Am J Perinatol 2020; 37(06): 652-658
DOI: 10.1055/s-0039-1688816
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Study of Gilbert's Syndrome-Associated UGT1A1 Polymorphism in Jaundiced Neonates of ABO Incompatibility Hemolysis Disease

Yingfang Yu
1   Department of Neonatology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
,
Lizhong Du
1   Department of Neonatology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
,
An Chen
1   Department of Neonatology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
,
Lihua Chen
1   Department of Neonatology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
› Author Affiliations
Further Information

Publication History

19 February 2019

27 March 2019

Publication Date:
14 May 2019 (online)

Abstract

Objective This study aimed to assess the probable relationship between icter in neonates with ABO incompatibility hemolysis and UGT1A1 gene polymorphism.

Study Design There were 65 ABO hemolytic disease of the newborn (HDN) neonates of full term in the study group and 82 non-ABO HDN neonates of full term in the compared group. We tested the UGT1A1 gene mutation of neonates of ABO HDN and non-ABO HDN. We compared the incidence of hyperbilirubinemia between neonates with and without UGT1A1 mutations in the ABO HDN and non-ABO HDN, to determine the relationship between icter in neonates with ABO HDN and UGT1A1 gene polymorphism. SPSS 13.0 were used to analyze those two groups' data.

Results There was statistically significant difference of the serum bilirubin level between the Gly71Arg homozygous and no mutation group in the ABO HDN patients (p < 0.05). When hyperbilirubinemia was defined as serum bilirubin concentration >342 μmol/L, the incidence of hyperbilirubinemia between patients of UGT1A1 and non-UGT1A1 mutations in the ABO HDN group was significantly different (p < 0.05). But in the non-ABO HDN group, no significant difference was found.

Conclusion Individuals with Gly71Arg homozygous contributed to their hyperbilirubinemia in ABO HDN patients.

 
  • References

  • 1 el-Beshbishi SN, Shattuck KE, Mohammad AA, Petersen JR. Hyperbilirubinemia and transcutaneous bilirubinometry. Clin Chem 2009; 55 (07) 1280-1287
  • 2 Cabra MA, Whitfield JM. The challenge of preventing neonatal bilirubin encephalopathy: a new nursing protocol in the well newborn nursery. Proc Bayl Univ Med Cent 2005; 18 (03) 217-219
  • 3 Bhutani VK, Gourley GR, Adler S, Kreamer B, Dalin C, Johnson LH. Noninvasive measurement of total serum bilirubin in a multiracial predischarge newborn population to assess the risk of severe hyperbilirubinemia. Pediatrics 2000; 106 (02) E17
  • 4 Ebbesen F, Bjerre JV, Vandborg PK. Relation between serum bilirubin levels ≥450 μmol/L and bilirubin encephalopathy; a Danish population-based study. Acta Paediatr 2012; 101 (04) 384-389
  • 5 Watchko JF, Lin Z. Exploring the genetic architecture of neonatal hyperbilirubinemia. Semin Fetal Neonatal Med 2010; 15 (03) 169-175
  • 6 Kaplan M, Hammerman C, Renbaum P, Klein G, Levy-Lahad E. Gilbert's syndrome and hyperbilirubinaemia in ABO-incompatible neonates. Lancet 2000; 356 (9230): 652-653
  • 7 Ota Y, Maruo Y, Matsui K, Mimura Y, Sato H, Takeuchi Y. Inhibitory effect of 5β-pregnane-3α,20β-diol on transcriptional activity and enzyme activity of human bilirubin UDP-glucuronosyltransferase. Pediatr Res 2011; 70 (05) 453-457
  • 8 Watchko JF, Lin Z, Clark RH, Kelleher AS, Walker MW, Spitzer AR. ; Pediatrix Hyperbilirubinemia Study Group. Complex multifactorial nature of significant hyperbilirubinemia in neonates. Pediatrics 2009; 124 (05) e868-e877
  • 9 Lin Z, Fontaine J, Watchko JF. Coexpression of gene polymorphisms involved in bilirubin production and metabolism. Pediatrics 2008; 122 (01) e156-e162
  • 10 Huang CS, Chang PF, Huang MJ, Chen ES, Hung KL, Tsou KI. Relationship between bilirubin UDP- glucuronosyl 1A1 gene and neonatal hyperbilirubinemia. Pediatr Res 2002; 52 (04) 601-605
  • 11 Odell GB. Neonatal Hyperbilirubinemia. New York: Grune and Stratton; 1980: 39-41
  • 12 Bhutani VK, Johnson LH, Jeffrey Maisels M. , et al. Kernicterus: epidemiological strategies for its prevention through systems-based approaches. J Perinatol 2004; 24 (10) 650-662
  • 13 Borlak J, Thum T, Landt O, Erb K, Hermann R. Molecular diagnosis of a familial nonhemolytic hyperbilirubinemia (Gilbert's syndrome) in healthy subjects. Hepatology 2000; 32 (4 Pt 1): 792-795
  • 14 Mercke Odeberg J, Andrade J, Holmberg K, Hoglund P, Malmqvist U, Odeberg J. UGT1A polymorphisms in a Swedish cohort and a human diversity panel, and the relation to bilirubin plasma levels in males and females. Eur J Clin Pharmacol 2006; 62 (10) 829-837
  • 15 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 Cells Mol Dis 2007; 38 (02) 78-82
  • 16 Peters WH, te Morsche RH, Roelofs HM. Combined polymorphisms in UDP-glucuronosyltransferases 1A1 and 1A6: implications for patients with Gilbert's syndrome. J Hepatol 2003; 38 (01) 3-8
  • 17 Azlin I, Wong FL, Ezham M, Hafiza A, Ainoon O. Prevalence of uridine glucuronosyl transferase 1A1 (UGT1A1) mutations in Malay neonates with severe jaundice. Malays J Pathol 2011; 33 (02) 95-100
  • 18 Tiwari PK, Bhutada A, Agarwal R, Basu S, Raman R, Kumar A. UGT1A1 gene variants and clinical risk factors modulate hyperbilirubinemia risk in newborns. J Perinatol 2014; 34 (02) 120-124
  • 19 Liu J, Long J, Zhang S, Fang X, Luo Y. Polymorphic variants of SLCO1B1 in neonatal hyperbilirubinemia in China. Ital J Pediatr 2013; 39: 49-53
  • 20 Maki K, Aikawa S, Hayasaka K. Neonatal hyperbilirubinemia and a common mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese. J Hum Genet 1999; 44 (01) 22-25
  • 21 Bucher KA, Patterson Jr AM, Elston RC, Jones CA, Kirkman Jr HN. Racial difference in incidence of ABO hemolytic disease. Am J Public Health 1976; 66 (09) 854-858
  • 22 Halis H, Ergin H, Köseler A, Atalay EÖ. The role of UGT1A1 promoter polymorphism and exon-1 mutations in neonatal jaundice. J Matern Fetal Neonatal Med 2017; 30 (22) 2658-2664
  • 23 Huang MJ, Kua KE, Teng HC, Tang KS, Weng HW, Huang CS. Risk factors for severe hyperbilirubinemia in neonates. Pediatr Res 2004; 56 (05) 682-689
  • 24 Zhou Y, Wang SN, Li H. , et al. Association of UGT1A1 variants and hyperbilirubinemia in breast-fed full-term Chinese infants. PLoS One 2014; 9 (08) e104251
  • 25 Sato H, Uchida T, Toyota K. , et al. Association of breast-fed neonatal hyperbilirubinemia with UGT1A1 polymorphisms: 211G>A (G71R) mutation becomes a risk factor under inadequate feeding. J Hum Genet 2013; 58 (01) 7-10
  • 26 Long J, Zhang S, Fang X, Luo Y, Liu J. Association of neonatal hyperbilirubinemia with uridine diphosphate-glucuronosyltransferase 1A1 gene polymorphisms: meta-analysis. Pediatr Int 2011; 53 (04) 530-540
  • 27 Yang H, Wang Q, Zheng L. , et al. Clinical significance of UGT1A1 genetic analysis in Chinese neonates with severe hyperbilirubinemia. Pediatr Neonatol 2016; 57 (04) 310-317
  • 28 Guo XH, Sun YF, Cui M, Wang JB, Han SZ, Miao J. Analysis of uridine diphosphate glucuronosyl transferase 1A1 gene mutations in neonates with unconjugated hyperbilirubinemia. Genet Mol Res 2016 15. (02):. Doi: 10.4238/gmr.15028373
  • 29 Sappal BS, Ghosh SS, Shneider B, Kadakol A, Chowdhury JR, Chowdhury NR. A novel intronic mutation results in the use of a cryptic splice acceptor site within the coding region of UGT1A1, causing Crigler-Najjar syndrome type 1. Mol Genet Metab 2002; 75 (02) 134-142
  • 30 Narter F, Can G, Ergen A, Isbir T, Ince Z, Çoban A. Neonatal hyperbilirubinemia and G71R mutation of the UGT1A1 gene in Turkish patients. J Matern Fetal Neonatal Med 2011; 24 (02) 313-316
  • 31 Wanlapakorn N, Nilyanimit P, Vorawandthanachai T, Deesudjit T, Dumrongpisutikul N, Poovorawan Y. A novel stop codon mutation in exon 1 (558C>A) of the UGT1A1 gene in a Thai neonate with Crigler-Najjar syndrome type I. Genet Mol Res 2015; 14 (01) 419-425
  • 32 Ferraris A, D'Amato G, Nobili V, Torres B, Marcellini M, Dallapiccola B. Combined test for UGT1A1 -3279T-->G and A(TA)nTAA polymorphisms best predicts Gilbert's syndrome in Italian pediatric patients. Genet Test 2006; 10 (02) 121-125
  • 33 Sun G, Wu M, Cao J, Du L. Cord blood bilirubin level in relation to bilirubin UDP-glucuronosyltransferase gene missense allele in Chinese neonates. Acta Paediatr 2007; 96 (11) 1622-1625
  • 34 Moyer AM, Skierka JM, Kotzer KE, Kluge ML, Black JL, Baudhuin LM. Clinical UGT1A1 genetic analysis in pediatric patients: experience of a reference laboratory. Mol Diagn Ther 2017; 21 (03) 327-335
  • 35 Ki CS, Lee KA, Lee SY. , et al. Haplotype structure of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene and its relationship to serum total bilirubin concentration in a male Korean population. Clin Chem 2003; 49 (12) 2078-2081
  • 36 Clarke DJ, Moghrabi N, Monaghan G. , et al. Genetic defects of the UDP-glucuronosyltransferase-1 (UGT1) gene that cause familial non-haemolytic unconjugated hyperbilirubinaemias. Clin Chim Acta 1997; 266 (01) 63-74
  • 37 Monaghan G, Monaghan G, Ryan M, Seddon R, Hume R, Burchell B. Genetic variation in bilirubin UDP-glucuronosyltransferase gene promoter and Gilbert's syndrome. Lancet 1996; 347 (9001): 578-581
  • 38 Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism?. Proc Natl Acad Sci U S A 1998; 95 (14) 8170-8174
  • 39 Skierka JM, Kotzer KE, Lagerstedt SA, O'Kane DJ, Baudhuin LM. UGT1A1 genetic analysis as a diagnostic aid for individuals with unconjugated hyperbilirubinemia. J Pediatr 2013; 162 (06) 1146-1152
  • 40 Mazur-Kominek K, Romanowski T, Bielawski K. , et al. Association between uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphism and neonatal hyperbilirubinemia. Acta Biochim Pol 2017; 64 (02) 351-356