Molecular-Ecogenetic study on the ethiology of alcoholism

酒精中毒是一种受基因-环境相互作用影响的多因素疾病。由于受体在行为和生理反应中的功能改变，其遗传变异可能与酒精依赖有关。本研究分析了胆囊收缩素B受体（CCKBR）、5-羟色胺1A受体（HT 1AR）、00 K基因和线粒体DNA的多态性。在CCKBR和HT 1AR外显子上发现了不同的突变，但酗酒者的基因型分布与对照组无显著差异。线粒体DNA分析表明，58%的酗酒者存在ATP酶491 bp的缺失，而对照组则无此现象。线粒体DNA的异质性缺失可能是酒精滥用的一个有用的标记。CCK基因存在两个核苷酸序列变异，一个是启动子区Spi结合顺式元件核心序列的-45位C → T突变，另一个是内含子2的1662位C → T突变。与对照组相比，谵妄患者的变异频率显著较高（x_24.91 p<0.03）。神经肽胆囊收缩素（CCK）及其受体在中枢神经系统中介导兴奋、焦虑和伤害性感受。提示00 K基因启动子区等位基因突变（-45T）的个体易患酒精所致谵妄。

Alcoholism is multifactorial diseases influenced by gene-environmental interaction. Genetic variation of receptor may be associated with alcohol dependance due to its modified function in behavioral and physiological responces. In the present study, polymorphic alleles of cholecystokinin B receptor ( CCKBR), serotonin 1A receptor (HT1AR) , 00K gene and mt-DNA were analyzed. Different mutations were found in the exon of CCKBR and HT1AR.However genotypic distribution of alcoholics was not significantly different with that in controls. Analysis of the mt-DNA showed that a491 bp deletion in the sequence of ATPase exists as heteroplasmy in 58% of alcoholics but not in controls. The heteroplasmic deletion of mt-DNA may be a useful marker for alcohol abuse. Two nticleotide sequence variants were found in CCK gene ; a frequent mutation at nucleotide position -45 Cto T involved in core sequence of Spi binding cis-element of the promoter region, and a C to T substitution at 1662 position in intron 2. Patients with delirium tremens showed significantly higher frequency of the variant compared with the controls (x_24.91 p<0.03). Neuropeptide cholecystokinin (CCK) and the CCK receptors in central nervous system mediate actions on increasing firings, anxiety and nociceptions. These data suggested that the individuals possessing allelic mutation ( -45T ) in the promoter region of 00K gene might be susceptible to delirium tremens caused by alcohol abuse.