Saeki Mayumi, Saito Yoshiro, Jinno Hideto, Tanaka-Kagawa Toshiko, Ohno Akiko, Ozawa Shogo, Ueno Kazuyuki, Kamakura Shiro, Kamatani Naoyuki, Komamura Kazuo, Kitakaze Masafumi, Sawada Jun-Ichi
Project Team for Pharmacogenetics, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
Drug Metab Dispos. 2004 Sep;32(9):1048-54.
Both UDP-glucuronosyltransferase 2B4 (UGT2B4) and UGT2B7 are expressed mainly in the human liver and have several overlapping substrates; e.g., catechol estrogens, bile acids, codeine, and carvedilol. To identify novel single nucleotide polymorphisms (SNPs) and haplotypes in a Japanese population, the enhancer/promoter regions, all the exons, and the surrounding intronic regions of UGT2B4 and UGT2B7 were sequenced from 136 Japanese individuals. We found 16 and 21 polymorphisms, including 10 and 4 novel ones in UGT2B4 and UGT2B7, respectively. The novel nonsynonymous SNPs were 1364A>G (K455R) and 1531T>C (C511R) in UGT2B4 and 1192G> A (D398N) in UGT2B7. From linkage disequilibrium analysis, several SNPs in UGT2B7 were found to be highly linked with each other. No close linkage between the SNPs in UGT2B4 and UGT2B7 was observed, indicating that each gene is located within an independent haplotype block. Thus, haplotype analysis was separately performed for the two genes. In UGT2B4, we unambiguously determined 8 haplotypes and inferred an additional 12 haplotypes using an expectation-maximization-based program. In UGT2B7, five haplotypes were unambiguously assigned and an additional eight haplotypes were inferred. The haplotype structure of UGT2B7 was more diverse than that of UGT2B4 in terms of the number of frequent SNPs. In addition, ethnic differences in the UGT2B4()2 and UGT2B7()2 haplotypes between the Japanese and the Caucasian and/or African populations were found. Our findings provide fundamental and useful information for genotyping UGT2B4 and UGT2B7 in the Japanese, and probably other populations.
尿苷二磷酸葡萄糖醛酸基转移酶2B4（UGT2B4）和UGT2B7均主要在人肝脏中表达，且有几种重叠的底物；例如，儿茶酚雌激素、胆汁酸、可待因和卡维地洛。为了鉴定日本人群中的新型单核苷酸多态性（SNP）和单倍型，对136名日本个体的UGT2B4和UGT2B7的增强子/启动子区域、所有外显子以及周围的内含子区域进行了测序。我们分别在UGT2B4和UGT2B7中发现了16个和21个多态性，其中包括10个和4个新型多态性。UGT2B4中的新型非同义SNP为1364A>G（K455R）和1531T>C（C511R），UGT2B7中的新型非同义SNP为1192G>A（D398N）。通过连锁不平衡分析，发现UGT2B7中的几个SNP彼此高度连锁。未观察到UGT2B4和UGT2B7中的SNP之间有紧密连锁，这表明每个基因位于一个独立的单倍型块内。因此，对这两个基因分别进行了单倍型分析。在UGT2B4中，我们明确确定了8种单倍型，并使用基于期望最大化的程序推断出另外12种单倍型。在UGT2B7中，明确分配了5种单倍型，并推断出另外8种单倍型。就常见SNP的数量而言，UGT2B7的单倍型结构比UGT2B4的更多样化。此外，还发现了日本人群与白种人和/或非洲人群在UGT2B4（）2和UGT2B7（）2单倍型上的种族差异。我们的研究结果为在日本人群以及可能在其他人群中对UGT2B4和UGT2B7进行基因分型提供了基础且有用的信息。
