Comprehensive variant screening of the UGT gene family.
Comprehensive variant screening of the UGT gene family.
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DOI：
10.3349/ymj.2014.55.1.232
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发表时间：
2014-01
影响因子：
2.4
通讯作者：
Shin HD
中科院分区：
文献类型：
--
作者：
Kim JY;Cheong HS;Park BL;Kim LH;Namgoong S;Kim JO;Kim HD;Kim YH;Chung MW;Han SY;Shin HD
UGT 1A 1、UGT 2B 7和UGT 2B 15是属于尿苷二磷酸葡萄糖醛酸转移酶基因家族的已知药物基因。对于个性化药物治疗，重要的是要研究不同种族群体中核心标志物频率的差异。因此，我们筛选了这三个基因的单核苷酸多态性（SNPs），并分析了它们在五个民族中的频率差异，以及试图预测新的SNPs的功能。我们直接测序了288名受试者，包括96名韩国人，48名日本人，48名中国汉族人，48名非洲裔美国人和48名欧洲裔美国人。随后，我们分析了每个基因的遗传变异，连锁不平衡（LD）结构和种族差异。我们还进行了计算机分析，以预测新的SNP的功能。共检测到87个SNP，其中7个药物遗传学核心SNP和31个新SNP。我们观察到UGT 1A 1 *6（rs 4148323）、UGT 1A 1 *60（rs 4124874）、UGT 1A 1 *93（rs 10929302）、UGT 2B 7 *2（rs7439366）、部分UGT 2B 7 *3（rs 12233719）和UGT 2B 15 *2（rs 1902023）的频率在亚洲人群和其他种族人群之间存在差异。另外的计算机模拟分析结果显示，发现UGT 1A 1 - 690 G>A和-689 A>C的两个新启动子SNP可能改变转录因子结合位点。此外，673 G>A（UGT 2B 7）、2552 T>C和23269 C>T（均来自UGT 2B 15的SNP）改变了氨基酸特性，这可能导致结构变形。本研究结果将为个体化用药和药物反应的遗传药理学研究提供参考。
UGT1A1, UGT2B7, and UGT2B15 are well-known pharmacogenes that belong to the uridine diphosphate glucuronyltransferase gene family. For personalized drug treatment, it is important to study differences in the frequency of core markers across various ethnic groups. Accordingly, we screened single nucleotide polymorphisms (SNPs) of these three genes and analyzed differences in their frequency among five ethnic groups, as well as attempted to predict the function of novel SNPs. We directly sequenced 288 subjects consisting of 96 Korean, 48 Japanese, 48 Han Chinese, 48 African American, and 48 European American subjects. Subsequently, we analyzed genetic variability, linkage disequilibrium (LD) structures and ethnic differences for each gene. We also conducted in silico analysis to predict the function of novel SNPs. A total of 87 SNPs were detected, with seven pharmacogenetic core SNPs and 31 novel SNPs. We observed that the frequencies of UGT1A1 *6 (rs4148323), UGT1A1 *60 (rs4124874), UGT1A1 *93 (rs10929302), UGT2B7 *2 (rs7439366), a part of UGT2B7 *3 (rs12233719), and UGT2B15 *2 (rs1902023) were different between Asian and other ethnic groups. Additional in silico analysis results showed that two novel promoter SNPs of UGT1A1 -690G>A and -689A>C were found to potentially change transcription factor binding sites. Moreover, 673G>A (UGT2B7), 2552T>C, and 23269C>T (both SNPs from UGT2B15) changed amino acid properties, which could cause structural deformation. Findings from the present study would be valuable for further studies on pharmacogenetic studies of personalized medicine and drug response.