Gilbert’s syndrome: High frequency of the (TA)<sub>7</sub>TAA allele in India and its interaction with a novel CAT insertion in promoter of the gene for bilirubin UDP-glucuronosyltransferase 1 gene

Farheen, Shabana; Sengupta, Sanghamitra; Santra, Amal; Pal, Sujay; Dhali, Gopal Krishna; Chakravorty, Meenakshi; Majumder, Partha P.; Chowdhury, Abhijit

doi:10.3748/wjg.v12.i14.2269

Cited by 54 publications

(37 citation statements)

References 34 publications

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“…This finding is similar to that recently reported in a healthy Singapore adult population [15] . The frequency in our Indians was similar to that previously reported in Indians (40%) [13] and to 35% in Singaporean Indians [15] . This rate was also comparable with that reported in the Dutch and German populations [10,16] .…”

Section: Discussionsupporting

confidence: 78%

UGT1A1 Haplotype Mutation among Asians in Singapore

Zhou

Lee²,

Ng³

et al. 2009

Neonatology

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Background: The uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) enzyme is responsible for conjugation of the bilirubin in the liver as well as for drug metabolism. Some of the polymorphisms have been associated with an increased risk of neonatal hyperbilirubinemia which may explain the increased incidence of jaundice in an Asian population as well as exaggerated irinotecan-induced leukopenia. Objective: The local Asian incidence of hypomorphic haplotypes, defined as gene mutations known to have a reduced function, has not been described. Clinical correlation between the mutations and the need for phototherapy for hyperbilirubinemia was carried out. Methods: A cohort of 241 consecutive term infants delivered in the National University Hospital, Singapore, was recruited with parental consent. Cord blood was collected, and the promoter and coding regions of the UGT1A1 gene were sequenced. Results: Six known haplotypes and 2 novel haplotypes were identified: 1 wild type, 5 with reduced function, while the 2 novel ones were predicted to have decreased function. The frequency of these hypomorphic haplotypes was high. Among the 241 infants screened, 35% had 1 hypomorphic haplotype and 12% had 2 hypomorphic haplotypes. The frequency was also different among ethnic groups, with 48% Chinese, 64% Indian and 31% Malay infants having at least 1 hypomorphic haplotype (χ² test, p < 0.05). There was a trend seen between the number of G71R mutations and the need for phototherapy (χ² test for trend, p < 0.05). Conclusions: The local Asian incidence of hypomorphic haplotypes was high and there was a trend between the number of G71R mutations and the need for phototherapy. The G71R mutation may account for the increased incidence of neonatal jaundice seen in Asian populations.

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Section: Discussionsupporting

confidence: 78%

UGT1A1 Haplotype Mutation among Asians in Singapore

Zhou

Lee²,

Ng³

et al. 2009

Neonatology

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“…Narter et al [1] have not looked into the influence of the TA insertion in the TATA box of the promoter region in the UGT1A1 gene on the development and severity of hyperbilirubinemia, whereas we found that the G71R mutation along with the TA insertion (either in TA6/7 or TA7/7) had a significant effect on unconjugated bilirubin levels and the severity of neonatal hyperbilirubinemia in our patients (data not shown). This finding is in agreement with those reported among the Japanese neonates [4] but discordant with the results on Gilbert's syndrome patients from the eastern part of India [5]. On the other hand, a complete absence of this mutation was observed among the neonates with or without hyperbilirubinemia from north India [6].…”

Section: To the Editorsupporting

confidence: 82%

G71R mutation of the UGT1A1 gene is not associated with neonatal hyperbilirubinemia in India

D’Silva

Colah

Ghosh

et al. 2012

The Journal of Maternal-Fetal & Neonatal Medicine

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“…In the confirmed variants of UGT1A1, the associated phenotypes were CN I, CN II (15), and Gilbert's syndrome (16) which are all closely related to bilirubin levels. To date, 47 mutant UGT1A1 alleles have been identified (Table VI; 17,18,39,[42][43][44][45][46][47][48][49][50][51][53][54][55][56][57][58][59]. Many of these SNPs were predicted to have phenotypical effects by the algorithms and the correct prediction rates were 68% and 81% by SIFT and PolyPhen, respectively.…”

Section: Validation Of the Prediction Resultsmentioning

confidence: 99%

“…The confirmed variants were collected from results derived from site-directed mutagenesis studies of the enzyme using biochemical characterization (18,(39)(40)(41)(42)(43)(44)(45)(46)(47) or clinical data from family-based and association studies (48)(49)(50)(51)(52)(53)(54)(55)(56). The biochemical/ in vitro and in vivo UGT variants and the predictions for their functional impact scores by SIFT and PolyPhen are displayed in Table VI.…”

Section: Validation Of the Prediction Resultsmentioning

confidence: 99%

Prediction of Deleterious Non-synonymous Single-Nucleotide Polymorphisms of Human Uridine Diphosphate Glucuronosyltransferase Genes

Chan

Wei

et al. 2009

AAPS J

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Abstract. UDP glucuronosyltransferases (UGTs) are an important class of Phase II enzymes involved in the metabolism and detoxification of numerous xenobiotics including therapeutic drugs and endogenous compounds (e.g. bilirubin). To date, there are 21 human UGT genes identified, and most of them contain single-nucleotide polymorphisms (SNPs). Non-synonymous SNPs (nsSNPs) of the human UGT genes may cause absent or reduced enzyme activity and polymorphisms of UGT have been found to be closely related to altered drug clearance and/or drug response, hyperbilirubinemia, Gilbert's syndrome, and Crigler-Najjar syndrome. However, it is unlikely to study the functional impact of all identified nsSNPs in humans using laboratory approach due to its giant number. We have investigated the potential for bioinformatics approach for the prediction of phenotype based on known nsSNPs. We have identified a total of 248 nsSNPs from human UGT genes. The two algorithms tools, sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen), were used to predict the impact of these nsSNPs on protein function. SIFT classified 35.5% of the UGT nsSNPs as "deleterious"; while PolyPhen identified 46.0% of the UGT nsSNPs as "potentially damaging" and "damaging". The results from the two algorithms were highly associated. Among 63 functionally characterized nsSNPs in the UGTs, 24 showed altered enzyme expression/activities and 45 were associated with disease susceptibility. SIFT and Polyphen had a correct prediction rate of 57.1% and 66.7%, respectively. These findings demonstrate the potential use of bioinformatics techniques to predict genotype-phenotype relationships which may constitute the basis for future functional studies.

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Gilbert’s syndrome: High frequency of the (TA)₇TAA allele in India and its interaction with a novel CAT insertion in promoter of the gene for bilirubin UDP-glucuronosyltransferase 1 gene

Abstract: The genetic epidemiology of GS is variable across ethnic groups and the epistatic interactions among UGT1A1 promoter variants modulate bilirubin glucuronidation.

Cited by 54 publications

References 34 publications

UGT1A1 Haplotype Mutation among Asians in Singapore

UGT1A1 Haplotype Mutation among Asians in Singapore

G71R mutation of the UGT1A1 gene is not associated with neonatal hyperbilirubinemia in India

Prediction of Deleterious Non-synonymous Single-Nucleotide Polymorphisms of Human Uridine Diphosphate Glucuronosyltransferase Genes

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Gilbert’s syndrome: High frequency of the (TA)7TAA allele in India and its interaction with a novel CAT insertion in promoter of the gene for bilirubin UDP-glucuronosyltransferase 1 gene

Abstract: The genetic epidemiology of GS is variable across ethnic groups and the epistatic interactions among UGT1A1 promoter variants modulate bilirubin glucuronidation.

Cited by 54 publications

References 34 publications

UGT1A1 Haplotype Mutation among Asians in Singapore

UGT1A1 Haplotype Mutation among Asians in Singapore

G71R mutation of the UGT1A1 gene is not associated with neonatal hyperbilirubinemia in India

Prediction of Deleterious Non-synonymous Single-Nucleotide Polymorphisms of Human Uridine Diphosphate Glucuronosyltransferase Genes

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Product

Resources

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Gilbert’s syndrome: High frequency of the (TA)₇TAA allele in India and its interaction with a novel CAT insertion in promoter of the gene for bilirubin UDP-glucuronosyltransferase 1 gene