ADH1B*2 is Associated With Reduced Severity of Nonalcoholic Fatty Liver Disease in Adults, Independent of Alcohol Consumption

Abstract

Background & Aims Alcohol dehydrogenase 1B (ADH1B) is involved in alcohol metabolism. The allele A ( ADH1B2) of rs1229984: A>G variant in ADH1B is associated a higher alcohol metabolizing activity, compared to the ancestral allele G ( ADH1B1). Moderate alcohol consumption is associated with reduced severity of nonalcoholic fatty liver disease (NAFLD), based on histologic analysis, compared with no alcohol consumption. However, it is unclear whether ADH1B2 modifies the relationship between moderate alcohol consumption and severity of NAFLD. We examined the association between ADH1B2 and moderate alcohol consumption and histologic severity of NAFLD. Methods We collected data from 1557 multi-ethnic adult patients with biopsy-proven NAFLD enrolled into 4 different studies conducted by the NASH Clinical Research Network. Histories of alcohol consumption were obtained from answers to standardized questionnaires. Liver biopsies were analyzed by histology and scored centrally according to the NASH CRN criteria. We performed covariate adjusted logistic regressions to identify associations between histologic features of NAFLD severity and moderate alcohol consumption and/or ADH1B2. Results A higher proportion of Asians/Pacific Islanders/Hawaiians carried the ADH1B2 allele (86%) than other racial groups (4%–13%). However, the study population comprised mostly non-Hispanic whites (1153 patients, 74%), so the primary analysis focused on this group. Among them, 433 were moderate drinkers and 90 were ADH1B2 carriers. After we adjusted for confounders, including alcohol consumption status, ADH1B2 was associated with lower frequency of steatohepatitis (odds ratio [OR], 0.52; P<.01) or fibrosis (odds ratio, 0.69; P=.050) compared with ADH1B1. Moderate alcohol consumption (g/day) reduced the severity of NAFLD in patients with ADH1B1 or ADH1B2. However, ADH1B2, compared to ADH1B1, was associated with a reduced risk of definite NASH ( ADH1B2 OR, 0.80; P<.01 vs ADH1B1 OR, 0.96; P=.036) and a reduced risk of an NAFLD activity score of 4 or higher ( ADH1B2 OR, 0.83; P=.012 vs ADH1B1 OR, 0.96; P=.048) ( P<.01 for the difference in the effect of moderate alcohol consumption between alleles). The relationship between body mass index and NAFLD severity was significantly modified by ADH1B2, even after we controlled for alcohol consumption. Conclusions ADH1B2 reduces the risk of NASH and fibrosis in adults with NAFLD regardless of alcohol consumption status. ADH1B2 might modify the association between high body mass index and NAFLD severity.