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.2011 Sep;68(9):901-10.
doi: 10.1001/archgenpsychiatry.2011.50. Epub 2011 May 2.

Using polymorphisms in FKBP5 to define biologically distinct subtypes of posttraumatic stress disorder: evidence from endocrine and gene expression studies

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Using polymorphisms in FKBP5 to define biologically distinct subtypes of posttraumatic stress disorder: evidence from endocrine and gene expression studies

Divya Mehta et al. Arch Gen Psychiatry.2011 Sep.

Abstract

Context: Polymorphisms in the gene encoding the glucocorticoid receptor (GR) regulating co-chaperone FKBP5 have been shown to alter GR sensitivity and are associated with an increased risk to develop posttraumatic stress disorder (PTSD).

Objective: To investigate interactions of the FKBP5 single-nucleotide polymorphism rs9296158 and PTSD symptoms on baseline cortisol level, low-dose dexamethasone suppression, and whole-blood gene expression.

Design: Association of FKBP5 genotypes and PTSD symptoms with endocrine measures and genome-wide expression profiles.

Setting: Waiting rooms of general medical and gynecological clinics of an urban hospital at Emory University.

Participants: The 211 participants were primarily African American (90.05%) and of low socioeconomic status and had high rates of trauma and PTSD.

Main outcome measures: Baseline and post-dexamethasone suppression cortisol measures and gene expression levels.

Results: In our endocrine study, we found that only risk allele A carriers of rs9296158 showed GR supersensitivity with PTSD; in contrast, baseline cortisol levels were decreased in PTSD only in patients with the GG genotype. Expression of 183 transcripts was significantly correlated with PTSD symptoms after multiple testing corrections. When adding FKBP5 genotype and its interaction with PTSD symptoms, expression levels of an additional 32 genes were significantly regulated by the interaction term. Within these 32 genes, previously reported PTSD candidates were identified, including FKBP5 and the IL18 and STAT pathways. Significant overrepresentation of steroid hormone transcription factor binding sites within these 32 transcripts was observed, highlighting the fact that the earlier-described genotype and PTSD-dependent differences in GR sensitivity could drive the observed gene expression pattern. Results were validated by reverse transcriptase-polymerase chain reaction and replicated in an independent sample (N = 98).

Conclusions: These data suggest that the inheritance of GR sensitivity-moderating FKBP5 polymorphisms can determine specific types of hypothalamic-pituitary-adrenal axis dysfunction within PTSD, which are also reflected in gene-expression changes of a subset of GR-responsive genes. Thus, these findings indicate that functional variants in FKBP5 are associated with biologically distinct subtypes of PTSD.

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Figures

Figure 1
Figure 1
Cortisol levels at baseline and after low-dose dexamethasone suppression. A, Baseline cortisol levels in individuals with and without posttraumatic stress disorder (PTSD) stratified by the rs9296158 A carrier status. In individuals carrying rs9296158 GG, PTSD symptom severity was negatively correlated with baseline cortisol level (Pearson correlation=−0.328), and in individuals carrying AA/AG, PTSD symptom severity was positively correlated with baseline cortisol level (Pearson correlation=0.157). B, Levels of serum cortisol suppression after low-dose (0.5-mg) dexamethasone suppression in individuals with and without PTSD stratified by rs9296158 A carrier status. Posttraumatic stress disorder was associated with increased dexamethasone suppression only in risk allele A carriers. The triple interaction of rs9296158 A carrier status and PTSD status on cortisol suppression was significant (P=.03). To convert cortisol to nanomoles per liter, multiply by 27.588.
Figure 2
Figure 2
Validation and replication ofFKBP5 expression differences in posttraumatic stress disorder (PTSD) using quantitative polymerase chain reaction (qPCR). The PTSD Symptom Scale (PSS) total scores are plotted on the x-axis against the expression levels as measured by log2 expression for the microarray data and 2−ΔCT (change in crossing thresholds) for the qPCR validation and replication on the y-axis. The Pearson correlation coefficients for the rs9296158 A carrier status groups are shown. Post hoc genotype-dependent differences of the correlation coefficients were established by converting them into Fisherz scores. Thez score differences between the 2 genotype groups were significant for the microarray expression (z=2.17; significant atP=.01), qPCR validation (z=2.12; significant atP=.05), and qPCR replication (z=2.87; significant atP=.01). RT-PCR indicates reverse transcriptase–polymerase chain reaction.
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