Communicated by Jacques Beckmann
Human alcohol dehydrogenases (ADHs) play important roles in metabolizing alcohol, and several lines of evidence suggest that variations in ADH genes affect the risk for alcoholism. Differences in regulatory sequences could affect the expression of ADH genes and thereby modify the risk for alcoholism. To explore this idea, we sequenced regulatory regions upstream of ADH1C and identified 13 polymorphisms, including one 66base pair (bp) insertion/deletion (in/del), one 5-bp variation, and 11 single nucleotide polymorphisms (SNPs), eight of which were newly identified. We examined the effects of naturally occurring haplotypes on gene expression. The 66-bp in/del alone did not change promoter activity, but when it was combined with three other SNP alleles, a twofold difference in transcription activity was observed in transient transfection assays in H4IIE-C3 cells. These data imply that there are interactions among polymorphisms in the cis-acting elements, and highlight the importance of studying regulatory polymorphisms within the context of their naturally occurring haplotypes. We also demonstrated tissue specificity in cis-acting elements by comparing gene expression in H4IIE-C3 and HeLa cells. Hum Mutat 25:150-155, 2005.