Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
Department of Veterans Affairs, Alcohol Research Center, VA Connecticut Healthcare System (116-A), West Haven, Connecticut.
Alcohol Clin Exp Res. 2017 Dec;41(12):2025-2032. doi: 10.1111/acer.13516. Epub 2017 Nov 13.
The heritable risk for alcohol use disorder (AUD) is expressed partly through alterations in subjective alcohol response. In this study, we investigated the effects of 2 AUD-risk-associated single nucleotide polymorphisms, GABRA2 rs279858 and GRIK1 rs2832407, on the subjective response to alcohol administered intravenously to healthy social drinkers in a laboratory setting.
In total, 93 self-identified European American social drinkers underwent 3 blinded laboratory sessions in which they received intravenous infusions of ethanol at 3 target blood alcohol levels (0.00 mg%, 40 mg%, and 100 mg%) using a "clamp" procedure. The self-reported Biphasic Alcohol Effects Scale (BAES) stimulation and sedation subscales were the primary outcome measures. We examined the effects of these 2 genetic variants on subjective response to alcohol.
For the BAES stimulation subscale scores, adjusting for age, baseline scores, and time effects, individuals with 2 copies of the GABRA2 rs279858 C "risk" allele for AUD exhibited the greatest stimulant responses to high-dose alcohol compared to the other risk allele counts (dose-by-allele count interaction effect, p = 0.001, post hoc contrast for C-allele, p = 0.012). For the BAES sedation subscale scores, adjusting for the same covariates, we detected a dose-by-allele count interaction effect (p = 0.0044) such that subjects with 2 copies of the GRIK1 C "risk" allele reported the greatest sedative response to the higher alcohol dose.
This study suggests that gene variants contributing to the risk for AUD may alter features of the alcohol dose-response relationship in specific ways. GABRA2 rs279858C enhances stimulant responses to higher levels of alcohol, while the GRIK1 rs2832407C-allele increases sedative responses. In summary, GRIK1 and GABRA2 variants have distinct effects on the dose-related subjective response to intravenous alcohol in humans.
酒精使用障碍（AUD）的遗传风险部分通过改变主观的酒精反应来表达。在这项研究中，我们研究了 2 个 AUD 风险相关的单核苷酸多态性，GABRA2 rs279858 和 GRIK1 rs2832407，对健康的社交饮酒者在实验室环境下静脉给予酒精时的主观反应的影响。
共有 93 名自我认定的欧洲裔美国社交饮酒者在 3 次盲法实验室会议中接受了静脉输注乙醇，使用“钳夹”程序在 3 个目标血液酒精水平（0.00mg%、40mg%和 100mg%）下进行。自我报告的双相酒精效应量表（BAES）刺激和镇静分量表是主要的结果测量指标。我们检查了这 2 个遗传变异对酒精主观反应的影响。
对于 BAES 刺激分量表评分，在调整年龄、基线评分和时间效应后，与其他风险等位基因计数相比，GABRA2 rs279858 基因的 C“风险”等位基因的个体对高剂量酒精表现出最大的兴奋剂反应（剂量-等位基因计数相互作用效应，p=0.001，C 等位基因的事后对比，p=0.012）。对于 BAES 镇静分量表评分，在调整相同的协变量后，我们检测到剂量-等位基因计数相互作用效应（p=0.0044），即 GRIK1 C“风险”等位基因的个体对更高的酒精剂量报告最大的镇静反应。
这项研究表明，导致 AUD 风险的基因变异可能以特定的方式改变酒精剂量-反应关系的特征。GABRA2 rs279858C 增强了对更高水平酒精的兴奋剂反应，而 GRIK1 rs2832407C 等位基因增加了镇静反应。总之，GRIK1 和 GABRA2 变异对人类静脉内酒精剂量相关的主观反应有不同的影响。
