Polymorphism
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Description
ALDH2 is one of 19 members of the human ALDH gene family of NAD(P)+-dependent enzymes (). ALDH2 is the principal enzyme involved in acetaldehyde oxidation at the physiological concentrations typically found when a person consumes alcohol. In addition to the aforementioned dehydrogenase activity, ALDH2 possesses an esterase activity () that catalyzes the hydrolysis of nitroglycerin to generate 1,2-glyceryl dinitrate (1,2-GDN) and nitrite (NO2�) (). A common polymorphism in exon 12, in which glutamate is replaced by lysine at position 504 (Glu504Lys), is known to essentially eliminate its dehydrogenase activity and therefore its ability to clear acetaldehyde in homozygotes and to decrease by approximately 94% the enzyme activity in heterozygotes (,). Worldwide, the Lys504 allele has the highest prevalence (30�50%) in Asian populations, including Chinese people (). ALDH2 is a tetramer, and 1 defective subunit is sufficient to render the entire enzyme inactive; thus, Glu504 homozygotes (ALDH2*1/1) exhibit normal enzymatic activity, Glu504/Lys504 heterozygotes (ALDH2*1/2) show approximately 6% of normal activity, and Lys504 homozygotes (ALDH2*2/2) show negligible activity toward acetaldehyde. The ALDH2*2 allele is thus inherited as an autosomal dominant trait (4,6,). This mutation has been considered as a protective factor against the development of alcoholism and may explain distinct alcohol drinking habits across various ethnic populations .
Discussion
The common G-to-A polymorphism in exon 12 of ALDH2 — resulting in a Glu504Lys replacement that virtually eliminates ALDH2 activity in both heterozygotes and homozygotes — is associated with a lack of efficacy of sublingual GTN in Chinese subjects.()
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