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 cochaperone, 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.

Peroxisome Proliferator‐Activated Receptors α and γ are Linked with Alcohol Consumption in Mice and Withdrawal and Dependence in Humans

“…Our proof of principle approach combines both mouse and human data to systematically evaluate and nominate specific PPARs. An overall similar approach recently showed that SNPs of FKBP5 were associated with alcohol withdrawal in humans, and Fkbp5 knockout mice also showed greater withdrawal severity (Huang et al, 2014). Our results provide support for the first human genetic link between PPARs and alcohol-related phenotypes and suggest that further studies are warranted to evaluate repurposing PPAR agonists for treating AD.…”

Alcohol and tobacco consumption alter hypothalamic pituitary adrenal axis DNA methylation

“…Prior studies have implicated FKBP5 sequence and expression variation in moderating responses to alcohol use. For example, a recent study by Huang and associates demonstrated that FKBP5 genetic variation moderated the severity of alcohol withdrawal in both humans and rodents (Huang et al, 2014). Using a genome wide approach, Bell and associates showed that acute alcohol intake in rats was associated with increased transcription of FKPB5 (Bell et al, 2009).…”

The influence of FKBP5 genotype on expression of FKBP5 and other glucocorticoid‐regulated genes, dependent on trauma exposure

“…Importantly, for the design and interpretation of DAE analyses, there is high LD across FKBP5 including between rs1360780 (A/G) and rs3800373 (G/T) (Bevilacqua et al , 2012, Binder et al , 2004, Huang et al , 2014, Roy et al , 2010). This haplotype has been associated with differential induction of FKBP5 mRNA and protein by GR activation (Binder et al , 2004) and with GR resistance such that A allele carriers of healthy controls have a prolonged cortisol response even to minor stressors (Ising et al , 2008).…”