Genetic variation in bilirubin UDP-glucuronosyltransferase gene promoter and Gilbert's syndrome

Monaghan, Gemma; Ryan, Max; Hume, Robert; Burchell, Brian; Seddon, Ryan J.

doi:10.1016/s0140-6736(96)91273-8

Cited by 549 publications

(441 citation statements)

References 15 publications

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“…66,[107][108][109] The 'wild-type' allele (UGT1A1*1) contains six TA repeats, whereas the most common variant allele (UGT1A1*28) contains seven TA repeats and is associated with the mild form of the inherited unconjugated hyperbilirubinemia syndrome (Gilbert's syndrome). 109,110 Gilbert's syndrome is also characterized by the absence of liver disease and by episodes of mild intermittent jaundice and is found in approximately 6-12% of the population. [109][110][111][112][113] Studies showed that mutations in the UGT1A1 gene, especially homozygosity for the UGT1A1*28 variant, are responsible for this syndrome.…”

Section: Ugt1a1mentioning

confidence: 99%

“…109,110 Gilbert's syndrome is also characterized by the absence of liver disease and by episodes of mild intermittent jaundice and is found in approximately 6-12% of the population. [109][110][111][112][113] Studies showed that mutations in the UGT1A1 gene, especially homozygosity for the UGT1A1*28 variant, are responsible for this syndrome. Moreover, this genetic variation of the UGT1A1 gene is a contributory factor in prolonged neonatal jaundice.…”

Section: Ugt1a1mentioning

confidence: 99%

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Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

2003

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UDP-glucuronosyltransferase (UGT) enzymes comprise a superfamily of key proteins that catalyze the glucuronidation reaction on a wide range of structurally diverse endogenous and exogenous chemicals. Glucuronidation is one of the major phase II drug-metabolizing reactions that contributes to drug biotransformation. This biochemical process is also involved in the protection against environmental toxicants, carcinogens, dietary toxins and participates in the homeostasis of numerous endogenous molecules, including bilirubin, steroid hormones and biliary acids. Over the years, significant progress was made in the field of glucuronidation, especially with regard to the identification of human UGTs, study of their tissue distribution and substrate specificities. More recently, the degree of allelic diversity has also been revealed for several human UGT genes. Some polymorphic UGTs have demonstrated a significant pharmacological impact in addition to being relevant to drug-induced adverse reactions and cancer susceptibility. This review focuses on human UGTs, the description of the nature of polymorphic variations and their functional impact. The pharmacogenomic implication of polymorphic UGTs is presented, more specifically the role of UGT polymorphisms in modifying cancer risk and their impact on individual risk to drug-induced toxicities.

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Section: Ugt1a1mentioning

confidence: 99%

Section: Ugt1a1mentioning

confidence: 99%

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

2003

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“…UGT1A1 genotyping assay: Genomic DNA was extracted from peripheral leukocytes by the salting-out procedure (Miller et al, 1989). Analysis of the A(TA)nTAA motif in the promoter region of the UGT1A1 gene was performed by PCR, according to Monaghan et al (1996), followed by separation of the amplified products on a 12% polyacrylamide gel (38 : 2 acrylamide : bisacrylamide). Following this protocol, DNA fragments containing six TA repeats measure 98 bp while those containing seven TA repeats occur as 100 bp bands.…”

Section: Clinical Parametersmentioning

confidence: 99%

UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer

et al. 2004

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SN-38 is the active metabolite of irinotecan and it is metabolised through conjugation by uridine diphosphate glucuronosyl transferase (UGT1A1). The major toxicity of irinotecan therapy is diarrhoea, which has been related to the enzymatic activity of UGT1A1. We examined the influence of the UGT1A1 gene promoter polymorphism in the toxicity profile, in the response rate and in the overall survival (OS) in 95 patients with metastatic colorectal cancer treated with an irinotecan-containing chemotherapy. Genotypes were determined by analysing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Clinical parameters and genotypes were compared by univariate and multivariate statistical methods. The more frequent adverse effects were asthenia (34 patients), diarrhoea (29 patients) and neutropenia (20 patients). Severe diarrhoea was observed in 7/10 homozygous (70%) and 15/ 45 heterozygous (33%) in comparison to 7/40 (17%) wild-type patients (P ¼ 0.005). These results maintained the statistical significance in logistic regression analysis (P ¼ 0.01) after adjustment for other clinical relevant variables. The presence of severe haematological toxicity increased from wild-type patients to UGT1A1*28 homozygotes, but without achieving statistical significance. No relationship was found between the UGT1A1*28 genotypes and infection, nausea or mucositis. In univariate studies, patients with the UGT1A1*28 polymorphism showed a trend to a poorer OS (P ¼ 0.09). In the multivariate analysis, the genotype was not related to clinical response or to OS. The role of the UGT1A1 genotype as a predictor of toxicity in cancer patients receiving irinotecan demands the performance of a randomized trial to ascertain whether genotype-adjusted dosages of the drug can help to establish safe and effective doses not only for patients with the UGT1A1*28 homozygous genotype but also for those with the most common UGT1A1 6/6 or 6/7 genotype.

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“…29,30 Such studies are likely to identify many functional variants, but may miss functional noncoding sequence variants, 31 as have already proved important for UGT1A1. 8,11,32 To focus on the regions of the entire UGT1A locus most likely to affect clinical phenotypes, we identified 29 kb of non-coding sequence highly conserved between humans and four mammalian species and resequenced these regions as well as over 8 kb of exon sequence in 72 individuals from three ethnic populations.…”

Section: Introductionmentioning

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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Genetic variation in bilirubin UDP-glucuronosyltransferase gene promoter and Gilbert's syndrome

Cited by 549 publications

References 15 publications

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer

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

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