Polymorphism of the human alcohol dehydrogenase 4 (ADH4) promoter affects gene expression

The human alcohol dehydrogenase 4 gene (ADH4) encodes the human pi-alcohol dehydrogenase (pi-ADH), which can contribute to ethanol metabolism at moderate and high concentrations of ethanol, There are no known structural variants of pi-ADH in humans, We report the first polymorphisms in the ADH4 gene, at three sites in the promoter: -192 bp, -159 bp and -75 bp, respectively, To determine whether these variations affected promoter function, different haplotypes of the ADH4 proximal promoter were subcloned into a luciferase reporter vector, and the relative promoter activity analysed in hepatoma cells, One of the three sites had a dramatic effect on promoter activity, while the others did not detectably affect activity, The -75A allele had promoter activity more than twice that of the -75C allele, Alcohol dehydrogenase activity is rate limiting for ethanol oxidation, We hypothesize that the different ADH4 alleles lead to different amounts of pi-ADH in liver, which affects the risk for alcoholism by modulating alcohol metabolism, Pharmacogenetics 9:25-30 (C) 1999 Lippincott Williams & Wilkins.