Polymorphisms in the promoter region of the human class II alcohol dehydrogenase (ADH4) gene affect both transcriptional activity and ethanol metabolism in Japanese subjects

Class 11 alcohol dehydrogenase (pi-ADH), encoded by alcohol dehydrogenase (ADH4), is considered to contribute to ethanol (EtOH) oxidation in the liver at high concentration. Four single nucleotide polymorphisms (SNPs) were found in the promoter region of this gene. Analysis of genotype distribution ill 102 unrelated Japanese subjects revealed that four loci were in strong linkage disequilibrium and Could be classified into three haplotypes. The effects of these polymorphisms on transcriptional activity were investigated ill HepG2 cells. Transcriptional activity was significantly higher in cells with the -136A allele than in those with the -136C allele. To investigate whether this difference in transcriptional activity caused a difference ill EtOH elimination, previous data on blood EtOH changes after 0.4 g/kg body weight alcohol ingestion were analyzed. When analyzed based oil aldehyde dehydrogenase-2 gene (ALDH2) (487)Glu/Lys genotype, the significantly lower level of EtOH at peak in subjects with -136C/A and -136A/A genotype compared with Subjects with -136C/C genotype indicated that -136 bp was a Suggestive locus for differences ill EtOH oxidation. This effect was observed only in subjects with ALDH2 (487)Glu/Glu. These results Suggested that the SNP at -136bp in the ADH4 promoter had all effect oil transcriptional regulation, and that the higher activity of the -136A allele compared with the -136C allele Caused a lower level of blood EtOH after alcohol ingestion; that is, individuals with the -136A allele May Consume more EtOH and might have a higher risk for development of alcohol dependence than those without file -136A allele.