Glucocorticoid receptor polymorphisms predict response to treatment in PTSD

Abstract

Rational: Increased GR sensitivity has been associated with PTSD severity in several studies, and in a recent report, was found to predict the extent of improvement in severity of PTSD symptoms from pre- to post-treatment. These findings provided the rational for an investigation of two GR genotype polymorphisms know to affect GR sensitivity in relation to PTSD severity and treatment response. The BclI (rs41423247) single nucleotide polymorphism (SNP) is an intronic restriction fragment length polymorphism located 646 bp downstream from GR exon 2. SNP 9β (rs6198) is located on exon 9β of the GR. It is believed to increase the stability of splice variant GRβ, an inhibitor of the wild-type GRα. Carriers of the BclI minor allele have been associated with an increased sensitivity to glucocorticoids (GCs), whereas 9β carriers have been linked to relatively diminished sensitivity. We studied these polymorphisms in the context of a treatment study in which participants were evaluated prior to and following treatment. Methods: For the treatment study, subjects were randomized into two treatment conditions, weekly prolonged exposure therapy and a minimal attention, in which participants received a weekly phone call to evaluate symptom severity and monitor for safety. Clinical outcome was assessed using pre- and post-treatment Clinician Administered PTSD Scale (CAPS) total scores. Pre-treatment genotype data were available for 27 of 36 receiving prolonged exposure and for 9 or 13 who received the minimal attention condition. DNA was isolated from lymphocytes using Ficoll-Paque Plus (Amersham Pharmacia Biotech) and extracted (using FlexGene DNA Kit, Qiagen); genotyping of SNPs BclI and 9β was performed using the allelic discrimination technique with custom designed probes and primers according to the published genomic sequences, with results that did not differ from Hardy–Weinberg equilibrium. Results: The presence of the G allele in the BclI SNP was inversely associated with lifetime, but not current, total CAPS score for treatment completers (t=2.94, df = 29, p=0.006), indicating a less severe lifetime course of PTSD. Polymorphisms at the Snp9Beta locus were not related to lifetime PTSD severity. The same polymorphism at BclI predicted the absence of a PTSD diagnosis following treatment (χ2(1) = 7.30, p=0.007). A similar relationship for Snp9Beta was not apparent. In order to test the relative strength of BclI genotype in the prediction of PTSD outcome, a logistic regression was performed with age, ethnicity, treatment type, and pre-treatment CAPS total score as covariates. In this model, only BclI genotype was a significant predictor (B= − 2.59, p=0.022, OR = 0.074). Without BclI genotype in the model, there was a trend for pre-treatment CAPS total score to predict PTSD at post-treatment (B=0.062, p=0.080, OR = 1.05). Conclusion: The BclI polymorphism is related to a less severe lifetime course of PTSD, and is a substantial predictor of positive outcome in response to short-term psychotherapy. The relation of this genotype to recovery from PTSD was even stronger than pre-treatment clinical severity or type of treatment. The result suggests that BclI genotype may be a useful biomarker in the selection of potential treatment candidates. This work should be repeated in additional, and larger samples for verification.

Keywords

• glucocorticoid receptor
• PTSD
• genetics
• BclI polymorphism
• predictors of treatment
• prolonged exposure therapy