Relationship between esophageal squamous cell carcinoma risk and alcohol‐related ALDH2 and ADH1B polymorphisms: Evidence from a meta‐analysis and Mendelian randomization analysis

BACKGROUND: Previous studies have shown that ALDH2 and ADH1B genes may be associated with alcohol metabolism and the risk of esophageal squamous cell carcinoma (ESCC), with inconsistent results. This meta‐analysis aimed at comprehensively assessing the associations between ALDH2 and ADH1B polymorphisms and the risk of ESCC to synthesize and clarify the evidence. METHODS: We calculated summary estimates of the associations between four genetic variants (rs671 and rs674 in ALDH2, and rs1229984 and rs1042026 in ADH1B) and the ESCC risk across 23 publications in the additive model and allelic model. Venice criteria, Bayesian false discovery probability (BFDP), and false‐positive reporting probability (FPRP) were used to assess the strength of epidemiological evidence. Heterogeneity among studies was evaluated by using the Higgin's I (2) statistic, and publication bias was assessed by using funnel plots and Begg's test. A Mendelian randomization (MR) analysis was performed to determine the causal association between alcohol intake and esophageal cancer risk. Data from the HaploReg v4.1 and PolyPhen‐2 were analyzed for functional annotations. RESULTS: Of the four genetic variants, rs671 of ALDH2 was associated with a significantly reduced risk of ESCC (OR: 0.60, 95% CI: 0.50–0.73), whereas rs1229984 of ADH1B was associated with a significantly increased risk (2.50, 95% CI: 1.70–3.69) in the additive model. In the allelic model, the variant rs1229984 of ADH1B also increased the risk of ESCC (OR: 1.50; 95% CI: 1.21–1.87). The result for the variant rs671 was considered as strong epidemiological evidence. Functional annotations identified that the four variants were related to the enhancer histone marks and motif changes. The other two variants were not associated with the ESCC risk (rs674 of ALDH2 OR: 1.22, 95% CI: 0.71–2.12; rs1042026 of ADH1B OR: 1.28, 95% CI: 0.52–3.14) in the additive model. The MR analysis did not find a causal effect of alcohol on the esophageal cancer risk. CONCLUSIONS: The results showed that ADH1B rs1229984 was significantly associated with an increased the risk of ESCC.