title: FKBP5 moderates alcohol withdrawal severity: human genetic association and functional validation in knockout mice.
abstract: Alcohol withdrawal is associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction. The FKBP5 gene codes for a co-chaperone, FK506-binding protein 5, that exerts negative feedback on HPA axis function. This study aimed to examine the effects of single-nucleotide polymorphisms (SNPs) of the FKBP5 gene in humans and the effect of Fkbp5 gene deletion in mice on alcohol withdrawal severity. We genotyped six FKBP5 SNPs (rs3800373, rs9296158, rs3777747, rs9380524, rs1360780, and rs9470080) in 399 alcohol-dependent inpatients with alcohol consumption 48 h before admission and recorded scores from the Clinical Institute Withdrawal Assessment-Alcohol revised (CIWA-Ar). Fkbp5 gene knockout (KO) and wild-type (WT) mice were assessed for alcohol withdrawal using handling-induced convulsions (HICs) following both acute and chronic alcohol exposure. We found the minor alleles of rs3800373 (G), rs9296158 (A), rs1360780 (T), and rs9470080 (T) were significantly associated with lower CIWA-Ar scores whereas the minor alleles of rs3777747 (G) and rs9380524 (A) were associated with higher scores. The haplotype-based analyses also showed an association with alcohol withdrawal severity. Fkbp5 KO mice showed significantly greater HICs during withdrawal from chronic alcohol exposure compared with WT controls. This study is the first to show a genetic effect of FKBP5 on the severity of alcohol withdrawal syndrome. In mice, the absence of the Fkbp5 gene enhances sensitivity to alcohol withdrawal. We suggest that FKBP5 variants may trigger different adaptive changes in HPA axis regulation during alcohol withdrawal with concomitant effects on withdrawal severity.
authors.affiliation: 1] Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan [2] Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ming-Chyi
authors.initials: MC
authors.lastname: Huang
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Schwandt
authors.affiliation: 1] Department of Psychological Sciences, Purdue University, West Lafayette, IN, USA [2] Department of Medicine, Indiana University, School of Medicine, Indianapolis, IN, USA.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Chester
authors.affiliation: 1] Department of Psychological Sciences, Purdue University, West Lafayette, IN, USA [2] Department of Medicine, Indiana University, School of Medicine, Indianapolis, IN, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Kirchhoff
authors.affiliation: Department of Public Health and Institute of Epidemiology and Preventive Medicine, College of Public Health, Taipei, Taiwan.
authors.forename: Chung-Feng
authors.initials: CF
authors.lastname: Kao
authors.affiliation: 1] Department of Psychological Sciences, Purdue University, West Lafayette, IN, USA [2] Department of Medicine, Indiana University, School of Medicine, Indianapolis, IN, USA.
authors.forename: Tiebing
authors.initials: T
authors.lastname: Liang
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jenica D
authors.initials: JD
authors.lastname: Tapocik
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Vijay A
authors.initials: VA
authors.lastname: Ramchandani
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: George
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism/National Institutes of Health, Bethesda, MD, USA.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Hodgkinson
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism/National Institutes of Health, Bethesda, MD, USA.
authors.forename: David
authors.initials: D
authors.lastname: Goldman
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
mesh_terms: D000328:Adult; D000818:Animals; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D013375:Substance Withdrawal Syndrome / Q000235:genetics*; D022021:Tacrolimus Binding Proteins / Q000235:genetics*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D000431:Ethanol; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5