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.


CONCLUSIONS
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.
Okubo
Takehito
T
Department of Psychiatry, Bungosou Hospital, Yasato, Ibaraki, Japan. to-okubo@bc4.so-net.ne.jp
Harada
Shoji
S
Higuchi
Susumu
S
Matsushita
Sachio
S
D000328:Adult; D000430:Alcohol Withdrawal Delirium / Q000201:enzymology / Q000235:genetics*; D000483:Alleles; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D004198:Disease Susceptibility; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006212:Hallucinations / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic / Q000235:genetics; D011808:Quinone Reductases / Q000235:genetics*
D005982:Glutathione Transferase; D016660:NAD(P)H Dehydrogenase (Quinone); D011808:Quinone Reductases; C447479:NQO1 protein, human; C419642:NRH - quinone oxidoreductase2