Genetic polymorphisms in ALDH2 greatly influence the metabolism of acetaldehyde and, consequently, the individual’s response to alcohol and its toxic effects. The ALDH2*2 polymorphism results in a deficient ALDH2 isoform with a very low capacity for acetaldehyde metabolism. This leads to acetaldehyde accumulation and a condition known as the “alcohol flush reaction”—facial flushing, nausea, and discomfort—which discourages heavy drinking and is thought to have a protective effect against AUD. In fact, research has consistently demonstrated that individuals homozygous or heterozygous for ALDH2*2 have markedly higher acetaldehyde levels and reduced risk for AUD (122, 172, 178–180), although they also have increased cancer risk (181, 182). There have been no specific studies examining the effect of ALDH1A1 on alcohol metabolism in humans, likely due to its lower catalytic efficiency compared to ALDH2. However, it is possible that the combined effect of ALDH1A1 and ALDH2 polymorphisms may lead to considerable variability in alcohol metabolism, affecting tolerance, dependence, and alcohol-related diseases across individuals and populations.
