GWAS have also identified a significant association between esophageal squamous cell cancer and SNPs on human chromosomes 4q21–23 and 12q24, which include the functional variants rs1229984 in ADH1B and rs671 in ALDH2, respectively (30). Tanaka et al. (121) demonstrated that the interaction of ADH1B and/or ALDH2 risk alleles with smoking and alcohol consumption significantly increases the risk for the development of esophageal squamous cell carcinoma. Studies have also shown that the combination of alcohol consumption with the inactive heterozygous ALDH2 genotype (ALDH2*1/*2) and less-active homozygous ADH1B genotype (ADH1B*1/*1) increases the risk of UADT squamous cell carcinoma in central European (59) and Japanese (7) populations. The effect of ALDH2*1/*2 results from the high level of acetaldehyde; the effect of ADH1B*1/*1 is due to heavy drinking that leads to longer exposure of the UADT to salivary ethanol and acetaldehyde. These studies point to significant gene-environment interactions that potentially lead toward complex pathophysiological pathways for the development of such diseases.
