Influence of alcohol consumption and gene polymorphisms ofADH2andALDH2on hepatocellular carcinoma in a Japanese population

Abstract

Although alcohol intake as well as hepatitis viruses has been associated with hepatocellular carcinoma (HCC), gene-alcohol interactions on HCC risk remain to be elucidated. We conducted a case-control study to examine whether polymorphisms of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) modified the HCC risk depending on the amount of alcohol intake. ADH2 and ALDH2 genotyping was performed by a duplex polymerase chain reaction with confronting two-pair primers in 209 newly diagnosed HCC cases and 2 different controls [275 hospital controls and 381 patients with chronic liver disease (CLD)]. Multiple logistic regression analyses revealed that heavy drinkers consuming 3 ''go''s/day of sake (69 g of ethanol/day) showed an increased risk of HCC based on comparison of HCC cases with hospital controls [adjusted odds ratio (OR) 5 13.5; 95% confidence interval (CI) 3.3-54.3] or CLD patients (adjusted OR 5 7.0; 95% CI 2.5-19.2), whereas the overall risk was not elevated among light to moderate drinkers consuming <3 ''go''s/day. Interestingly, light to moderate drinking was associated with an increased risk among those with ALDH2*1/*2 (adjusted OR 5 4.5 or 2.0), but not among those with ALDH2*1/*1 (adjusted OR 5 0.8 or 1.0; p interaction 5 0.03 or 0.13). However, this gene-alcohol interaction was not observed for heavy drinking. Among light to moderate drinkers, people with the combination of ALDH2*1/ *2 and ADH2*2/*2 revealed the highest risk of HCC. These findings indicate that the ALDH2 polymorphism may modify HCC risk among light to moderate drinkers. ' 2005 Wiley-Liss, Inc.

Alcohol Drinking Mediates the Association between Polymorphisms of ADH1B and ALDH2 and Hepatitis B–Related Hepatocellular Carcinoma

“…Traditional multivariate analyses in this study found significant association between alcohol drinking and hepatocellular carcinoma, with a greater than 2.5-fold OR, but did not show any direct association between hepatocellular carcinoma and the SNPs rs1229984 and rs671. Past studies examining the association between alcohol drinking and ADH1B/ALDH2 also did not find significantly increased risk for hepatocellular carcinomaamong drinkers with chronic liver disease or chronic HBV who carried at least one polymorphism (25)(26)(27).…”

“…Only some studies have examined the association between these SNPs and the development of hepatocellular carcinoma, and results have been inconclusive, and either consisted of small sample sizes, did not control for confounding factors, or did not fully examine the interaction or mediation effects between these variants and alcohol drinking on hepatocellular carcinoma risk (25)(26)(27). Moreover, very few studies have studied these interactions among patients chronically infected with HBV (25).…”

Impact of theAlcohol-Dehydrogenase(ADH)1CandADH1Bpolymorphisms on drinking behavior in nonalcoholic Japanese

“…The genes that encode these representative alcohol-metabolizing enzymes display polymorphisms that modulate individual differences in alcoholand acetaldehyde-oxidizing capacity [Bosron and Li, 1986;Marchand et al, 1999;Yokoyama et al, 2001]. Moreover, these individual differences in genes modify the risk of several type of cancers [Matsuo et al, , 2006aSakamoto et al, 2006;Yang et al, 2005;Yokoyama et al, 1998]. …”

Roles of defective ALDH2 polymorphism on liver protection and cancer development

“…Accumulating evidence suggests that a drinking habit for an individual with the ALDH2*2 allele increases the risk of cancerous diseases, including upper aerodigestive, gastric, colorectal, hepatic, and lung cancer [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47]. For example, it was reported that individuals with the ALDH2*1/*2 genotype who were heavy drinkers (C46 g ethanol/day and C5 days/week) had a 38-fold greater risk of developing oesophageal cancer compared to non-drinking individuals with the ALDH2*1/*1 genotype, while drinkers with the ALDH2*1/*1 allele had only a 2-fold greater risk [47].…”