Association of Neonatal Hyperbilirubinemia With Bilirubin UDP-Glucuronosyltransferase Polymorphism

Maruo, Yoshihiro; Nishizawa, Kenji; Sato, Hiroshi; Doida, Yukio; Shimada, Morimi

doi:10.1542/peds.103.6.1224

Cited by 148 publications

(184 citation statements)

References 15 publications

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“…Among the four mutations, 211G>A was the most common as shown above, and resulted in a change of glycine to arginine at position 71 (G71R). The A allele frequency in the case group was 20.4%, which is higher than data from Turkish (4.3%) (13) and North India (0%) (14), but lower than values in Korean (32%) (15) and Japan (34%) (16), and close to our previous study (23.3%) (17). The frequency of the 211G>A mutation was significantly higher in hyperbilirubinemia infants than controls in this study, indicating its close relationship to neonatal hyperbilirubinemia in Guangxi Heiyi Zhuang and Han populations.…”

Section: Articlessupporting

confidence: 61%

UGT1A1 gene mutations and neonatal hyperbilirubinemia in Guangxi Heiyi Zhuang and Han populations

Zhong

Xie

et al. 2015

Pediatr Res

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Articles Population Study nature publishing groupBackground: Uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT1A1) gene mutation was shown to be responsible for neonatal hyperbilirubinemia. This study aimed to investigate whether UGT1A1 gene mutation is associated with neonatal hyperbilirubinemia in Guangxi Heiyi Zhuang and Han populations. Methods: Two hundred and eighteen infants with hyperbilirubinemia (118 Heiyi Zhuang, 100 Han) and 190 control subjects (110 Heiyi Zhuang, 80 Han) were enrolled. Polymerase chain reaction and gene sequencing were used to detect the TATA-box and exon 1 of UGT1A1. results: (TA)7 insertion mutation, 211G>A (G71R), 686C>A (P229Q), and 189C>T (D63D) were detected. Logistic regression analysis showed odds ratios (OR) of 2.64 (95% confidence interval (CI) 1.64-4.24; P < 0.001) and 0.69 (95%CI 0.43-1.10; P = 0.115) for neonates who carried UGT1A1 G71R and (TA)7 insertion mutation, respectively. G71R homozygosity increased the odds of dangerous bilirubin levels by a factor 34.23, and G71R heterozygosity only by 2.10. conclusion: We found that UGT1A1 G71R mutation is a risk factor for neonatal hyperbilirubinemia in Guangxi Heiyi Zhuang and Han populations. Meanwhile, the UGT1A1 (TA)7 insertion mutation is not associated with neonatal hyperbilirubinemia in the two ethnic groups.

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Section: Articlessupporting

confidence: 61%

UGT1A1 gene mutations and neonatal hyperbilirubinemia in Guangxi Heiyi Zhuang and Han populations

Zhong

Xie

et al. 2015

Pediatr Res

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“…The most dominant genotype (observed in nine patients) was homozygous UGT1A1*6, which results from a transition of nucleotide c.211G>A, leading to the replacement of glycine to arginine at codon 71 (p.G71R) and reduced glucuronidation activity toward bilirubin. UGT1A1*6 is an important polymorphism as a cause of Gilbert syndrome and breast milk jaundice, and is also a risk factor for neonatal hyperbilirubinemia in the early neonatal period (14,17). The allelic frequency of UGT1A1*6 is 0.16 in the Japanese population.…”

Section: Discussionmentioning

confidence: 99%

Contribution of UGT1A1 variations to chemotherapy-induced unconjugated hyperbilirubinemia in pediatric leukemia patients

et al. 2016

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Background: Chemotherapy for malignant neoplasms sometimes induces unconjugated hyperbilirubinemia, resulting in the early cessation of treatment. We evaluated the role of variations in the bilirubin uridine-5-diphosphate (UDP)-glucuronosyltransferase gene (UGT1A1) in unconjugated hyperbilirubinemia development during chemotherapy in pediatric patients with leukemia. Methods: UGT1A1 allelic variations were evaluated in 25 Japanese pediatric leukemia patients with hyperbilirubinemia (peak serum bilirubin concentration 3.57 ± 1.02 mg/dl) and 25 control patients without hyperbilirubinemia (0.92 ± 0.32 mg/dl) by PCR-direct sequencing. results: In the hyperbilirubinemic group, 22 of 25 patients showed biallelic variations of UGT1A1. Nine (36%) patients were homozygous for UGT1A1*6 and eight (32%) were compound heterozygous for UGT1A1*6 and UGT1A1*28. Three (12%) patients were homozygous for UGT1A1*28. There were no biallelic variations in UGT1A1 in the non-hyperbilirubinemic group. The allelic frequencies of UGT1A1*6 in the hyperbilirubinemic group (0.58) was significantly higher than those of the non-hyperbilirubinemic group (0.1) (χ 2 = 25.7, P < 0.05). conclusion: The high frequency of biallelic variations of UGT1A1 in the hyperbilirubinemic group suggests an association with Gilbert syndrome. Therefore, it is not necessary to cease chemotherapy in patients with these mutations who develop unconjugated hyperbilirubinemia without associated liver dysfunction.

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“…This mutation is predominant in Japanese and does not seem to be linked to the A(TA) 7 TAA polymorphic site. [119][120][121] Polymorphisms of the UGT1A1 Gene as Risk Factors for Drug-Induced Toxicity Patients affected by Gilbert's syndrome display lower glucuronidation rates for a number of therapeutic drugs including acetaminophen, tolbutamide and lorazepam. [20][21][22][34][35][36][37] Since Gilbert's syndrome is associated with the UGT1A1*28 (TA 7 polymorphism), it is more likely that patients with this allele will present an altered drug clearance compared to patients with the wild-type genotype.…”

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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Association of Neonatal Hyperbilirubinemia With Bilirubin UDP-Glucuronosyltransferase Polymorphism

Abstract: The missense mutation causing G71R is the first reported polymorphism for UGT1A1, and the mutation is a risk factor for nonphysiologic neonatal hyperbilirubinemia. The high incidence of hyperbilirubinemia in the Japanese may be attributable to the high frequency of this missense mutation.

Cited by 148 publications

References 15 publications

UGT1A1 gene mutations and neonatal hyperbilirubinemia in Guangxi Heiyi Zhuang and Han populations

UGT1A1 gene mutations and neonatal hyperbilirubinemia in Guangxi Heiyi Zhuang and Han populations

Contribution of UGT1A1 variations to chemotherapy-induced unconjugated hyperbilirubinemia in pediatric leukemia patients

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

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