Genetic Variations and Haplotypes of UGT1A4 in a Japanese Population

Saeki, Mayumi; Saito, Yoshiro; Jinno, Hideto; Sai, Kimie; Hachisuka, Akiko; Kaniwa, Nahoko; Ozawa, Shogo; Kawamoto, Manabu; Kamatani, Naoyuki; Shirao, Kuniaki; Minami, Hironobu; Ohtsu, Atsushi; Yoshida, Teruhiko; Saijo, Nagahiro; Komamura, Kazuo; Kotake, Takeshi; Morishita, Hideki; Kamakura, Shiro; Kitakaze, Masafumi; Tomoike, Hitonobu; Sawada, Jun‐ichi

doi:10.2133/dmpk.20.144

Cited by 51 publications

(38 citation statements)

References 14 publications

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“…When expressed in HEK293 cells, both variants exhibited decreased activity toward benzidine, androsterone and dihydrotestosterone compared to the wild-type protein. For the mutations reported by Saeki et al (2005a), again no significant differences were found between allele frequencies of 60 healthy volunteers and 88 cancer patients.…”

Section: Ugt1a4mentioning

confidence: 84%

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Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

2006

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The uridine diphosphoglucuronosyltransferases (UGTs) belong to a superfamily of enzymes that catalyse the glucuronidation of numerous endobiotics and xenobiotics. Several human hepatic and extrahepatic UGT isozymes have been characterized with respect to their substrate specificity, tissue expression and gene structure. Genetic polymorphisms have been identified for almost all the UGT family members. A wide variety of anticancer drugs, dietary chemopreventives and carcinogens are known to be conjugated by members of both UGT1A and UGT2B subfamilies. This review examines in detail each UGT isozyme known to be associated with cancer and carcinogenesis. The cancer-related substrates for several UGTs are summarized, and the functionally relevant genetic polymorphisms of UGTs are reviewed. A number of genotype-phenotype association studies have been carried out to characterize the role of UGT pharmacogenetics in several types of cancer, and these examples are discussed here. In summary, this review focuses on the role of the human UGT genetic polymorphisms in carcinogenesis, chemoprevention and cancer risk.

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Section: Ugt1a4mentioning

confidence: 84%

“…Of these 21 mutations, eight lead to aminoacid changes, five are silent mutations, whereas the remaining eight are in non-coding regions of the gene (Ehmer et al, 2004;Saeki et al, 2005a). Haplotype analysis of the detected SNPs resulted in the assignment of 16 observed haplotypes in a Japanese population (Saeki et al, 2005a).…”

Section: Ugt1a4mentioning

confidence: 99%

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

2006

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“…As for 1A6, 1A4, 1A1, and common exons 2-5, their SNPs and segmental haplotypes have already been reported. [19][20][21] UGT1A5 was omitted from the current analysis because the expression of 1A5 mRNA has not been shown in any tissue.…”

Section: Resultsmentioning

confidence: 99%

“…[19][20][21] In this study, additional first exons (1A3, 1A7, 1A8, 1A9, and 1A10) and their surrounding promoter or intronic regions were sequenced for the same 196 Japanese subjects as used for the analysis of 1A1, 1A4, and 1A6, and the haplotypes for the UGT1A complex were inferred in linkage disequilibrium (LD) blocks, 1A8-1A10, 1A9-1A7-1A6, and 1A3-1A1. Then, the tagged polymorphisms with functional changes were genotyped for additional 105 Japanese subjects.…”

Section: Introductionmentioning

confidence: 99%

Haplotype structures of the UGT1A gene complex in a Japanese population

et al. 2005

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Genetic polymorphisms of UDP-glucuronosyltransferases (UGTs) are involved in individual and ethnic differences in drug metabolism. To reveal cooccurrence of the UGT1A polymorphisms, we first analyzed haplotype structures of the entire UGT1A gene complex using the polymorphisms from 196 Japanese subjects. Based on strong linkage disequilibrium between UGT1A8 and 1A10, among 1A9, 1A7, and 1A6, and between 1A3 and 1A1, the complex was divided into five blocks, Block 8/10, Block 9/6, Block 4, Block 3/1, and Block C, and the haplotypes for each block were subsequently determined/inferred. Second, using pyrosequencing or direct sequencing, additional 105 subjects were genotyped for 41 functionally tagged polymorphisms. The data from 301 subjects confirmed the robustness of block partitioning, but several linkages among the haplotypes with functional changes were found across the blocks. Thus, important haplotypes and their linkages were identified among the UGT1A gene blocks (and segments), which should be considered in pharmacogenetic studies.

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“…Thus, this polymorphism causes an increase of glucuronidation activity. It has been reported that the frequency of UGT1A4 (142T>G) polymorphism is 8% in Caucasians 20) and 12% in Japanese, 21) no marked difference. On the other hand, the frequency of UGT2B7*2 (802C>T) polymorphism, which is linked with −161C>T, 22) was reported to be 48.9-53.7% 23,24) in Caucasians and only 24.4-29.3% 24,25) in Japanese.…”

Section: Discussionmentioning

confidence: 96%