Differential allelic expression of c.1568C > A at UGT2B15 is due to variation in a novel cis-regulatory element in the 3'UTR

Differential allelic expression (DAE) is a powerful tool to identify cis-regulatory elements for gene expression. The UDP-glucuronosyltransferase 2 family, polypeptide B15 (UGT2B15), is an important enzyme involved in the metabolism of multiple endobiotics and xenobiotics. In the present study, we measured the relative expression of two alleles at SNP c.1568C>A (rs4148269) in this gene, which causes an amino acid substitution (T523K). An excess of the C over the A allele was consistently observed in both liver (P = 0.0021) and breast (P = 0.012) samples, suggesting that SNP(s) in strong linkage disequilibrium (LD) with c.1568C>A can regulate UGT2B15 expression in both tissues. By resequencing, one such SNP, c.1761T>C (rs3100) in 3′ untranslated region (UTR), was identified. Reporter gene assays showed that the 1761T allele results in a significantly higher gene expression level than the 1761C allele in HepG2, MCF-7, LNCaP, and Caco-2 cell lines (all P < 0.001), thus indicating that this variation can regulate UGT2B15 gene expression in liver, breast, colon, and prostate tissues. Considering its location, we postulated that this SNP is within an unknown microRNA binding site and can influence microRNA targeting. Considering the importance of UGT2B15 in metabolism, we proposed that this SNP might contribute to multiple cancer risk and variability in drug response.