Genetic Variants in the <i>UDP-glucuronosyltransferase 1A1</i> Gene Predict the Risk of Severe Neutropenia of Irinotecan

Innocenti, Federico; Undevia, Samir D.; Iyer, Lalitha; Chen, Pei Xian; Das, Soma; Kocherginsky, Masha; Karrison, Theodore; Janisch, Linda; Ramı́rez, Jacqueline; Rudin, Charles M.; Vokes, Everett E.; Ratain, Mark J.

doi:10.1200/jco.2004.07.173

Cited by 918 publications

(702 citation statements)

References 25 publications

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“…Two variants of À3279T4G and the À3156G4A in the UGT1A1 enhancer region, and two nonsynonymous polymorphisms of 211G4A and 686C4A in exon1 were also associated with decreased enzyme activity for SN-38 glucuronidation. 5,6 The À3279 T4G in the UGT1A1 enhancer was very common (39.7%), while the À3156G4A variant was registered only 12.4% compared to 30% reported in a Japanese study. 11 The 211G4A (G71R) was found at a frequency of 14.8% over the combined groups, which is consistent with the frequency of 13-23% found in other Asian populations.…”

Section: Intra-ethnic Differences In Genetic Variantsmentioning

confidence: 74%

“…Some genetic variants in UGT1A1 gene have been observed to have lower SN-38 glucuronidation rates and greater susceptibility to irinotecan induced gastrointestinal and bone marrow toxicity. [3][4][5][6] It is important that patients should be pre-screened and received reduced, safe irinotecan starting doses before treatment according to their genotypes. 7 Global studies of polymorphisms in UGT1A have shown alleles and genotypes to be unequally distributed among different ethnic human populations across the world.…”

Section: Introductionmentioning

confidence: 99%

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Intra-ethnic differences in genetic variants of the UGT-glucuronosyltransferase 1A1 gene in Chinese populations

et al. 2006

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Variants within the human UGT1A1 gene are associated with irinotecan induced severely adverse reactions and hyperbilirubinemia. Intra-ethnic differences in the genetic variation and haplotypes of UGT1A1 gene have been analyzed in the present study. Relationship between the concentrations of total serum bilirubin (T-bil) and haplotype structure of UGT1A1 in healthy people were also evaluated. We genotyped five functional polymorphisms including À3279T4G and À3156G4A in the enhancer region, (TA)647 in the TATA box, and 211G4A (G71R), 686C4A (P229Q) in the exon1 region of UGT1A1 in three groups of healthy Chinese ethnic populations, consisting of 264 subjects of She origin, 539 of Han origin and 273 of Dong origin. The distribution of À3279T4G, (TA)647, 211G4A of UGT1A1 differed greatly as between the three ethnic groups. All of six haplotypes differed considerably between at least two of the three groups, which highlighted the need to analyze clinically irinotecan toxicity relevant SNPs and haplotypes in a variety of different racial groups within the Chinese population. Total bilirubin concentration in homozygous carriers of the À3279G and (TA)7 allele were significantly higher than those in heterozygous carriers or homozygous carriers of wild-type alleles. Carriers of the variant haplotypes (À3279G; À3156A; (TA)7; 211G; 686C) had higher serum T-Bil concentrations compared with the other groups. Our results indicate that heterogeneity among different ethnic populations is possibly the result of microevolution and is relevant to studies into the effect of tailored drug treatment.

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Section: Intra-ethnic Differences In Genetic Variantsmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Intra-ethnic differences in genetic variants of the UGT-glucuronosyltransferase 1A1 gene in Chinese populations

et al. 2006

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“…[16][17][18] The same common UGT1A1 variants associated with mild elevations of serum bilirubin are associated with diminished in vitro glucuronidation of the active irinotecan metabolite, SN-38, [19][20][21][22] and prolonged exposure and increased toxicity in patients receiving this agent. [23][24][25] As shown by Sai et al, 25 re-sequencing of the UGT1A1 gene in 85 Japanese patients treated with irinotecan confirmed that the haplotypes containing lower expression variants were associated with both a low SN-38G/SN-38 AUC ratio and elevated pretreatment bilirubin concentration. Importantly, however, additional haplotypes appeared to have distinct modifying effects on the SN-38 AUC ratio and total bilirubin level phenotypes, suggesting that more complete genetic variation data for UGT1A may better predict bilirubin and irinotecan metabolism phenotypes.…”

Section: Introductionmentioning

confidence: 84%

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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“…20,21 The clinical application of the genetic test for the UGT1A1*28 allele before irinotecan therapy has been in practice in the United States since 2005, based on a cumulative evidence supporting the significant association of this variant with severe irinotecan toxicity. 20,[22][23][24][25] The five most associated SNPs included rs4148323 (G4A, UGT1A1*6). Homozygotes of the UGT1A1*6 allele showed significantly high values in serum total bilirubin levels, supporting the evidence from earlier studies.…”

Section: Discussionmentioning

confidence: 99%

Association study between single-nucleotide polymorphisms in 199 drug-related genes and commonly measured quantitative traits of 752 healthy Japanese subjects

2009

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With dense single-nucleotide polymorphism (SNP) maps for 199 drug-related genes, we examined associations between 4190 SNPs and 38 commonly measured quantitative traits using data from 752 healthy Japanese subjects. On analysis, we observed a strong association between five SNPs within the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene and serum total bilirubin levels (minimum P-value in Mann-Whitney test¼1.82Â10 10 ). UGT1A1 catalyzes the conjugation of bilirubin with glucuronic acid, thus enhancing bilirubin elimination. This enzyme is known to play an important role in the variation of serum bilirubin levels. The five SNPs, including a nonsynonymous SNP-rs4148323 (211G4A or G71R variant allele known as UGT1A1*6)-showed strong linkage disequilibrium with each other. No other genes were clearly associated with serum total bilirubin levels. Results of linear multiple regression analysis on serum total bilirubin levels followed by analysis of variance showed that at least 13% of the variance in serum total bilirubin levels could be explained by three haplotype-tagging SNPs in the UGT1A1 gene.

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Genetic Variants in the UDP-glucuronosyltransferase 1A1 Gene Predict the Risk of Severe Neutropenia of Irinotecan

Cited by 918 publications

References 25 publications

Intra-ethnic differences in genetic variants of the UGT-glucuronosyltransferase 1A1 gene in Chinese populations

Intra-ethnic differences in genetic variants of the UGT-glucuronosyltransferase 1A1 gene in Chinese populations

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

Association study between single-nucleotide polymorphisms in 199 drug-related genes and commonly measured quantitative traits of 752 healthy Japanese subjects

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