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SINGLE NUCLEOTIDE POLYMORPHISMS AND HAPLOTYPE FREQUENCIES OF UGT2B4 AND UGT2B7 IN A JAPANESE POPULATION

Project Team for Pharmacogenetics (M.S., Y.S., H.J., A.O., S.O., J.S.), Division of Biochemistry and Immunochemistry (Y.S., J.S.), Division of Environmental Chemistry (H.J., T.T.-K., A.O.), and Division of Pharmacology (S.O.), National Institute of Health Sciences, Tokyo, Japan; Department of Pharmacy (K.U.), Department of Cardiology (S.K., K.K., M.K.), and Department of Cardiovascular Dynamics Research Institute (K.K.), National Cardiovascular Center, Osaka, Japan; and Division of Genomic Medicine, Department of Advanced Biomedical Engineering and Science (N.K.), Tokyo Women's Medical University, Tokyo, Japan

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.