Taylor Matthew J, Collins Joseph M, Montalvo Abelardo D, Wang Danxin
Department of Pharmacotherapy and Translational Research, College of Pharmacy, Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, FL 32610, USA.
Genes (Basel). 2025 Aug 18;16(8):971. doi: 10.3390/genes16080971.
UDP-glucuronosyltransferase 1A1 (UGT1A1) metabolizes endogenous substances and pharmaceuticals. Genetic polymorphisms, particularly TA repeats in the UGT1A1 promoter TATA region (UGT1A128/36/37) 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. 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. Both rs887829 and UGT1A128/37 showed similar associations with UGT1A1 expression in AA and EA samples. Reporter gene assays confirmed that UGT1A136 (5TA) had significantly higher activity than reference UGT1A11 (6TA), while UGT1A128 (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 UGT1A128/*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%). 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.
尿苷二磷酸葡萄糖醛酸基转移酶1A1（UGT1A1）可代谢内源性物质和药物。基因多态性，尤其是UGT1A1启动子TATA区域（UGT1A128/36/37）中的TA重复序列以及附近的单核苷酸多态性（SNP）rs887829，与UGT1A1相关表型有关，并用作指导药物治疗的生物标志物。然而，这些关联并不一致，尤其是在非洲裔个体中。本研究的目的是调查从欧美（EA，n = 119）和非裔美国人（AA，n = 138）供体获得的肝脏样本中UGT1A1表达与其基因变异之间的关联，并阐明基因变异的功能。使用多元线性回归分析测试UGT1A1表达与基因变异之间的关联，并使用报告基因测定法测试基因变异的转录活性。rs887829和UGT1A128/37在AA和EA样本中与UGT1A1表达显示出相似的关联。报告基因测定法证实，UGT1A136（5TA）的活性明显高于参考UGT1A11（6TA），而UGT1A128（7TA）和37（8TA）的活性较低。相比之下，rs887829对启动子活性没有直接影响，表明其关联可能是由与UGT1A128/*37的高连锁不平衡引起的。此外，我们发现，与反式作用调节因子以及组合的基因变异和转录因子的关联中的祖先差异，在EA中占UGT1A1表达总变异性的比例比在AA中高得多（53%对39%）。我们的研究结果揭示了AA和EA人群之间UGT1A1调节的差异，并表明在非洲裔个体中仍有待发现调节UGT1A1表达的其他顺式和/或反式作用因子。
