Functional Variants in ADH1B and ALDH2 Coupled With Alcohol and Smoking Synergistically Enhance Esophageal Cancer Risk

BACKGROUND & AIMS: Esophageal squamous cell carcinoma (ESCC) is prevalent among Asian populations, with marked regional variations in incidence and mortality. Patients with ESCC have a very poor prognosis, but detection of ESCC at earlier stages could improve clinical outcome. Therefore, identification of epidemiologic factors that influence the development of ESCC would facilitate prevention and/or early detection of the disease. METHODS: We performed a 2-step genome-wide association study with subsequent replication analysis using a total of 1070 Japanese ESCC cases and 2836 controls. We also used logistic regression analysis to estimate the effect of gene-gene and gene-environmental interactions. RESULTS: We identified the significant associations of ESCC with 4q21-23 and 12q24 regions, which include nonsynonymous single nucleotide polymorphisms (SNP) in ADH1B (rs1229984, P = 6.76 x 10(-35)) and ALDH2 (rs671, P = 3.68 x 10(-68)) that were previously shown to be associated with ESCC susceptibility. Multiple logistic regression analysis revealed SNP rs671, rs1229984, alcohol drinking, and smoking as the independent risk factors for ESCC (odds ratios of 1.66, 1.85, 1.92, and 1.79, respectively). Moreover, individuals who had both genetic and lifestyle-related risk factors had a nearly 190 times higher risk of ESCC than those who had neither of these. CONCLUSIONS: We found 2 known functional variants involved in the metabolism of alcohol and tobacco by-products as the most significant risk factors for the development of ESCC in a Japanese population. The individuals carrying both risk genotypes have a higher baseline risk of ESCC that is substantially increased by 2 lifestyle risk factors.