Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

UGT1A1 gene variants and clinical risk factors modulate hyperbilirubinemia risk in newborns

Journal of Perinatology volume 34, pages 120–124 (2014)Cite this article

Subjects

Abstract

Objective:

To study the contribution of UGT1A1 gene variants and clinical risk factors in modulating hyperbilirubinemia risk in newborns.

Study design:

Seven UGT1A1 gene variants and clinical risk factors were studied in 113 hyperbilirubinemia cases and 218 control newborns. Hyperbilirubinemia was defined as the total serum bilirubin levels >95th percentile of the American Academy of Pediatrics nomogram. The study population included term (37 to 41 weeks) newborns below 2 weeks of age.

Result:

UGT1A1 gene variants, namely, c.211G>A, g.−3279T>G, TATA box polymorphism and CAT insertion were identified as independent molecular risk factors for neonatal hyperbilirubinemia, whereas c.686C>A, c.1091C>T and c.1456T>G were not detected in study cohort. Among clinical risk factors, excessive weight loss, sepsis and ABO incompatibility emerged as independent risk factors. Co-expression of UGT1A1 variants and clinical risk factors further accentuated the risk of neonatal hyperbilirubinemia.

Conclusion:

Multiple risk factors, whether genetic or clinical, are instrumental in modulating hyperbilirubinemia risk in newborns. Disordered bilirubin conjugation through interactions of UG1TA1 gene variants contributes to the clinical phenotype of neonatal hyperbilirubinemia.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Bhutani VK, Johnson L, Sivieri EM . Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbiliru- binemia in healthy term and near-term newborns. Pediatrics 1999; 103: 6–14.

    Article  CAS  Google Scholar 

  2. Kaplan M, Muraca M, Hammerman C, Rubaltelli FF, Vilei MT, Vreman HJ et al. Imbalance between production and conjugation of bilirubin: a fundamental concept in the mechanism of neonatal jaundice. Pediatrics 2002; 110: e47.

    Article  Google Scholar 

  3. Huang MJ, Kua KE, Teng HC, Tang KS, Weng HW, Huang CS . Risk factors for severe hyperbilirubinemia in neonates. Pediatr Res 2004; 56: 682–689.

    Article  CAS  Google Scholar 

  4. Watchko JF, Lin Z, Clark RH, Kelleher AS, Walker MW, Spitzer AR . Complex multifactorial nature of significant hyperbilirubinemia in neonates. Pediatrics 2009; 124: e868–e877.

    Article  Google Scholar 

  5. Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Eng J Med 1995; 333: 1171–1175.

    Article  CAS  Google Scholar 

  6. Beutler E, Gelbart T, Demina A . Racial variability in the UDP-glucuronosyl-transferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci USA 1998; 95: 8170–8174.

    Article  CAS  Google Scholar 

  7. Yamamoto K, Sato H, Fujiyama Y, Doida Y, Bamba T . Contribution of two missense mutations (G71R and Y486D) of the bilirubin UDP glycosyltransferase (UGT1A1) gene to phenotypes of Gilbert’s syndrome and Crigler–Najjar syndrome type II. Biochem Biophys Acta 1998; 1406: 267–273.

    CAS  PubMed  Google Scholar 

  8. Sugatani J, Yamakawa K, Yoshinari K, Machida T, Takagi H, Mori M et al. Identification of a defect in the UGT1A1 gene promoter and its association with hyperbilirubinemia. Biochem Biophys Res Commun 2002; 292: 492–497.

    Article  CAS  Google Scholar 

  9. Long J, Zhang S, Fang X, Luo Y, Liu J . Neonatal hyperbilirubinemia and Gly71Arg mutation of UGT1A1 gene: a Chinese case-control study followed by systematic review of existing evidence. Acta Paediatr 2011; 100: 966–971.

    Article  CAS  Google Scholar 

  10. Agrawal SK, Kumar P, Rathi R, Sharma N, Das R, Prasad R et al. UGT1A1 gene polymorphisms in North Indian neonates presenting with unconjugated hyperbilirubinemia. Pediatr Res 2009; 65: 675–680.

    Article  CAS  Google Scholar 

  11. Akaba K, Kimura T, Sasaki A, Tanabe S, Wakabayashi T, Hiroi M et al. Neonatal hyperbilirubinemia and mutation of the bilirubin uridine diphosphateglucuronosyltransferase gene: a common missense mutation among Japanese, Koreans and Chinese. Biochem Mol Biol Int 1998; 46: 21–26.

    CAS  PubMed  Google Scholar 

  12. American Academy of Pediatrics, Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004; 114: 297–316.

    Article  Google Scholar 

  13. Miller SA, Dykes DD, Polesky HF . A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 215.

    Google Scholar 

  14. Ostanek B, Furlan D, Mavec T, Lukac-Bajalo J . UGT1A1 (TA)n promoter polymorphism: a new case of a (TA)8 allele in Caucasians. Blood Cell Mol Dis 2007; 38: 78–82.

    Article  CAS  Google Scholar 

  15. Huang YY, Huang MJ, Yang SS, Chen H, Huang CS . Variation in the UDP-glucuronosyltransferase 1A1 gene for the development of unconjugated hyperbilirubinemia in Taiwanese. Pharmacogenomics 2008; 9: 1229–1235.

    Article  CAS  Google Scholar 

  16. Koiwai O, Nishizawa M, Hasada K, Aono S, Adachi Y, Mamiya N et al. Gilbert’s syndrome is caused by a heterozygous missense mutation in the gene for bilirubin UDPglucuronosyltransferase. Hum Mol Genet 1995; 4: 1183–1186.

    Article  CAS  Google Scholar 

  17. Farheen S, Sengupta S, Santra A, Pal S, Dhali GK, Chakravorty M et al. Gilbert’s syndrome: high frequency of the (TA)7 TAA allele in India and its interaction with a novel CAT insertion in promoter of the gene from bilirubin UDP-glucuronosyltransferase 1 gene. World J Gastroenterol 2006; 12: 2269–2275.

    Article  CAS  Google Scholar 

  18. Yusoff S, Takeuchi A, Ashi C, Tsukada M, Ma'amor NH, Zilfalil BA 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 2010; 67: 401–406.

    Article  CAS  Google Scholar 

  19. Kanai M, Kijima K, Shirahata E, Sasaki A, Akaba K, Umetsu K et al. Neonatal hyperbilirubinemia and the bilirubin uridine diphosphate-glucuronosyltransferase gene: the common-3263T>G mutation of phenobarbital response enhancer module is not associated with the neonatal hyperbilirubinemia in Japanese. Pediatr Int 2005; 47: 137–141.

    Article  CAS  Google Scholar 

  20. Ergin H, Bican M, Atalay OE . A causal relationship between UDP-glucuronosyltransferase 1A1 promoter polymorphism and idiopathic hyperbilirubinemia in Turkish newborns. Turk J Pediatr 2010; 52: 28–34.

    PubMed  Google Scholar 

  21. Bancroft JD, Kreamer B, Gourley GR. . Gilbert syndrome accelerates development of neonatal jaundice. J Pediatr 1998; 132: 656–660.

    Article  CAS  Google Scholar 

  22. Roy-Chowdhury N, Deocharan B, Bejjanki HR, Roy-Chowdhury J, Koliopoulos C, Petmezaki S et al. Presence of the genetic marker for Gilbert syndrome is associated with increased level and duration of neonatal jaundice. Acta Paediatr 2002; 91: 100–102.

    Article  CAS  Google Scholar 

  23. Balram C, Sabapathy K, Fei G, Khoo KS, Lee E . Genetic polymorphisms of UDP-glucuronosyltransferase in Asians: UGT1A1*28 is a common allele in Indians. Pharmacogenetics 2002; 12: 81–83.

    Article  CAS  Google Scholar 

  24. Premawardhena A, Fisher CA, Liu YT, Verma IC, de Silva S, Arambepola M et al. The global distribution of length polymorphisms of the promoters of the glucuronosyltransferase 1 gene (UGT1A1): Hematologic and evolutionary implications. Blood Cells Mol Dis 2003; 31: 98–101.

    Article  CAS  Google Scholar 

  25. Gourley GR . Breast-feeding, neonatal jaundice and kernicterus. Semin Neonatol 2002; 7: 135–141.

    Article  Google Scholar 

  26. Whitmer DI, Gollan JL . Mechanisms and significance of fasting and dietary hyperbilirubinemia. Semin Liver Dis 1983; 3: 42–51.

    Article  CAS  Google Scholar 

  27. Kotal P, Vitek L, Fevery J . Fasting-related hyperbilirubinemia in rats: the effect of decreased intestinal motility. Gastroenterol 1996; 111: 217–223.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

AK thanks the Department of Biotechnology, Government of India, New Delhi, for funding this study and PKT thanks the Council of Scientific and Industrial Research (CSIR), New Delhi, for Junior and Senior Research Fellowship.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

    P K Tiwari, A Bhutada, R Agarwal, S Basu & A Kumar

  2. Department of Zoology, Cytogenetics Laboratory, Faculty of Science, Banaras Hindu University, Varanasi, India

    R Raman

Authors
  1. P K Tiwari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Bhutada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Agarwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Basu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R Raman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Kumar.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tiwari, P., Bhutada, A., Agarwal, R. et al. UGT1A1 gene variants and clinical risk factors modulate hyperbilirubinemia risk in newborns. J Perinatol 34, 120–124 (2014). https://doi.org/10.1038/jp.2013.140

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jp.2013.140

Keywords

This article is cited by

Search

Advanced search

Quick links