Gilbert’s syndrome is a contributory factor in prolonged unconjugated hyperbilirubinemia of the newborn

Monaghan, Gemma; McLellan, Ailsa; McGeehan, Anne; Volti, S. Li; Mollica, F; Salemi, Isabella; Din, Zahida; Cassidy, Andrew J.; Hume, Robert; Burchell, Brian

doi:10.1016/s0022-3476(99)70201-5

Cited by 142 publications

(78 citation statements)

References 21 publications

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“…18,30,31 Two studies have found that UGT1A1*28 contributed to prolonged neonatal jaundice. 32,33 Thus, our primary outcome is consistent with most of the previous findings.…”

Section: Strengths and Limitationssupporting

confidence: 91%

Extreme Neonatal Hyperbilirubinemia and a Specific Genotype: A Population-Based Case-Control Study

Petersen

Henriksen²,

Hollegaard

et al. 2014

Pediatrics

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WHAT'S KNOWN ON THIS SUBJECT: For newborn infants, extreme hyperbilirubinemia ($24.5 mg/dL) is associated with risk for severe bilirubin encephalopathy. The causal factor of extreme hyperbilirubinemia is often not established. The genotype of Gilbert syndrome, the UGT1A1*28 allele, is considered a potential risk factor. WHAT THIS STUDY ADDS:The UGT1A1*28 allele was not associated with risk for developing extreme hyperbilirubinemia. abstract OBJECTIVES: Extreme hyperbilirubinemia (plasma bilirubin $24.5 mg/dL) is an important risk factor for severe bilirubin encephalopathy. Several risk factors for hyperbilirubinemia are known, but in a large number of patients, a causal factor is never established. UGT1A1 is the rate-limiting enzyme in bilirubin' s metabolism. The genotype of Gilbert syndrome, the UGT1A1*28 allele, causes markedly reduced activity of this enzyme, but its association with neonatal hyperbilirubinemia is uncertain and its relationship with extreme hyperbilirubinemia has not been studied. We examined whether the UGT1A1*28 allele is associated with extreme hyperbilirubinemia. METHODS:The UGT1A1*28 allele was assessed in a case-control study of 231 white infants who had extreme hyperbilirubinemia in Denmark from 2000 to 2007 and 432 white controls. Cases were identified in the Danish Extreme Hyperbilirubinemia Database that covers the entire population. Genotypes were obtained through the Danish Neonatal Screening Biobank. Subgroup analysis was done for AB0 incompatible cases. RESULTS:No association was found between the UGT1A1*28 allele and extreme hyperbilirubinemia. With the common genotype as reference, the odds ratio of extreme hyperbilirubinemia was 0.87 (range, 0.68-1.13) for UGT1A1*28 heterozygotes and 0.77 (range, 0.46-1.27) for homozygotes. Also, no association was found for AB0 incompatible cases.

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“…18,30,31 Two studies have found that UGT1A1*28 contributed to prolonged neonatal jaundice. 32,33 Thus, our primary outcome is consistent with most of the previous findings.…”

Section: Strengths and Limitationssupporting

confidence: 91%

Extreme Neonatal Hyperbilirubinemia and a Specific Genotype: A Population-Based Case-Control Study

Petersen

Henriksen²,

Hollegaard

et al. 2014

Pediatrics

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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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“…Only the (TA) 6 and (TA) 7 alleles were used for pharmacogenetic analysis, as patients with at least one copy of the rarer alleles were excluded from the relative risk calculations. The number of such cases was too small to allow them to be treated as independent genotype classes, and the details of their expected effects are not clear enough 16 to warrant grouping them with other genotypes. In addition to (A(TA)nTAA), other UGT1A1 polymorphisms 17,18 and haplotypes 19 have been associated with bilirubin levels and Gilbert's syndrome.…”

Section: Max Grade P2mentioning

confidence: 99%

UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia

Singer¹,

et al. 2007

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Nilotinib is a novel BCR-ABL inhibitor with significantly improved potency and selectivity over imatinib. In Phase I and Phase II clinical studies of nilotinib in patients with a variety of leukemias, infrequent instances of reversible, benign elevation of bilirubin were observed. Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) glucuronidates bilirubin in humans, and a polymorphism in the promoter of the gene that encodes it has been associated with hyperbilirubinemia during treatment with a number of drugs. Pharmacogenetic analysis of that TArepeat polymorphism found an association between the (TA) 7 / (TA) 7 genotype and risk of hyperbilirubinemia in Phase I patients with imatinib-resistant/intolerant chronic myeloid leukemia (CML) or relapsed/refractory Ph þ acute lymphoblastic leukemia (ALL); this result was replicated in two separate analyses of the chronic phase (CP) and accelerated phase (AP) CML arms of a Phase II study. As nilotinib is not known to be glucuronidated by UGT1A1, the combined impact of inhibition of UGT1A1 activity by nilotinib and genetic polymorphism is the most likely cause of the increased rate of hyperbilirubinemia.

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Gilbert’s syndrome is a contributory factor in prolonged unconjugated hyperbilirubinemia of the newborn

Cited by 142 publications

References 21 publications

Extreme Neonatal Hyperbilirubinemia and a Specific Genotype: A Population-Based Case-Control Study

Extreme Neonatal Hyperbilirubinemia and a Specific Genotype: A Population-Based Case-Control Study

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia

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