Analysis of genes for bilirubin UDP-glucuronosyltransferase in Gilbert's syndrome

Aono, Sachiko; Keino, Hiroomi; Yamada, Yasukazu; Adachi, Yukihiko; Nanno, Tatsuo; Uyama, Eiichiro; Koiwai, Osamu; Sato, Hiroshi

doi:10.1016/s0140-6736(95)90702-5

Cited by 176 publications

(108 citation statements)

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“…Arrows highlight variants previously shown to be associated with human-health phenotypes in either multiple human subject studies or in individual association studies involving more than 100 human subjects; these include the UGT1A8*2 allele, 70,71 the three non-synonymous coding SNPs in UGT1A7 (*2,*3,*10), 69,72,73,81,82 two nsSNPs in UGT1A6 (*2,*3), 67,68,70 rs887829 -the SNP revealing the strongest association with tranilast-induced hyperbilirubinemia, 28 and the UGT1A1*6 allele. 10,24,25,[50][51][52][53][54][55][56][57][83][84][85][86][87] Figure 4 Two-point LD maps for variants of UGT1A1, UGT1A6, and UGT1A9 mapped by population. The patterns of pairwise LD, summarized by |D 0 |, include 60 variants in African-Americans (left), 52 in European-Americans (center), and 49 in Asians (right).…”

Section: Prediction Of Functional Effects Of Amino-acid Replacement Vmentioning

confidence: 99%

Comparative genomics analysis of human sequence variation in the UGT1A gene cluster

et al. 2005

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Common polymorphisms within the human UGT1A gene locus are associated with irinotecan and tranilast toxicity. To uncover additional functional variation across this gene cluster, cross-species sequence comparisons were performed. Evolutionarily conserved segments (a total of 47.1 kb) were re-sequenced in 24 African-American, 24 European-American, and 24 Asian individuals, and 381 segregating sites (including 123 singletons) were identified. Highly conserved coding sites were less likely to be polymorphic than diverged sites (Po0.0001) but this pattern was not observed at noncoding sites (P ¼ 0.1025). Among coding variants, the distribution of those computationally predicted to affect function was skewed toward low frequencies. Some alleles occurred at similar frequencies in each population; others had wide disparities. Although strong linkage disequilibrium was detected among the hepatically expressed genes, the degree of linkage disequilibrium varied among populations. These results suggest that rare functional gene variants and inter-population variability must be considered in the interpretation of association studies between UGT1A and drug metabolism/toxicity phenotypes.

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Section: Prediction Of Functional Effects Of Amino-acid Replacement Vmentioning

confidence: 99%

Comparative genomics analysis of human sequence variation in the UGT1A gene cluster

et al. 2005

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“…Each showed heterozygous missense mutations of biliity and hepatic secretory capability of UCB as well as many rubin UGT (B-UGT), usually in exon 1A. 163 Because B-UGT other substances. 154 Microsomal vesicles from rat liver nor-reputedly is a tetramer, 164 the mean 70% decrease in enzyme mally are poorly permeable (latent) to uridine diphosphate activity observed in Gilbert's syndrome may result from in-(UDP)-glucuronic acid (UDPGA) and many other substrates, terference by the two abnormal B-UGT monomomers with which may thus require carrier proteins for their transloca-the formation of a functional tetramer.…”

Section: Translocation Across the Microsomal Membrane Of Substrates Omentioning

confidence: 99%

New Concepts in Bilirubin and Jaundice: Report of the Third International Bilirubin Workshop, April 6–8, 1995, Trieste, Italy

Tiribelli

Ostrow

1996

Hepatology

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only partial and temporary relief of hyperbilirubinemia; tocytic transporters of UCB and related organic anions extracorporeal liver assist devices have had some sucwere described. Special emphasis was given to the adencess in initial human studies; and inhibition of heme osine triphosphate (ATP)-dependent canalicular multioxygenase (HO) with metalloporphyrins, especially tin specific organic anion transporter that is defective in mesoporphyrin, which markedly decreases bilirubin production for prolonged periods, is a new alternative dipyrrole (Fig. 1). In solution, however, this structure is flexi- Received October 3, 1995; accepted June 6, 1996. ble, and small changes ({40Њ) in the interplanar angle (u)

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“…12 Several studies have demonstrated that the genetic predisposition to Gilbert's syndrome is associated with a TA repeat expansion in the TATAA box of the UGT1A1 gene. [13][14][15] Individuals homozygous for the (TA) 7 allele have higher serum bilirubin levels when compared to individuals who carry one or more copy of the (TA) 6 allele. 13,[15][16][17] Reporter construct analysis showed that the activity of the A(TA) 7 TAA promoter was approximately 18-33% that of the wild-type construct.…”

Section: Introductionmentioning

confidence: 99%

“…20,21 It was suggested that the GLY71Arg polymorphism may contribute to Gilbert's syndrome, particularly in Japanese and Asian patients. 14,22,23 Given these data, we set out to investigate the possible association of both the TA repeat and the GLY71Arg polymorphisms within UGT1A1, with hyperbilirubinemia observed during repeat dosing with tranilast in the PRESTO cohort. Our results supported the hypothesis that genetic predisposition to Gilbert's syndrome predicted susceptibility to hyperbilirubinemia following administration of tranilast.…”

Section: Introductionmentioning

confidence: 99%

A Gilbert's syndrome UGT1A1 variant confers susceptibility to tranilast-induced hyperbilirubinemia

Chen

et al. 2003

Pharmacogenomics J

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Tranilast (N-(3 0 4 0 -demethoxycinnamoyl)-anthranilic acid (N-5)) is an investigational drug for the prevention of restenosis following percutaneous transluminal coronary revascularization. An increase in bilirubin levels was observed in 12% of patients upon administration of tranilast in a phase III clinical trial. To identify the potential genetic factors that may account for the drug-induced hyperbilirubinemia, we examined polymorphisms in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene in over a thousand patients. Our results suggested that the TA repeat polymorphism in UGT1A1, which predisposes some individuals to Gilbert's syndrome, predicted the susceptibility to tranilast-induced hyperbilirubinemia. The (TA) 7 /(TA) 7 genotype was present in 39% of the 127 hyperbilirubinemic patients vs 7% of the 909 controls (P ¼ 2 Â 10 À22 ). Rapid identification of genetic factors accounting for the observed adverse effect during the course of a double-blind clinical trial demonstrated the potential application of pharmacogenetics in the clinical development of safe and effective medicines.

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Analysis of genes for bilirubin UDP-glucuronosyltransferase in Gilbert's syndrome

Cited by 176 publications

References 10 publications

Comparative genomics analysis of human sequence variation in the UGT1A gene cluster

Comparative genomics analysis of human sequence variation in the UGT1A gene cluster

New Concepts in Bilirubin and Jaundice: Report of the Third International Bilirubin Workshop, April 6–8, 1995, Trieste, Italy

A Gilbert's syndrome UGT1A1 variant confers susceptibility to tranilast-induced hyperbilirubinemia

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