title: Using polymorphisms in FKBP5 to define biologically distinct subtypes of posttraumatic stress disorder: evidence from endocrine and gene expression studies.
abstract: BACKGROUND
  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.
  
  
  METHODS
  Association of FKBP5 genotypes and PTSD symptoms with endocrine measures and genome-wide expression profiles.
  
  
  METHODS
  Waiting rooms of general medical and gynecological clinics of an urban hospital at Emory University.
  
  
  METHODS
  The 211 participants were primarily African American (90.05%) and of low socioeconomic status and had high rates of trauma and PTSD.
  
  
  METHODS
  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.
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstrasse, Munich, Germany.
authors.forename: Divya
authors.initials: D
authors.lastname: Mehta
authors.forename: Mariya
authors.initials: M
authors.lastname: Gonik
authors.forename: Torsten
authors.initials: T
authors.lastname: Klengel
authors.forename: Monika
authors.initials: M
authors.lastname: Rex-Haffner
authors.forename: Andreas
authors.initials: A
authors.lastname: Menke
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rubel
authors.forename: Kristina B
authors.initials: KB
authors.lastname: Mercer
authors.forename: Benno
authors.initials: B
authors.lastname: Pütz
authors.forename: Bekh
authors.initials: B
authors.lastname: Bradley
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Ressler
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
mesh_terms: D000328:Adult; D000483:Alleles; D004247:DNA / Q000097:blood; D003907:Dexamethasone; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D053727:Interleukin-18 Receptor alpha Subunit / Q000235:genetics; D008297:Male; D010912:Pituitary-Adrenal Function Tests / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D012313:RNA / Q000097:blood; D012720:Severity of Illness Index; D013313:Stress Disorders, Post-Traumatic / Q000097:blood / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000235:genetics*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D004247:DNA; D003907:Dexamethasone; D006854:Hydrocortisone; D053727:Interleukin-18 Receptor alpha Subunit; D012313:RNA; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C508572:IL18R1 protein, human