Background: Aldehyde dehydrogenase 2 (ALDH2
rs671, Glu504Lys) and alcohol dehydrogenase 1B (ADH1B
rs1229984, His47Arg) polymorphisms have a strong impact on carcinogenic acetaldehyde accumulation after alcohol drinking. To date, however, evidence for a significant ALDH2–alcohol drinking interaction and a mediation effect of ALDH2/ADH1B through alcohol drinking on gastric cancer have remained unclear. We conducted two case–control studies to validate the interaction and to estimate the mediation effect on gastric cancer. Methods: We calculated odds ratios (OR) and 95% confidence intervals (CI) for ALDH2/ADH1B genotypes and alcohol drinking using conditional logistic regression models after adjustment for potential confounding in the HERPACC-2 (697 cases and 1372 controls) and HERPACC-3 studies (678 cases and 678 controls). We also conducted a mediation analysis of the combination of the two studies to assess whether the effects of these polymorphisms operated through alcohol drinking or through other pathways. Results: ALDH2 Lys alleles had a higher risk with increased alcohol consumption compared with ALDH2 Glu/Glu (OR for heavy drinking, 3.57
95% CI 2.04–6.27
P for trend = 0.007), indicating a significant ALDH2–alcohol drinking interaction (Pinteraction = 0.024). The mediation analysis indicated a significant positive direct effect (OR 1.67
95% CI 1.38–2.03) and a protective indirect effect (OR 0.84
95% CI 0.76–0.92) of the ALDH2 Lys alleles with the ALDH2–alcohol drinking interaction. No significant association of ADH1B with gastric cancer was observed. Conclusion: The observed ALDH2–alcohol drinking interaction and the direct effect of ALDH2 Lys alleles may suggest the involvement of acetaldehyde in the development of gastric cancer.