Emerging Associations of the ALDH2*2 Polymorphism with Disease Susceptibility

Abstract

Ethanol is metabolized by Alcohol Dehydrogenase (ADH) to acetaldehyde and then irreversibly oxidized by Aldehyde Dehydrogenase (ALDH) to nontoxic acetate. In individuals expressing the ALDH2*2 variant enzyme, the rate of conversion from acetaldehyde to acetate is reduced and leads to flushing, nausea, and tachycardia due to increased blood levels of acetaldehyde. The ALDH2*2 variant has a lowered NAD+ coenzyme binding affinity, which results in a lowered clearance capacity toward acetaldehyde. This polymorphism is caused by the substitution of glutamate for lysine at position 487 within the catalytic active site of ALDH2, resulting in effects on subunit and quaternary complex activity. ALDH2*2 alleles are dominant over ALDH2*1 and therefore are expected to contribute to the formation of inactive heterotetramers decreased enzymatic activity in both homozygous and heterozygous individuals. Consequently, a higher susceptibility to various diseases such as Alzheimer’s, osteoporosis, and acute coronary syndrome has been associated with ALDH2*2 carriers. Additionally, the polymorphism seems to affect the efficacy of Glyceryl Trinitrate (GTN), a drug intended to treat coronary heart disease, in carriers of ALDH2*2 alleles. However, the polymorphism is believed to afford a protective effect against alcoholism as the side effects of acetaldehyde build-up are undesirable. Disulfiram, a drug historically used to treat alcohol dependency, induces the same undesirable physiological effects as the variant enzyme in non-carriers by inhibiting the normal functioning of ALDH2 enzyme.