Functional Study of Haplotypes in UGT1A1 Promoter to Find a Novel Genetic Variant Leading to Reduced Gene Expression. Issue 3 (June 2015)

• Record Type: Journal Article
• Authors: Shin, Hee Jung; Kim, Jason Yongha; Cheong, Hyun Sub; Na, Han Sung; Shin, Hyoung Doo; Chung, Myeon Woo
• Is Part Of: Therapeutic drug monitoring. Volume 37:Issue 3(2015:Jun.)
• Publication Date: 2015-06
• Subjects: Pharmacokinetics -- Periodicals; Patient monitoring -- Periodicals; Drugs -- Analysis -- Periodicals; Body fluids -- Analysis -- Periodicals; Drug Therapy -- Periodicals; Monitoring, Physiologic -- Periodicals; Pharmacology -- Periodicals; 615.7
• DOI: 10.1097/FTD.0000000000000154
• Languages: English
• ISSNs: 0163-4356

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background:</title> <p> <italic>Uridine diphosphate glucuronyltransferase 1 family</italic>, <italic>A1</italic> (<italic>UGT1A1</italic>) encodes for an enzyme that is a part of glucuronidation pathway, and a number of studies have shown that the promoter polymorphisms of <italic>UGT1A1</italic> are associated with various diseases and drug response. In this study, we examined a possible association between <italic>UGT1A1</italic> promoter haplotypes and the gene expression level.</p> </sec> <sec> <title>Methods:</title> <p>To identify promoter haplotype structure population, we directly sequenced the promoter region of <italic>UGT1A1</italic> in 192 healthy Korean to identify 10 <italic>UGT1A1</italic> promoter single-nucleotide polymorphisms (SNPs). Then, we genotyped the 10 SNPs in additional 192 non-Korean samples comprised of Chinese, Japanese, European American, and African American, and constructed haplotype structures. Furthermore, we conducted luciferase assay for the promoter SNP haplotypes to examine a possible expression change.</p> </sec> <sec> <title>Results:</title> <p> <italic>rs3755319</italic>C—<italic>rs2003569</italic>A—<italic>rs887829</italic>C—<italic>rs8175347</italic>(TA)<sub>6</sub> (6.60 ± 0.15) and <italic>rs3755319</italic>A—<italic>rs2003569</italic> G—<italic>rs887829</italic>C–<italic>rs8175347</italic>(TA)<sub>7</sub> (2.79 ± 0.97) led to significantly lower gene expression when compared with <italic>rs3755319</italic>C—<italic>rs2003569</italic> G—<italic>rs887829</italic>T—<italic>rs8175347</italic>(TA)<sub>6</sub> (8.28 ± 0.60).</p> </sec> <sec> <title>Conclusions:</title> <p>Our result suggests that the haplotypes in <italic>UGT1A1</italic> promoter region can affect the expression level of the gene and drug metabolism associated with <italic>UGT1A1</italic>. Furthermore, in addition to <italic>rs8175347</italic>, <italic>rs3755319</italic> was found to induce lower gene expression of <italic>UGT1A1</italic>.</p> </sec> </abstract>