Developmental research on the novel genetic factors related to alcohol metabolism

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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.