Scanning of genetic effects of alcohol metabolism gene (ADH1BandADH1C) polymorphisms on the risk of alcoholism

Abstract

Alcoholism is a multifactorial and polygenic disorder involving complex gene‐to‐gene and gene‐to‐environment interactions. Alcohol metabolism is one of the biological determinants that could significantly be influenced by genetic polymorphisms in alcohol‐metabolism genes. These genetic polymorphisms are believed to influence drinking behavior and development of alcoholism. Direct DNA sequencing of whole ADH1B and ADH1C genes revealed 36 sequence variants, including six nonsynonymous and 14 novel polymorphisms. Seventeen polymorphisms among them were selected for genotyping in a larger study (n=352) based on linkage disequilibria (LDs) among SNPs, locations, and frequencies. Hardy‐Weinberg equilibrium (HWE) analyses of polymorphisms revealed severe deviations only in alcoholics, which strongly suggest that a selection bias (or pressure) may be involved. The analyses of genotype distribution in alcoholics (n=106) and normal controls (n=246) showed dramatic associations with the risk of alcoholism. Fourteen polymorphisms in ADH1C and ADH1B showed a series of different strengths of association and magnitudes of risk. Based on referent and subgroup analysis, it was strongly suggested that the genetic effects come from the ADH1B*47Arg/*47Arg genotype, and that the positive signals from other sites are just tracking the genetic effect of ADH1B His47Arg. In this article we present summaries of previous studies and of the present study, to give an overview of the worldwide effects of ADH1B His47Arg on the risk of alcoholism. The information derived from this study could be valuable for understanding the genetic factors involved in the risk of alcoholism and facilitate further investigation in other ethnic groups. Hum Mutat 26(3), 224–234, 2005.