Interaction of coding region mutations and the Gilbert-type promoter abnormality of the UGT1A1 gene causes moderate degrees of unconjugated hyperbilirubinaemia and may lead to neonatal kernicterus

Kadakol, Ajit; Sappal, Baljit S.; Ghosh, Siddhartha Sankar; Lowenheim, Mark; Chowdhury, Abhijit; Chowdhury, Sujit; Santra, Amal; Arias, Irwin M.; Chowdhury, Jayanta Roy; Chowdhury, Namita Roy

doi:10.1136/jmg.38.4.244

Cited by 58 publications

(42 citation statements)

References 31 publications

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“…Moreover, this genetic variation of the UGT1A1 gene is a contributory factor in prolonged neonatal jaundice. [114][115][116][117] A significant difference in the prevalence of the variant UGT1A1 promoter alleles has been observed. A detailed analysis of data available in the literature revealed that overall, the UGT1A1 isoform seems to be expressed at a lower level in approximately 0-3% of the Asian population, 2-13% of the Caucasian population and up to 16-19% of Africans (Table 2).…”

Section: Ugt1a1mentioning

confidence: 99%

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%

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

2003

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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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“…Of great interest in the current study is the dramatic effect combined OATP-2 and UDP-GT1A1 G71R mutations has on neonatal jaundice and provides another compelling example of dose dependent genetic interactions that enhance the development of marked neonatal hyperbilirubinemia (10,11). These phenomena are analogous to that observed in Western infants with 1) combined Gilbert genotype and G6PD deficiency, 2) combined Gilbert genotype and hereditary spherocytosis, and 3) compound heterozygosity for the Gilbert genotype and UDP-GT1A1 coding sequence mutations, in increasing the risk for neonatal hyperbilirubinemia (10,11) and even kernicterus (14). This growing body of literature underscores the importance of increasing our understanding of the biology of neonatal hyperbilirubinemia at the molecular level.…”

Section: Genetics Of Bilirubin Conjugation and Neonatal Hyperbilirubimentioning

confidence: 68%

Genetics and the Risk of Neonatal Hyperbilirubinemia: Commentary on the article by Huang et al. on page 682

Watchko

2004

Pediatr Res

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Interaction of coding region mutations and the Gilbert-type promoter abnormality of the UGT1A1 gene causes moderate degrees of unconjugated hyperbilirubinaemia and may lead to neonatal kernicterus

Cited by 58 publications

References 31 publications

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

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

Genetics and the Risk of Neonatal Hyperbilirubinemia: Commentary on the article by Huang et al. on page 682

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