic events may influence PTSD pathophysiology via genetic and epigenetic modulation of the FKBP5 and alcohol problem may be a moderating factor of PTSD. Further prospective research examining genetic variants and epigenetic changes of FKBP5 locus in people exposed to trauma might shed light on the role and the biological basis of FKBP5 in susceptibility to PTSD.