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In our previous study, we found that polymorphisms of alcohol and aldehyde dehydrogenase (ADH1BandALDH2) are important risks for esophageal squamous cell carcinoma in a Taiwanese population. In this study, we increased the sample size to investigate the modifying effect of lifetime alcohol consumption on the association betweenADH1BandALDH2genotypes and the risks of esophageal cancer. A multicenter hospital-based case–control study was conducted between August 2000 and June 2004. Three hundred and thirty newly-diagnosed esophageal squamous cell carcinoma patients and 592 controls were recruited from National Taiwan University Hospital in Taipei and Kaohsiung Veterans General Hospital and Kaohsiung Medical University Hospital in Kaohsiung, Taiwan. Controls were matched to the case patients by gender and age within 4 years (case:control = 1:1–4). Polymorphisms ofADH1BandALDH2were genotyped by the method of PCR-RFLP. Individuals withADH1B*1/*1genotype had a 3.99-fold risk (95% CI = 2.13–7.48) of developing esophageal cancer, compared with those withADH1B*2/*2genotype, after adjusted for appropriate covariates. Individuals withALDH2*1/*2andALDH2*2/*2had 4.99-fold risk (95% CI = 3.11–7.99) and 4.24-fold risk (95% CI = 1.52–11.84), respectively, of developing esophageal cancer, compared with those withALDH2*1/*1, after adjusted for appropriate covariates. We also found a modifying effect of lifetime alcoholic consumption on the association between genotypes ofADH1BandALDH2on esophageal cancer risk. These results suggest thatADH1BandALDH2polymorphisms play a pivotal role on esophageal cancer and that the effect of these polymorphisms was modified by the amount of alcohol consumed.