Causal Alcohol-Cancer Link Modified by Genotype

A prospective study in China revealed that certain genotypes of alcohol metabolism might reduce or exacerbate the effects of alcohol on several cancers. Aldehyde dehydrogenase 2 (ALDH2)-rs671 G>A and alcohol dehydrogenase 1B (ADH1B)-rs1229984 G>A were genotyped in 150 722 adults, enrolled from 10 areas in China from 2004 to 2008. With 11 years follow-up, 9339 individuals developed cancer. Cox regression was used to estimate hazard ratios (HRs) for site-specific cancers associated with these genotypes, and their potential interactions with alcohol consumption. They were common genetic variants, the A-allele frequency was 0.21 for ALDH2-rs671 and 0.69 for ADH1B-rs1229984, with A-alleles strongly associated with lower alcohol consumption. Among men, ALDH2-rs671 AA genotype was associated with HR of 0.69 for alcohol-related cancers (n=1900), compared to GG genotype. For ADH1B-rs1229984, the HRs of AG and AA vs GG genotype were 0.80 and 0.75 for alcohol-related cancers, 0.61 and 0.61 for head and neck cancer(n=196) and 0.68 and 0.60 for esophageal cancer (n=546), respectively. There were no significant associations of these genotypes with risks of liver (n=651), colorectal (n=556), stomach (n=725) or lung (n=1135) cancers. Among male drinkers, the risks associated with higher alcohol consumption were greater among ALDH2-rs671 AG than GG carriers for head and neck, esophageal and lung cancers. Only 2% of women drank alcohol regularly, with no comparable associations observed between genotype and cancer. The findings support the causal effects of alcohol consumption on upper aerodigestive tract cancers, with ALDH2-rs671 AG genotype further exacerbating the risks. The loss-of-function variant in the ALDH2-rs671 G>A substantially decreases the break-down of acetaldehyde, which is a human carcinogen and a toxic metabolite produced during alcohol metabolism, causing the characteristic East Asian alcohol flushing response. The other variant in the ADH1B-rs1229984 G>A accelerates acetaldehyde formation from alcohol. Source: https://onlinelibrary.wiley.com/