title: Effect of the common functional FKBP5 variant (rs1360780) on the hypothalamic-pituitary-adrenal axis and peripheral blood gene expression.
abstract: Regulation of hypothalamic-pituitary-adrenal (HPA) axis reactivity plays an important role in the development of stress-related psychiatric disorders. FK506 binding protein 5 (FKBP5) modulates HPA axis reactivity via glucocorticoid receptor (GR; NR3C1) sensitivity and signaling. The T allele of the single nucleotide polymorphism, FKBP5 rs1360780 (C/T), is associated with higher FKBP5 induction by glucocorticoids. In the present study, we performed the dexamethasone/corticotropin releasing hormone (DEX/CRH) test and quantitative real-time PCR analysis of peripheral blood mononuclear cell (PBMC) cDNA samples in 174 and 278 non-clinical individuals, respectively. We found increased suppression of the stress hormone (cortisol) response to the DEX/CRH test (P=0.0016) in aged (>50 years) individuals carrying the T allele compared with aged non-T allele carriers. T carriers showed significant age-related changes in GR and FKBP5 mRNA expression levels in PBMCs (P=0.0013 and P=0.00048, respectively). Our results indicate that FKBP5 rs1360780 regulates HPA axis reactivity and expression levels of GR and FKBP5 in PBMCs in an age-dependent manner. Because these phenotypes of aged T carriers are similar to endophenotypes of people with post-traumatic stress disorder, our findings may be useful for determining the molecular mechanisms, treatment, and preventive strategies for this disease.
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hori
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Ota
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Hattori
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Teraishi
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Daimei
authors.initials: D
authors.lastname: Sasayama
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Higuchi
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8502, Japan. Electronic address: hkunugi@ncnp.go.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kunugi
mesh_terms: D000328:Adult; D000367:Age Factors; D000483:Alleles; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D010912:Pituitary-Adrenal Function Tests; D010913:Pituitary-Adrenal System / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D022021:Tacrolimus Binding Proteins / Q000235:genetics*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5
keywords: Age-dependent; Dexamethasone/corticotropin-releasing hormone test; FK506 binding protein 5; Glucocorticoid receptor; Hypothalamic-pituitary-adrenal axis; Polymorphism; Post-traumatic stress disorder