Genetic polymorphisms of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 and liver cirrhosis, chronic calcific pancreatitis, diabetes mellitus, and hypertension among Japanese alcoholic men.

BACKGROUND

The presence of the less-active form of alcohol dehydrogenase-1B encoded by ADH1B*1/*1 (vs. 2 allele) and active form of aldehyde dehydrogenase-2 (ALDH2) encoded by ALDH21/*1 (vs. *2 allele) increases the risk of alcoholism in East Asians.

METHODS

The subjects in this cross-sectional survey were 1,902 Japanese alcoholic men (≥40 years) who underwent ADH1B/ALDH2 genotyping.

RESULTS

Age-adjusted daily alcohol consumption did not differ according to the ADH1B/ALDH2 genotypes. The age-adjusted odds ratios (AORs; 95% confidence interval) for liver cirrhosis (LC; n = 359, 1.58 [1.19 to 2.09]), chronic calcific pancreatitis (CP; n = 80, 2.24 [1.20 to 4.20]), and diabetes mellitus (DM; n = 383, 1.51 [1.15 to 1.99]) were higher in the ADH1B2 allele carriers than in the ADH1B1/1 carriers. The AORs for LC (1.43 [1.01 to 2.02]), CP (1.68 [0.80 to 3.53]), DM (1.63 [1.15 to 2.30]), and hypertension (HT; n = 495, 1.52 [1.11 to 2.07]) were higher in the ALDH21/1 carriers than in the ALDH21/2 carriers. The ADH1B2-associated AOR for LC was 2.08 (1.46 to 2.94) among those aged 40 to 59 years, but 0.89 (0.56 to 1.43) among those aged 60 years or over, and the interaction between ADH1B genotype and age on the LC risk was significant (p = 0.009). When the group with non-LC and no/mild fibrosis was used as controls, the ADH1B2-associated AORs increased according to the severity of their liver disease: 1.67 (1.32 to 2.11) for the group with non-LC and serum type IV collagen values ≥200 ng/ml, 1.81 (1.24 to 2.63) for the group of Child-Pugh class A LC, and 3.17 (1.98 to 5.07) for the group with Child-Pugh class B/C LC. Anti-hepatitis C virus (HCV) antibody was positive in 103 patients, and the groups with a high anti-HCV antibody titer and either the ADH1B2/2 genotype or the ALDH21/1 genotype had the highest AORs (8.83 and 4.90, respectively). The population attributable fraction (PAF) due to the ADH1B2 allele was 29% for LC, 47% for CP, and 27% for DM, and the PAF due to the ALDH2*1/*1 genotype was 26% for LC, 34% for DM, and 30% for HT.

CONCLUSIONS

The ADH1B2 allele increased the AORs for LC, CP, and DM of the alcoholics, and the ALDH21/*1 genotype increased their AORs for LC, DM, and HT. HCV infection and genetic susceptibility had a synergistic effect on the AOR for LC.