Polymorphism of Alcohol-Metabolizing Genes Affects Drinking Behavior and Alcoholic Liver Disease in Japanese Men

Abstract

Alcohol is known to be mainly metabolized in the liver by alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2), and cytochrome P-450IIEI. The purpose of this study was to clarify the role of polymorphism of these ethanol-metabolizing enzymes in drinking behavior and the progression of alcoholic liver disease among Japanese men. Polymorphism of the ADH2, ALDH2, and P-45IIEI genes were determined by polymerase chain reaction, followed by restriction fragment-length polymorphism analysis in 189 normal Japanese men and 26 male patients with alcoholic liver disease. Drinking behavior was estimated by self-assessment according to DSM-III-R criteria. Facial flushing was reported in 91 subjects heterozygous for ALDH2*1/*2 and in two subjects homozygous for ALDH2*2/*2, but was not found in 96 subjects homozygous for ALDH2*1/*1. In contrast, polymorphism of ADH2 and P-450IIEI did not differ between flushers and nonflushers. Although the flushers only drank a small amount of alcohol (< 20 g of ethanol/day), the nonflushers were divided into a group of moderate drinkers (20 to 80 g/day; n = 54) and a group of heavy drinkers (> 80 g/day; n = 42). A high preponderance of heterozygosity for the ADH2*1/*2 genes (20/42; 60%) and a high frequency of the ADH2*1 allele were found in heavy drinkers, compared with moderate drinkers. However, cytochrome P-45IIEI gene polymorphism was similar among the moderate and heavy drinkers. Not only a high frequency of the ALDH2*1 and ADH2*1 alleles, but also a high frequency of the P-450IIEI c2 allele was found in the patients with alcoholic liver disease. From these results, the drinking behavior of Japanese men is strongly influenced by the ALDH2*1 allele, and the level of alcohol intake is affected by the ADH2*1 allele, but not by cytochrome P-45IIEI. However, progression to alcoholic liver disease among heavy drinkers may be affected by the cytochrome P-450IIEI c2 allele.

Roles of Cytochrome P4502E1 Gene Polymorphisms and the Risks of Alcoholic Liver Disease: A Meta-Analysis

“…The pooled results showed that c2c2 genotype was significantly associated with increased risk of ALD in Asians ( Table S2 ). These data were well consistent with many previous studies [14], [29], [48]. Another important finding was that a significant association between the CYP2E1 Pst I/Rsa I polymorphism and the ALD risk was also found in Caucasians (c1c2 vs. c1c1: OR = 1.63, 95%CI 1.05–2.53; c2c2/c1c2 vs. c1c1: OR = 1.58, 95%CI 1.04–2.42), although many pervious studies reported no association [11], [17], [19], [21], [23], [26], [27], [33], [36], [38].…”

Hepatitis B virus infection and alcohol consumption

“…ALDH2 gene polymorphism can determine flushing after ethanol ingestion. Flushing was reported in subjects homozygous for ALDH2*2/*2 and heterozygous for ALDH2*1/*2, but not in those homozygous for ALDH2*1/*1[47]. Concerning polymorphisms of the CYP2E1 gene, subjects heterozygous for the promoter alleles C1/C2 or homozygous C2/C2 are better able to metabolize alcohol, which might increase free radical generation and lipid peroxidation, and promote fatty change in the liver[9].…”

Addiction Genetics and Pleiotropic Effects of Common Haplotypes that Make Polygenic Contributions to Vulnerability to Substance Dependence

“…There is an exception: the “flushing syndrome” variants at the aldehyde (ALDH) and alcohol (ADH) dehydrogenase loci in Asian individuals do provide genes of major effect in this population. Individuals with these gene variants are at lower risk for becoming dependent on alcohol than individuals with other genotypes (Chen et al, 1999) in Chinese (Thomasson et al, 1991; Chen et al, 1996), Korean (Shen et al, 1997), Japanese (Higuchi, 1994; Higuchi et al, 1994, 1995; Maezawa et al, 1995; Nakamura et al, 1996; Tanaka et al, 1997), and other populations (Luczak et al, 2002; Schuckit & Duby, 1982). Homozygous ALDH2*2 individuals are strongly protected from alcohol dependence (Higuchi, 1994; Higuchi et al, 1994).…”