Neonatal Med.  2024 Feb;31(1):1-8. 10.5385/nm.2024.31.1.1.

Should We Consider UGT1A1 Mutation Analysis in Evaluating the Prolonged Jaundice of Newborn Infants?

• Kim YD

• KMID: 2553143
• DOI: http://doi.org/10.5385/nm.2024.31.1.1

Abstract

Purpose
Uridine diphosphate glucuronosyltransferase 1A isoform 1 (UGT1A1) is a crucial enzyme in bilirubin metabolism. Mutations in this gene cause prolonged unconjugated hyperbilirubinemia in infants. This study aimed to investigate the prevalence of UGT1A1 mutations and their association with prolonged, unexplained, and unconjugated hyperbilirubinemia in infants.
Methods
From July 2019 to March 2023, 74 infants with prolonged jaundice lasting >21 days were enrolled in this study. Diagnostic evaluations, including UGT1A1 mutation analysis, were performed to identify the underlying causes of hyperbilirubinemia. This retrospective review evaluated the incidence and types of mutations in UGT1A1. The clinical and laboratory findings were compared based on the specific mutations detected.
Results
Thirty-three infants agreed to UGT1A1 mutation analysis, and 30 (90.9%) were positive for UGT1A1 mutations. Single-nucleotide variants were detected in 20 (66. %) infants. The remaining 10 (33.3%) infants had multiple variants. No significant demographic differences were observed between the group that underwent UGT1A1 mutation analysis and the group that did not. Among the identified genetic variants, c.211G>A (46.5%) and c.-3275T>G (30.2%) were the two most common variants. The other variants had the following percentages: c.1456T>G, c.-64G>C, and c.1091C>T (4.7% each); and c.-3152G>A, c.189C>T, and c.-41.-40 dup (2.3% each). Among the 20 infants with the c.211G>A variant, eight (40.0%) had a homozygous genotype and 12 (60.0%) had a heterozygous genotype. Infants harboring other variants exhibited heterozygous genotypes. When comparing the group with confirmed UGT1A1 mutations to the group without detected mutations, breastfeeding was the only significant factor (p=0.027). No significant differences were found between the group with singlenucleotide variants and the group with multiple genetic variants or between the homozygous genotype group with c.211G>A and the heterozygous genotype group.
Conclusion
Neonates with prolonged unconjugated hyperbilirubinemia may have a higher chance of UGT1A1 mutation than expected. Analysis of UGT1A1 mutations may be beneficial in infants with prolonged unexplained jaundice.

Keyword

UGT1A1; Mutation; Hyperbilirubinemia; Jaundice; Infant

Figure

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  Figure 1. (A, B) Genotype frequencies and distribution of uridine diphosphate glucuronosyltransferase 1A isoform 1 (UGT1A1) polymorphisms in studied patients.

Reference

1. Logan S, Stanton A. Screening for biliary atresia. Lancet. 1993; 342:256.

2. McKiernan PJ. Neonatal cholestasis. Semin Neonatol. 2002; 7:153–65.

3. Lee WS, Kelly DA. Useful investigation in the assessment of liver disease. In: Kelly DA, editor. Disease of the liver and biliary system in children. 4th ed. Wiley-Blackwell, 2017:35-41.

4. Guillemette C. Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J. 2003; 3:136–58.

5. Mackenzie PI, Owens IS, Burchell B, Bock KW, Bairoch A, Belanger A, et al. The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics. 1997; 7:255–69.

6. Bosma PJ, Chowdhury NR, Goldhoorn BG, Hofker MH, Oude Elferink RP, Jansen PL, et al. Sequence of exons and the flanking regions of human bilirubin-UDP-glucuronosyltransferase gene complex and identification of a genetic mutation in a patient with Crigler-Najjar syndrome, type I. Hepatology. 1992; 15:941–7.

7. Bosma PJ, Seppen J, Goldhoorn B, Bakker C, Oude Elferink RP, Chowdhury JR, et al. Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. J Biol Chem. 1994; 269:17960–4.

8. 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 Engl J Med. 1995; 333:1171–5.

9. Monaghan G, Ryan M, Seddon R, Hume R, Burchell B. Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert’s syndrome. Lancet. 1996; 347:578–81.

10. Monaghan G, McLellan A, McGeehan A, Li Volti S, Mollica F, Salemi I, et al. Gilbert’s syndrome is a contributory factor in prolonged unconjugated hyperbilirubinemia of the newborn. J Pediatr. 1999; 134:441–6.

11. Kaplan M, Hammerman C, Maisels MJ. Bilirubin genetics for the nongeneticist: hereditary defects of neonatal bilirubin conjugation. Pediatrics. 2003; 111(4 Pt 1):886–93.

12. Ritter JK, Yeatman MT, Ferreira P, Owens IS. Identification of a genetic alteration in the code for bilirubin UDP-glucuronosyltransferase in the UGT1 gene complex of a Crigler-Najjar type I patient. J Clin Invest. 1992; 90:150–5.

13. Crigler JF Jr, Najjar VA. Congenital familial nonhemolytic jaundice with kernicterus. Pediatrics. 1952; 10:169–80.

14. Moghrabi N, Clarke DJ, Boxer M, Burchell B. Identification of an A-to-G missense mutation in exon 2 of the UGT1 gene complex that causes Crigler-Najjar syndrome type 2. Genomics. 1993; 18:171–3.

15. Strassburg CP. Pharmacogenetics of Gilbert’s syndrome. Pharmacogenomics. 2008; 9:703–15.

16. Burchell B, Hume R. Molecular genetic basis of Gilbert’s syndrome. J Gastroenterol Hepatol. 1999; 14:960–6.

17. Owens D, Evans J. Population studies on Gilbert’s syndrome. J Med Genet. 1975; 12:152–6.

18. Lampe JW, Bigler J, Horner NK, Potter JD. UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians: relationships to serum bilirubin concentrations. Pharmacogenetics. 1999; 9:341–9.

19. 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; 91:100–1.

20. Liu W, Ramirez J, Gamazon ER, Mirkov S, Chen P, Wu K, et al. Genetic factors affecting gene transcription and catalytic activity of UDP-glucuronosyltransferases in human liver. Hum Mol Genet. 2014; 23:5558–69.

21. Shin HJ, Kim JY, Cheong HS, Na HS, Shin HD, Chung MW. Functional study of haplotypes in UGT1A1 promoter to find a novel genetic variant leading to reduced gene expression. Ther Drug Monit. 2015; 37:369–74.

22. Takeuchi K, Kobayashi Y, Tamaki S, Ishihara T, Maruo Y, Araki J, et al. Genetic polymorphisms of bilirubin uridine diphosphateglucuronosyltransferase gene in Japanese patients with Crigler-Najjar syndrome or Gilbert’s syndrome as well as in healthy Japanese subjects. J Gastroenterol Hepatol. 2004; 19:1023–8.

23. Huang CS, Luo GA, Huang ML, Yu SC, Yang SS. Variations of the bilirubin uridine-diphosphoglucuronosyl transferase 1A1 gene in healthy Taiwanese. Pharmacogenetics. 2000; 10:539–44.

24. Kadakol A, Ghosh SS, Sappal BS, Sharma G, Chowdhury JR, Chowdhury NR. Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype. Hum Mutat. 2000; 16:297–306.

25. Beutler E, Gelbart T, Demina A. Racial variability in the UDPglucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A. 1998; 95:8170–4.

26. Maruo Y, Nishizawa K, Sato H, Doida Y, Shimada M. Association of neonatal hyperbilirubinemia with bilirubin UDP-glucuronosyltransferase polymorphism. Pediatrics. 1999; 103(6 Pt 1):1224–7.

27. Ko JS, Chang JY, Moon JS, Yang HR, Seo JK. Molecular analysis of the UGT1A1 gene in Korean patients with Crigler-Najjar syndrome type II. Pediatr Gastroenterol Hepatol Nutr. 2014; 17:37–40.

28. Lee JM, Han YJ, Kim JS, Kim ER. The relationship between Gly71Arg and TATA box polymorphism of UGT1A1 gene and prolonged hyperbilirubinemia of breast milk feeding infant in Korean. Korean J Pediatr. 2008; 51:150–5.

29. Kang H, Lim JH, Kim JS, Kim ER, Kim SD, Lee HJ, et al. The association of neonatal hyperbilirubinemia with UGT1A1 and CYP1A2 gene polymorphism in Korean neonates. Korean J Pediatr. 2005; 48:380–6.

30. Kim JY, Kim MY, Kim JS, Kim ER, Yoon SH, Lee HJ, et al. 1828G > A polymorphism of the UDP-glucuronosyltransferase gene (UGT1A1) for neonatal hyperbilirubinemia in Koreans. Korean J Pediatr. 2006; 49:34–9.

31. Kim JJ, Oh J, Kim Y, Lee KA. Genetic spectrum of UGT1A1 in Korean patients with unconjugated hyperbilirubinemia. Ann Lab Med. 2020; 40:281–3.

32. Nguyen TT, Zhao W, Yang X, Zhong DN. The relationship between hyperbilirubinemia and the promoter region and first exon of UGT1A1 gene polymorphisms in Vietnamese newborns. Pediatr Res. 2020; 88:940–4.

33. Maruo Y, Nakahara S, Yanagi T, Nomura A, Mimura Y, Matsui K, et al. Genotype of UGT1A1 and phenotype correlation between Crigler-Najjar syndrome type II and Gilbert syndrome. J Gastroenterol Hepatol. 2016; 31:403–8.

34. Wu XJ, Zhong DN, Xie XZ, Ye DZ, Gao ZY. UGT1A1 gene mutations and neonatal hyperbilirubinemia in Guangxi Heiyi Zhuang and Han populations. Pediatr Res. 2015; 78:585–8.

35. Sato H, Adachi Y, Koiwai O. The genetic basis of Gilbert’s syndrome. Lancet. 1996; 347:557–8.

36. Liu JY, Qu K, Sferruzza AD, Bender RA. Distribution of the UGT1A1*28 polymorphism in Caucasian and Asian populations in the US: a genomic analysis of 138 healthy individuals. Anticancer Drugs. 2007; 18:693–6.

37. Preer GL, Philipp BL. Understanding and managing breast milk jaundice. Arch Dis Child Fetal Neonatal Ed. 2011; 96:F461–6.

38. Soldi A, Tonetto P, Varalda A, Bertino E. Neonatal jaundice and human milk. J Matern Fetal Neonatal Med. 2011; 24 Suppl 1:85–7.

39. Maruo Y, Nishizawa K, Sato H, Sawa H, Shimada M. Prolonged unconjugated hyperbilirubinemia associated with breast milk and mutations of the bilirubin uridine diphosphate-glucuronosyltransferase gene. Pediatrics. 2000; 106:E59.

40. Yang Z, Lin F, Xu JX, Yang H, Wu YH, Chen ZK, et al. UGT1A1*6 mutation associated with the occurrence and severity in infants with prolonged jaundice. Front Pediatr. 2022; 10:1080212.

41. Alaee E, Bazrafshan B, Azaminejad AR, Fouladinejad M, Shahbazi M. The association between prolonged jaundice and UGT1A1 gene polymorphism (G71R) in Gilbert’s syndrome. J Clin Diagn Res. 2016; 10:GC05–8.

42. 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. Biochim Biophys Acta. 1998; 1406:267–73.

43. Arias IM, Gartner LM, Cohen M, Ezzer JB, Levi AJ. Chronic nonhemolytic unconjugated hyperbilirubinemia with glucuronyl transferase deficiency: clinical, biochemical, pharmacologic and genetic evidence for heterogeneity. Am J Med. 1969; 47:395–409.

44. Abuduxikuer K, Fang LJ, Li LT, Gong JY, Wang JS. UGT1A1 genotypes and unconjugated hyperbilirubinemia phenotypes in post-neonatal Chinese children: a retrospective analysis and quantitative correlation. Medicine (Baltimore). 2018; 97:e13576.

45. Satrom KM, Gourley GR. Neonatal jaundice and disorders of bilirubin metabolism. In: Suchy FJ, Sokol RJ, Balistreri WF, Bezerra JA, Mack CL, Shneider BL, editors. Liver disease in children. 5th ed. Cambridge University Press, 2021:182-203.

46. Takano M, Sugiyama T. UGT1A1 polymorphisms in cancer: impact on irinotecan treatment. Pharmgenomics Pers Med. 2017; 10:61–8.

47. Iyer L, King CD, Whitington PF, Green MD, Roy SK, Tephly TR, et al. Genetic predisposition to the metabolism of irinotecan (CPT-11): role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest. 1998; 101:847–54.

48. Burchell B, Soars M, Monaghan G, Cassidy A, Smith D, Ethell B. Drug-mediated toxicity caused by genetic deficiency of UDPglucuronosyltransferases. Toxicol Lett. 2000; 112-113:333–40.

49. Lankisch TO, Moebius U, Wehmeier M, Behrens G, Manns MP, Schmidt RE, et al. Gilbert’s disease and atazanavir: from phenotype to UDP-glucuronosyltransferase haplotype. Hepatology. 2006; 44:1324–32.

50. Deterding K, Grungreiff K, Lankisch TO, Potthoff A, Bahr MJ, Manns MP, et al. Gilbert’s syndrome and antiviral therapy of hepatitis C. Ann Hepatol. 2009; 8:246–50.

51. Xu CF, Reck BH, Xue Z, Huang L, Baker KL, Chen M, et al. Pazopanib-induced hyperbilirubinemia is associated with Gilbert’s syndrome UGT1A1 polymorphism. Br J Cancer. 2010; 102:1371–7.

52. Bale G, Avanthi US, Padaki NR, Sharma M, Duvvur NR, Vishnubhotla VR. Incidence and risk of gallstone disease in Gilbert’s syndrome patients in Indian population. J Clin Exp Hepatol. 2018; 8:362–6.

53. Tsezou A, Tzetis M, Giannatou E, Spanos I, Roma E, Fretzayas A, et al. Gilbert syndrome as a predisposing factor for cholelithiasis risk in the Greek adult population. Genet Test Mol Biomarkers. 2009; 13:143–6.