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Developmental research on the novel genetic factors related to alcohol metabolism

酒精代谢相关新型遗传因素的进展研究

基本信息

批准号：
12470106
负责人：
NAKAMURA Jiro
金额：
$ 4.22万
依托单位：
University of Tsukuba
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

1) We analyzed 600 nucleotides of the promoter region in addition to exon 12 from 571 Japanese, 68 Chinese, 80 Myanmar, 60 Mongolians, and 82 North-American Caucasians using single-strand conformational change polymorphism (SSCP) analysis. A novel polymorphism at -357 with a G to A substitution was found in all the population groups, including North-American Caucasians. A total of 206 healthy male controls and 185 alcoholic male patients with the homozygous ALDH2^*1 genotype were analyzed for the polymorphism in the promoter. The A allele frequencies for alcoholics and controls were 0.24 and 0.27, respectively. A chi2 test for the entire 3×2 table indicated significant variations in the three genotypes (chi2=6.40, p<0.05).2) NRH-quinone oxidoreductase 2 (NQO2) is involved in phase II detoxification reactions, and along with Glutathione S-transferase M1 (GSTM1) and NAD(P)H-quinone oxidoreductase 1 (NQO1) is thought to be important for detoxification of catechol o-quinones in the Central Nervous System. In this study, we investigated a possible association between polymorphisms of the GSTM1, NQO1 and NQO2 genes and alcohol withdrawal symptoms such as delirium tremens, hallucination, and seizure. A significant difference was found between alcoholic patients and controls in genotype frequency at an insertion/deletion (I/D) site in the promoter region of the NQO2 gene (p=0.0014). The frequency of the homozygous genotype for the .D allele at this locus was significantly higher in delirium tremens positive patients (p=0.0004) and in hallucination positive patients (p=0.0001), and in patients displaying both delirium tremens and hallucination (p=0.0002), than in controls. Moreover, the GSTM1 gene deletion showed significant association with alcohol seizure symptoms. Present data suggest that an I/D polymorphism in the promoter region of the NQO2 gene plays an important role in the pathogenesis of alcoholism and alcohol withdrawal symptoms.

1)我们使用单链构象变化多态性（SSCP）分析了571名日本人、68名中国人、80名缅甸人、60名蒙古人和82名北美高加索人的启动子区以及外显子12的600个核苷酸。在包括北美高加索人在内的所有人群中都发现了-357位点G至A取代的新型多态性。对206名健康男性对照和185名ALDH 2 ^*1纯合基因型男性酒精中毒患者进行了启动子多态性分析。酗酒者和对照组的A等位基因频率分别为0.24和0.27。对3×2表格进行卡方检验，结果表明3种基因型间存在显著差异（chi 2 =6.40，p<0.05）。2）NRH-醌氧化还原酶2（NQO 2）参与II相解毒反应，沿着谷胱甘肽S-转移酶M1（GSTM 1）和NAD（P）H-醌氧化还原酶1（NQO 1）被认为对邻苯二酚o-醌类在中枢神经系统。在这项研究中，我们调查了GSTM 1，NQO 1和NQO 2基因多态性与酒精戒断症状，如谵妄，幻觉和癫痫发作之间的可能关联。在NQO 2基因启动子区的插入/缺失（I/D）位点的基因型频率中，酒精中毒患者和对照组之间存在显著差异（p=0.0014）。与对照组相比，在谵妄阳性患者（p=0.0004）和幻觉阳性患者（p=0.0001）中，以及在同时显示谵妄和幻觉的患者（p =0.0002）中，该位点D等位基因的纯合基因型频率显著较高。此外，GSTM 1基因缺失与酒精性癫痫症状显著相关。目前的数据表明，在NQO 2基因的启动子区域的I/D多态性在酒精中毒和酒精戒断症状的发病机制中起着重要的作用。