Abstract

Identification of functional polymorphisms in the UDP-glucuronosyltransferase 2B7 (UGT2B7) gene predicting interpatient variability in the glucuronidation of drugs that are primarily metabolized by UGT2B7 has been the subject of many studies. These studies have shown linkage disequilibrium (LD) covering the region from −2 kb to 16 kb of the UGT2B7 gene. We identified three novel single-nucleotide polymorphisms (SNPs) and extended this LD in the 5′-upstream direction to cover an additional nine prevalent polymorphisms in the distal −2600- to −4000-base pair (bp) promoter. We further showed complete LD between these distal promoter SNPs and the SNP (802C>T) in exon 2 in a panel of 26 livers. Because of this LD, we showed that all of the 23 prevalent polymorphisms in the 4-kb UGT2B7 promoter are linked together, defining two major haplotypes (i.e., I and II). The addition of the minor allele of a rare polymorphism and allele exchanges between haplotypes I and II generated subhaplotypes of I and II. We demonstrated a higher promoter activity of haplotype II over haplotype I, and this higher activity was abolished by an A-to-G change at a single SNP (−900A>G). This mutation changed a consensus activating protein-1 (AP-1) site (TGAGTCA) as occurred in haplotype II to a mutated AP-1 site (TGAGTCG) as occurred in haplotype I. Finally, we showed that the previously reported Alu element resides exclusively in haplotype I and is a highly conserved CG-rich Alu Y element.