FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice
FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice
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DOI：
10.1038/npp.2014.55
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发表时间：
2014-07-01
影响因子：
7.6
通讯作者：
Heilig, Markus
中科院分区：
文献类型：
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作者：
Huang, Ming-Chyi;Schwandt, Melanie L.;Heilig, Markus
酒精戒断与下丘脑-垂体-肾上腺(HPA)轴功能障碍有关。FKBP5基因编码辅助伴侣FK506结合蛋白5，对HPA轴功能起负反馈作用。本研究旨在探讨人类FKBP5基因单核苷酸多态(SNPs)和小鼠FKBP5基因缺失对酒精戒断程度的影响。我们在入院前48h对399例酒依赖住院患者进行了6个FKBP5单核苷酸多态(rs3800373、rs9296I58、rs3777747、rs9380524、rsI 360780和rs9470080)基因分型，并记录了临床研究所戒酒评定量表(CIWA-AR)的评分。FKBP5基因敲除(KO)和野生型(WT)小鼠在急性和慢性酒精暴露后，使用处理诱导的惊厥(HIC)评估了酒精戒断的情况。我们发现rs3800373(G)、rs9296I58(A)、rsI360780(T)和rs9470080(T)的次要等位基因与较低的CIWA-AR得分显著相关，而rs3777747(G)和rs9380524(A)的次要等位基因与较高的得分相关。基于单倍型的分析还表明，酒精戒断的严重程度与此有关。与WT对照组相比，FKBP5 KO小鼠在慢性酒精暴露戒断过程中HIC显著增加。这项研究首次显示了FKBP5对酒精戒断综合症严重程度的遗传效应。在小鼠中，FKBP5基因的缺失增强了对酒精戒断的敏感性。我们认为，在酒精戒断过程中，FKBP5变异可能触发HPA轴调节的不同适应性变化，并伴随着对戒断严重程度的影响。
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, rs9296I58, rs3777747, rs9380524, rs I 360780, 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), rs9296I58 (A), rsI360780 (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.