A novel polymorphism (-357 G/A) of the ALDH2 gene: Linkage disequilibrium and an association with alcoholism

Background: Human mitochondrial aldehyde dehydrogenase (ALDH2) is a major e nzyme responsible for the oxidation of acetaldehyde derived from ethanol me tabolism. The human ALDH2 gene shows genetic polymorphism at position 1510 with a G to A transition in exon 12. This mutation leads to ALDH2 enzyme de ficiency and protection against alcoholism. As yet, no polymorphism for the promoter region of the ALDH2 gene has been reported. Methods: We analyzed 600 nucleotides of the promoter region in addition to exon 12 from 571 Japanese, 68 Chinese, 80 Myanmar, 60 Mongolians, and 82 No rth-American Caucasians using single-strand conformational change polymorph ism (SSCP) analysis and the polymerase chain reaction (PCR). PCR products t hat showed an aberrant banding pattern detected by,the SSCP analysis were s ubjected to PCR direct sequencing. Results: A novel polymorphism at -357 with a G to A substitution was found in all the population groups, including North-American Caucasians. In addit ion, the polymorphic status in the promoter and exon 12 suggested linkage d isequilibrium between the two loci, which indicated that among Japanese, th e ALDH2*2 allele is linked to the G promoter allele, and the ALDH2*1 allele is linked to the A allele. A total of 206 healthy male controls and 185 al coholic male patients with the homozygous ALDH2*1 genotype were analyzed fo r the polymorphism in the promoter. Genotypic frequencies of GG, GA, and AA for alcoholics were 54.1%, 44.3%, and 1.6%, and those for controls were 52 .9%, 40.3%, and 6.8%, respectively. The A allele frequencies for alcoholics and controls were 0.24 and 0.27, respectively. A chi(2) test for the entir e 3 x 2 table indicated significant variations in the three genotypes (chi( 2) = 6.40, P < 0.05). However, no significant difference in allelic frequen cies between the two groups was observed. Conclusion: This new polymorphism in the ALDH2 promoter is present in all p opulations studied. Further analysis in other ethnic groups is necessary to establish this as an additional risk factor for alcoholism.