Association analyses between polymorphisms of the phase II detoxification enzymes (GSTM1, NQO1, NQO2) and alcohol withdrawal symptoms.

BACKGROUND: NRH-quinone oxidoreductase 2 (NQO2) along with glutathione S-transferase M1 (GSTM1) and NAD(P)H-quinone oxidoreductase 1 (NQO1), which is involved in phase II detoxification reactions, is thought to be important for detoxification of catechol o-quinones in the central nervous system. Our previous study revealed that the human NQO2 gene is highly polymorphic. 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. METHODS: A total of 247 Japanese male alcoholic patients with alcohol withdrawal symptoms or without the symptoms, and 134 age-matched Japanese male controls (nonhabitual drinkers), were examined by using polymerase chain reaction (PCR), PCR restriction fragment length polymorphism, PCR-based single-strand conformational change polymorphism, and PCR direct sequencing analyses. RESULTS A significant difference was found between alcoholic patients and controls in genotype frequency at an insertion/deletion 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. The values were still significant after Bonferroni correction. On the other hand, no significant difference was detected for allele frequencies or genotype frequencies for the other polymorphic loci of the NQO2 gene. Moreover, GSTM1 gene deletion and missense mutation (Pro187Ser) of the NQO1 gene showed no significant association with alcohol withdrawal symptoms. CONCLUSION: Present data suggest that an insertion/deletion polymorphism in the promoter region of the NQO2 gene plays an important role in the pathogenesis of alcoholism and alcohol withdrawal symptoms.

Association analysis of an (AC)n repeat polymorphism in the GABA(B) receptor gene and schizophrenia.

The human gamma-aminobutyric acid type B (GABA(B)) receptor gene is a candidate gene for schizophrenia due to its chromosomal location and neurobiologic roles. In the present study, association analyses of genetic polymorphisms of the GABA(B) receptor gene with schizophrenia were carried out in 102 unrelated schizophrenic patients and 100 healthy controls, using a polymerase chain reaction-based, single-strand conformational polymorphism analysis. Although the Ala20Val and Gly489Ser mutations were not found in our samples, we found a novel polymorphism of (AC)n dinucleotide repeats located approximately 1.6 kb upstream from the translational start site. No significant difference in allele frequencies was found between controls and patients with schizophrenia (P = 0.0587) using the Monte Carlo method. Significant differences were found between controls and patients with continuous-course schizophrenia (P = 0.0019), and between controls and patients with a positive family history of psychoses (P = 0.0015). These differences, however, were not significant after Bonferroni correction. These data did not support our hypothesis that polymorphisms of the GABA(B) receptor gene may confer vulnerability for schizophrenia.

Investigation of quantitative trait loci in the CCKAR gene with susceptibility to alcoholism.

BACKGROUND: Cholecystokinin (CCK) plays an important role in the function of the central nervous system by interacting with dopamine and other neurotransmitters. We previously reported genetic variations in the promoter and coding regions of the CCKA receptor (CCKAR), CCKBR, and CCK genes and a possible association between polymorphisms of the CCKAR gene and alcoholism. In this study, association analyses were re-examined between the polymorphisms of the promoter region of the CCKAR gene and patients with alcohol withdrawal symptoms, in addition to patients with alcoholic liver injury. METHODS: A total of 131 Japanese male patients with alcohol withdrawal symptoms, 70 Japanese patients with alcoholic liver injury, and 98 age-matched Japanese male controls (nonhabitual drinkers) were examined using polymerase chain reaction-based single strand conformational polymorphism and sequencing analyses. RESULTS: Significant differences between patients with hallucination and controls were found in the allele frequencies at the -388 and -85 loci of the CCKAR gene (p = 0.0095, p = 0.0087, respectively), but these differences were not significant after Bonferroni correction for multiple testing. In contrast, the frequency of the homozygous genotype -85CC was significantly higher in hallucination-positive patients than in controls (p = 0.0031) and in patients with hallucination accompanying delirium tremens than in controls (p = 0.0022), and these differences were significant after Bonferroni correction. CONCLUSIONS: The data from the case control suggest that polymorphisms of the promoter region of the CCKAR gene do not play a major role in the pathogenesis of alcohol withdrawal symptoms or alcoholic liver injury. However, a significant association was found between polymorphism at the -85 locus of the CCKAR gene and patients with hallucination, and especially patients with hallucination accompanying delirium tremens.