GABRA2基因分型与近期饮酒的相互作用影响了对酒精主观反应的适应性。
Adaptation of Subjective Responses to Alcohol is Affected by an Interaction of GABRA2 Genotype and Recent Drinking.
作者信息
Kosobud Ann E K, Wetherill Leah, Plawecki Martin H, Kareken David A, Liang Tiebing, Nurnberger John L, Windisch Kyle, Xuei Xiaoling, Edenberg Howard J, Foroud Tatiana M, O'Connor Sean J
机构信息
Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
出版信息
Alcohol Clin Exp Res. 2015 Jul;39(7):1148-57. doi: 10.1111/acer.12749. Epub 2015 Jun 19.
BACKGROUND
Subjective perceptions of alcohol intoxication are associated with altered risk for alcohol abuse and dependence. Acute adaptation of these perceptions may influence such risk and may involve genes associated with pleasant perceptions or the relief of anxiety. This study assessed the effect of variation in the GABAA receptor genes GABRG1 and GABRA2 and recent drinking history on the acute adaptation of subjective responses to alcohol.
METHODS
One hundred and thirty-two nondependent moderate to heavy drinkers, aged 21 to 27, participated in 2 single-blind, counterbalanced sessions, approximately 1 week apart. One session was an intravenous alcohol "clamp," during which breath alcohol concentration was held steady at 60 mg/dl (60 mg%) for 3 hours, and the other an identical session using saline infusion. Subjective perceptions of Intoxication, Enjoyment, Stimulation, Relaxation, Anxiety, Tiredness, and Estimated Number of Drinks were acquired before (baseline), and during the first and final 45 minutes of the clamp. A placebo-adjusted index of the subject's acute adaptation to alcohol was calculated for each of the 7 subjective measures and used in a principal component analysis to create a single aggregate estimate for each subject's adaptive response to alcohol. Analysis of covariance tested whether GABRA2 and GABRG1 single nucleotide polymorphism (SNP) genotypes, gender, placebo session, family history of alcoholism, recent drinking history, and the genotype × recent drinking history interaction significantly predicted the adaptive response.
RESULTS
Recent drinking history (p = 0.01), and recent drinking history × genotype interaction (p = 0.01) were significantly associated with acute adaptation of the subjective responses to alcohol for the GABRA2 SNP rs279858.
CONCLUSIONS
Higher recent drinking was found to be associated with reduced acute tolerance to positive, stimulating effects of alcohol in carriers of the rs279858 risk allele. We postulate that the GABRA2 effect on alcohol dependence may, in part, be due to its effect on subjective responses to alcohol.
背景
对酒精中毒的主观认知与酒精滥用和依赖风险的改变有关。这些认知的急性适应性变化可能会影响此类风险，并且可能涉及与愉悦感认知或焦虑缓解相关的基因。本研究评估了γ-氨基丁酸A（GABAA）受体基因GABRG1和GABRA2的变异以及近期饮酒史对酒精主观反应急性适应性的影响。
方法
132名年龄在21至27岁之间、无酒精依赖的中度至重度饮酒者参加了2次单盲、平衡顺序的实验，两次实验间隔约1周。一次实验是静脉注射酒精“钳夹”，在此期间呼气酒精浓度在3小时内稳定保持在60mg/dl（60mg%），另一次实验是使用生理盐水输注进行相同操作。在（基线）、酒精“钳夹”的前45分钟、中间45分钟和最后45分钟期间获取对中毒、愉悦感、刺激感、放松感、焦虑感、疲劳感和估计饮酒量的主观认知。针对7项主观测量指标中的每一项，计算出受试者对酒精急性适应性的安慰剂调整指数，并用于主成分分析，以得出每个受试者对酒精适应性反应的单一综合估计值。协方差分析测试了GABRA2和GABRG1单核苷酸多态性（SNP）基因型、性别、安慰剂实验、酗酒家族史、近期饮酒史以及基因型×近期饮酒史的交互作用是否能显著预测适应性反应。
结果
对于GABRA2 SNP rs279858，近期饮酒史（p = 0.01）以及近期饮酒史×基因型交互作用（p = 0.01）与酒精主观反应的急性适应性显著相关。
结论
研究发现，对于rs279858风险等位基因携带者，近期饮酒量较高与对酒精积极刺激作用的急性耐受性降低有关。我们推测，GABRA2对酒精依赖的影响可能部分归因于其对酒精主观反应的影响。
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