Alcohol drinking is a major risk factor for
esophageal cancer in Japan and its impact may be modulated by levels of ALDH2, ADH2 and
CYP2E1, three representative alcohol-metabolizing
enzymes which display genetic polymorphisms altering individual alcohol-oxidizing capacity and drinking behavior. To assess the actual influence of ADH2 Arg47His, ALDH2 Glu487Lys and
CYP2E1 variant c2 allele polymorphisms on
esophageal cancer risk with conjunction with alcoholic consumption, the present 1:3 matched case-control study was conducted. The 165 histologically diagnosed Japanese
esophageal cancer cases were here compared with 495 randomly selected controls, matched with respect to sex and age. Conditional logistic regression was used to calculated Odds Ratios (
ORs) and 95% confidence intervals (95% CI). Significant gene-environment interactions between alcohol drinking and both ADH2 and ALDH2 were observed regarding
esophageal cancer risk. The ADH2 Arg47His polymorphism showed moderately increased risk (OR for Arg/His and
Arg/Arg relative to
His/His: 2.01 (1.39-2.90)). In the ALDH2 case, comparing the Glu/Lys with the
Glu/Glu genotype,
ORs were markedly increased to 9.64 (3.23-28.8) and 95.4 (28.7-317) from 1.88 (0.42-8.37) and 4.62 (0.93-23.1) for moderate drinking and heavy drinking, respectively. No significant alteration in risk was observed with the
CYP2E1 polymorphism. In conclusion, the present study revealed a significant gene-environment interaction between alcohol drinking and the ALDH2 polymorphism regarding
esophageal cancer risk among a general population in Japan, providing concrete evidence of a role for
acetaldehyde in neoplastic development. Interactions between ALDH2 and ADH2 need further clarification.