汉维族重度饮酒者饮酒行为与ADH1、ALDH2、OPRM1、GABAA基因多态性的相关性研究

Alcohol dependence and abuse is a kind of mental disorder with high prevelance and a pathological behavior syndrome with serious hazard outcome. Alcohol use disorder is the third leading disease among the total risk factors that cause the total global disease burden. Mass research shew that constant binge and heavy drinking can also increase the risk of alcohol related problem in adult life besides the alcoholism family history. The subjective response to alcohol will influence an individual's drinking behaviour,and different subjective responses to alcohol perhaps relate to the susceptibility of alcohol dependence.Our study wants to observe the subjective response to alcohol in heavy and light social drinkers both in Han and Uyghur nationalities, and to find if some difference will exsit in the two ethnic drinkers.Moreover,we are also interested in that if the subjective response to alcohol will influence the individuals'attitude and behavior towards alcohol. Additional, we are also interested in the genes related to alcohol pharmacodynamic and pharmacokinetic processes, such as ADH1B, ALDH2, OPRM1, GABAA α6. So the difference in genetic polymorphisms of ADH1B His47Arg, ALDH2*2 Glu487Lys, OPRM1 A118G, and GABAA α6 (Pro385Ser)will be analyzed in heavy and light drinkers between Han and Uyghur ethnicity,and their relation with the subjective response to alcohol and heavy drinking also be analyzed. The goal of this study is to explore the underlying factor causing alcohol dependence and abuse especially the potential mechanism of genetic and environmental factors in alcohol dependence. Moreover to provide some proof for individualized interventions to people with high risk to develop into alcohol use disorder or dependence.

酒依赖与酒精滥用是高发、危害重大的精神障碍，在全球疾病总负担中，位于第三位。研究证明，除遗传因素外，饮酒方式特别是狂饮也是形成酒精相关问题的风险因素之一。个体对酒精的主观反应影响个体的饮酒行为，并且与酒依赖的易感性有关。本研究以汉、维族重度与轻度饮酒人群为对象进行酒精激发实验，研究不同民族间饮酒人群对酒精的主观反应的差异，及其与个体饮酒行为之间的关系。并对两民族饮酒者的酒精代谢相关基因如ADH1B基因 His47Arg位点、ADH1C*1位点和ALDH2基因Glu487Lys位点，以及酒药效相关基因如OPRM1基因的A118G （rs1799971），GABAA α6 Pro385Ser位点的多态性进行分析，探索它们与个体酒精主观反应和饮酒行为之间的相关性，从而研究酒依赖的分子生物学机制与环境、行为之间的关系，并为今后对具有酒依赖与酒精滥用高风险的个体制定个体化干预方案提供理论基础。

除遗传因素外，个体对酒精的主观反应也与酒精滥用与依赖的易感性有关。本研究以汉、维族轻、重度饮酒人群进行酒精激发实验，研究不同民族轻重度饮酒人群对酒精的主观反应的差异，并探讨ADH1B、ALDH2、OPRM1、GABAA与个体饮酒行为、酒精主观反应之间的关系。共招募593例受试者（酒依赖者汉族100例、维族93例，轻、重度饮酒者汉、维族各50例，共200例，对照组汉、维族各100例），轻重度饮酒者、酒依赖者完成酒精挑战实验，对酒依赖者及对照组的酒精代谢酶、酒精药效酶及其他相关基因的30个位点进行测序，并分析与个体饮酒行为、酒精主观反应之间的关系。结果显示：1.汉、维族重度饮酒者均在饮酒后血液酒精浓度上升阶段表现出兴奋作用及镇静作用逐渐增强，在血液酒精浓度下降阶段，兴奋作用及镇静作用逐渐下降，而轻度饮酒者则表现出兴奋作用的逐渐下降，而镇静作用先增强，之后逐渐下降。2.汉、维族重度饮酒者均较轻度饮酒者在饮酒后表现出更高的“喜欢”和“还想要一些”效应及兴奋作用，及更低的镇静作用。维族重度饮酒者较汉族在饮酒后表现出更高的兴奋作用、“喜欢”和“还想要一些”效应及更低的镇静作用。3.汉、维族受试者中rs671（ALDH2）等位基因位点A、rs1229984（ADH1B）位点T是酒依赖的保护性因素；维族受试者者中，rs11568817（HTR1B）位点A是酒依赖危险因素，rs3782025（HTR3B）位点A、rs4964057（ARNTL2）位点G是酒依赖的保护因素。rs1229984（ADH1B）与个体最大饮酒量、每周饮酒量有关。rs1799971（OPRM1）等位基因型中，GG、GA型的个体最大饮酒量、周饮酒量均大于AA型者。饮酒后GG、GA型的个体较AA型者表现出更高的“喜欢”和“还想要一些”及兴奋作用。因此，酒精代谢酶基因ALDH2、ADH1B与不同民族酒依赖的风险相关，HTR1B、HTR3B、ARNTL2与维族酒依赖风险相关，需要进一步验证在汉族酒依赖风险中的作用。OPRM1基因虽未显示与酒依赖风险相关，但与个体酒精主观反应相关。