GENETICS AND CELL BIOLOGY A Promoter Polymorphism in the ALDH2 Gene Affects Its Basal and Acetaldehyde/Ethanol-Induced Gene Expression in Human Peripheral Blood Leukocytes and HepG2 Cells

Aims: To assess the effect of the −360G/A polymorphism in the promoter region of the human aldehyde dehydrogenase-2 (ALDH2) gene on its transcription, basal and acetaldehyde/ethanol-induced gene expression was examined by in vivo and in vitro experiments. Methods: Human peripheral blood leukocytes were collected before and after alcohol ingestion (0.4 g/kg body weight) in 21 healthy young Japanese volunteers with a deficient phenotype of ALDH2 ( 487 Glu/Lys), and the levels of ALDH2 mRNA were quantified by real-time RT-PCR. The transcriptional activity of the ALDH2 promoter was investigated by a reporter assay using HepG2 cells in the presence or absence of acetaldehyde/ethanol. Results: The basal level of ALDH2 mRNA was significantly higher in −360A heterozygous subjects than in −360G homozygous subjects. In all subjects, regardless of the genotype, ALDH2 mRNA increased following ethanol ingestion. The promoter activity of a reporter plasmid for −360G was significantly lower than that of a reporter plasmid for −360A. Exposure to acetaldehyde induced a significant increase in the transcriptional activity of the −360G reporter, but not the −360A reporter. Conclusions: In vivo and in vitro experiments showed that the −360G allele has lower basal transcriptional activity than the −360A allele, whereas acetaldehyde/ethanol-induced gene expression, in general, seems to be more enhanced in individuals homozygous for the −360G allele than in those with the −360A allele. Thus, the promoter polymorphism may be involved in individual differences in acetaldehyde elimination.