Association Between UGT1A1 mRNA Expression and Cis-Acting Genetic Variants and Trans-Acting Transcriptional Regulators in Human Liver Samples

<b>Background:</b> UDP-glucuronosyltransferase 1A1 (UGT1A1) metabolizes endogenous substances and pharmaceuticals. Genetic polymorphisms, particularly TA repeats in the UGT1A1 promoter TATA region (UGT1A1*28/*36/*37) and a nearby single-nucleotide polymorphism (SNP) rs887829, are associated with UGT1A1-related phenotypes and used as biomarkers for guiding drug therapy. However, these associations are inconsistent, especially in individuals of African ancestry. The objectives of this study are to investigate the association between UGT1A1 expression and its genetic variants in liver samples obtained from European American (EA, n = 119) and African American (AA, n = 138) donors and to clarify the function of genetic variants. <b>Methods:</b> The associations between UGT1A1 expression and genetic variants were tested using multiple linear regression analysis, and the transcriptional activities of genetic variants were tested using reporter gene assays. <b>Results:</b> Both rs887829 and UGT1A1*28/*37 showed similar associations with UGT1A1 expression in AA and EA samples. Reporter gene assays confirmed that UGT1A1*36 (5TA) had significantly higher activity than reference UGT1A1*1 (6TA), while UGT1A1*28 (7TA) and *37 (8TA) had lower activity. In contrast, rs887829 showed no direct effect on promoter activity, indicating that its association is likely caused by high LD with UGT1A1*28/*37. Additionally, we found that ancestral differences in associations with trans-acting regulators and combined genetic variants and TFs account for substantially higher total variability in UGT1A1 expression in EAs than in AAs (53% vs. 39%). <b>Conclusions:</b> Our findings reveal differences in UGT1A1 regulation between AA and EA populations and suggest that additional cis- and/or trans-acting factors regulating UGT1A1 expression remain to be discovered in individuals of African ancestry.