Genetic polymorphisms of alcohol and aldehyde dehydrogenases and glutathione S-transferase M1 and drinking, smoking, and diet in Japanese men with esophageal squamous cell carcinoma.
The genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2), alcohol dehydrogenase-2 (ADH2), ADH3, and glutathione S-transferase M1 (GSTM1) influence the metabolism of alcohol and other carcinogens. The ALDH2*1/2*2 genotype, which encodes inactive ALDH2, and ADH2*1/2*1, which encodes the low-activity form of ADH2, enhance the risk for esophageal cancer in East Asian alcoholics. This case-control study of whether the enzyme-related vulnerability for esophageal cancer can be extended to a general population involved 234 Japanese men with esophageal squamous cell carcinoma and 634 cancer-free Japanese men who received annual health checkups. The GSTM1 genotype was not associated with the risk for this cancer. Light drinkers (1-8.9 units/week) with ALDH2*1/2*2 had an esophageal cancer risk 5.82 times that of light drinkers with ALDH2*1/2*1 (reference category), and their risk was similar to that of moderate drinkers (9-17.9 units/week) with ALDH2*1/2*1 (odds ratio = 5.58). The risk for moderate drinkers with ALDH2*1/2*2 (OR = 55.84) exceeded that for heavy drinkers (18+ units/week) with ALDH2*1/2*1 (OR = 10.38). Similar increased risks were observed for those with ADH2*1/2*1. A multiple logistic model including ALDH2, ADH2, and ADH3 genotypes showed that the ADH3 genotype does not significantly affect the risk for esophageal cancer. For individuals with both ALDH2*1/2*2 and ADH2*1/2*1, the risk of esophageal cancer was enhanced in a multiplicative fashion (OR = 30.12), whereas for those with either ALDH2*1/2*2 or ADH2*1/2*1 alone the ORs were 7.36 and 4.11. In comparison with the estimated population-attributable risks for preference for strong alcoholic beverages (30.7%), smoking (53.6%) and for lower intake of green and yellow vegetables (25.7%) and fruit (37.6%), an extraordinarily high proportion of the excessive risk for esophageal cancer in the Japanese males can be attributed to drinking (90.9%), particularly drinking by persons with inactive heterozygous ALDH2 (68.5%). Education regarding these risky conditions in connection with ALDH2 and ADH2 is vitally important in a new strategic approach aimed at preventing esophageal cancer in East Asians.
Yokoyama
Akira
A
National Institute on Alcoholism, Kurihama National Hospital, Yokosuka, Kanagawa 239-0841, Japan.
Kato
Hoichi
H
Yokoyama
Tetsuji
T
Tsujinaka
Toshimasa
T
Muto
Manabu
M
Omori
Tai
T
Haneda
Tatsumasa
T
Kumagai
Yoshiya
Y
Igaki
Hiroyasu
H
Yokoyama
Masako
M
Watanabe
Hiroshi
H
Fukuda
Haruhiko
H
Yoshimizu
Haruko
H
D000328:Adult; D000368:Aged; D000426:Alcohol Dehydrogenase / Q000235:genetics*; D000428:Alcohol Drinking / Q000453:epidemiology*; D000444:Aldehyde Dehydrogenase / Q000172:deficiency / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics; D016022:Case-Control Studies; D004032:Diet / Q000706:statistics & numerical data; D004938:Esophageal Neoplasms / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics; D005483:Flushing / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D005638:Fruit; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006358:Hot Temperature; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012907:Smoking / Q000453:epidemiology*; D011795:Surveys and Questionnaires; D014675:Vegetables
D000426:Alcohol Dehydrogenase; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D005982:Glutathione Transferase; D007527:Isoenzymes; C096127:ALDH2 protein, human