Abstract
The uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT1A1) gene encodes the enzyme responsible for bilirubin glucuronidation. To evaluate the contribution of UGT1A1 promoter mutations to neonatal jaundice, we determined the genotypes of c.-3279T>G, c.-3156G>A, and A(TA)7TAA in Malay infants with neonatal jaundice (patients) and in infants without neonatal jaundice (controls). In our population study, only c.-3279T>G was associated with neonatal jaundice. The genotype distributions between both groups were significantly different (p = 0.003): the frequency of homozygosity for c.-3279G was much higher in patients than those in controls. Allele frequency of c.-3279G was significantly higher in patients than those in controls (p = 0.006). We then investigated changes in transcriptional activity because of c.-3279T>G. Luciferase reporter assay in HepG2 cells demonstrated that transcriptional activity of the c.-3279G allele was significantly lower than that of the c.-3279T allele in both the absence and presence of bilirubin. Luciferase reporter assay in COS-7 cells elucidated that c.-3279T>G modified the synergistic effects of the nuclear factors associated with transcriptional machinery. In conclusion, the c.-3279T>G mutation in the UGT1A1 promoter is a genetic risk factor for neonatal jaundice.
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Abbreviations
- AhR:
-
human aryl hydrocarbon receptor
- Arnt:
-
human aryl hydrocarbon receptor nuclear translocator
- CAR:
-
human constitutive androstane receptor
- GS:
-
Gilbert's syndrome
- gtPBREM:
-
Phenobarbital responsive enhancer module in UGT1A1
- RXR:
-
human retinoid X receptor α
- UGT1A1:
-
uridine diphosphoglucuronate-glucuronosyltransferase 1A1
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Acknowledgements
We thank the neonatal ward staffs in the Hospital of University Sains Malaysia, and infants and their parents for their willing participation in our study.
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Supported by grants from the Ministry of Science, Culture, and Sports of Japan (Research Project Number: 15406036) and from the Ministry of Science, Technology and Innovation (MOSTI) eScience Fund of Malaysia (Research Project Number: 06-01-05-SF0166).
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Yusoff, S., Takeuchi, A., Ashi, C. et al. A Polymorphic Mutation, c.-3279T>G, in the UGT1A1 Promoter Is a Risk Factor for Neonatal Jaundice in the Malay Population. Pediatr Res 67, 401–406 (2010). https://doi.org/10.1203/PDR.0b013e3181d22f78
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DOI: https://doi.org/10.1203/PDR.0b013e3181d22f78
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