UGT1A1 gene polymorphisms and jaundice in Indonesian neonates

Main Article Content

Rinawati Rohsiswatmo
Radhian Amandito
http://orcid.org/0000-0002-1211-7973
Andiani Wanda Putri
Nilam Sartika
Amarila Malik

Abstract

Background Uridine diphospho-glucuronocyltransferase 1A1 (UGT1A1) polymorphisms are a risk factor for unconjugated hyperbilirubinemia in neonates. UGT1A1 polymorphisms decrease bilirubin conjugation, thus causing hyperbilirubinemia. A variety of polymorphisms have been reported, with UGT1A1*60 and UGT1A1*6 especially prominent in the Asian population. Hyperbilirubinemia polymorphism studies are lacking in Indonesian populations.


Objective To identify UGT1A1*60 and UGT1A1*6 profiles in Indonesian populations of heterogeneous ethnicity.


Methods We enrolled 42 jaundiced neonates who were born from January to April 2017 and treated in the Neonatal Intensive Care Unit of our national referral center, Cipto Mangunkusumo Hospital, Jakarta, Indonesia. Genetic mutations *60 of exon 1 and *6 of the promoter region were analyzed by polymerase chain reaction – restriction fragment length polymorphism methods, with DraI and AvaII as restriction enzymes, respectively. Clinical data including total serum bilirubin and racial information were obtained by medical records and interviews with parents.


Results There were no homozygous mutations of UGT1A1*6, but 4.8% of subjects were heterozygous. As for UGT1A1*60, 4.8% were heterozygous and 95.2% were homozygous. Racial variations were not observed for UGT1A1*60, while Betawi descendents were found to have many heteroygous forms of UGT1A1*6.


Conclusion Polymorphisms of the UGT1A1 gene were found in Indonesian neonates. Some ethnicities also showed increased tendency towards its incidence, such as the heterozygous form of  UGT1A1*6.

Article Details

How to Cite
1.
Rohsiswatmo R, Amandito R, Putri A, Sartika N, Malik A. UGT1A1 gene polymorphisms and jaundice in Indonesian neonates. PI [Internet]. 20Jun.2019 [cited 19Jul.2019];59(3). Available from: https://paediatricaindonesiana.org/index.php/paediatrica-indonesiana/article/view/2162
Section
Neonatology
Received 2019-03-14
Accepted 2019-06-19
Published 2019-06-20

References

1. Maisels MJ. The clinical approach to the jaundiced newborn. Neonatal jaundice. Amsterdam: Harwood Academic Publishers; 2000.p. 139-68.
2. Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. New Engl J Med. 2001;344:581-90.
3. Le Pichon JB, Riordan SM, Watchko J, Shapiro SM. The neurological sequelae of neonatal hyperbilirubinemia: definitions, diagnosis and treatment of the kernicterus spectrum disorders (KSDs). Curr Pediatr Rev. 2017;13:199-209.
4. Kaplan M, Hammerman C. Understanding severe hyperbilirubinaemia and preventing kernicterus: adjuncts in the interpretation of neonatal serum bilirubin. Clin Chim Acta. 2005;356:9-21.
5. Huang MJ, Kua KE, Teng HC, Tang KS, Weng HW, Huang CS. Risk factors for severe hyperbilirubinemia in neonates. Pediatr Res. 2004;56:682-9.
6. Costa E. Hematologically important mutations: bilirubin UDP-glucuronosyltransferase gene mutations in Gilbert and Crigler-Najjar syndromes. Blood Cells Mol Dis. 2006;36:77-80.
7. Kaniwa N, Kurose K, Jinno H, Tanaka-Kagawa T, Saito Y, Saeki M, et al. Racial variability in haplotype frequencies of UGT1A1 and glucuronidation activity of a novel single nucleotide polymorphism 686C> T (P229L) found in an African-American. Drug Metab Dispos. 2005;33:458-65.
8. 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.
9. Travan L, Lega S, Crovella S, Montico M, Panontin E, Demarini S. Severe neonatal hyperbilirubinemia and UGT1A1 promoter polymorphism. J Pediatr. 2014;165:42-5.
10. Sugatani J, Mizushima K, Osabe M, Yamakawa K, Kakizaki S, Takagi H, et al. Transcriptional regulation of human UGT1A1 gene expression through distal and proximal promoter motifs: implication of defects in the UGT1A1 gene promoter. Naunyn-Schmiedebergs Arch Pharmacol. 2008;377:597-605.
11. Huang YY, Huang MJ, Yang SS, Teng HC, Huang CS. Variations in the UDP-glucuronosyltransferase 1A1 gene for the development of unconjugated hyperbilirubinemia in Taiwanese. Pharmacogenomics. 2008;9:1229-35.
12. 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;67:401-6.
13. Dastgerdy E, Mamori G, Afshari J, Saeedi R, Shahbazi F, Shirazi M. Association of G71R mutation of the UGT1A1 gen with neonatal hyper bilirubinemia in the Iranian population. J Family Reprod Health. 2012;6:35-8.
14. Sutomo R, Talib NA, Yusoff NM, Van Rostenberghe H, Sadewa AH, Sunarti, et al. Screening for G71R mutation of the UGT1A1 gene in the Javanese-Indonesian and Malay-Malaysian populations. Pediatr Int. 2004;46:565-9.
15. Amandito R, Putradista R, Jikesya C, Utaminingsih D, Rusin J, Rohsiswatmo R, et al. UGT1A1 gene and neonatal hyperbilirubinemia: a preliminary study from Bengkulu, Indonesia. BMC Res Notes. 2018;11:172.
16. Yu Z, Zhu K, Wang L, Liu Y, Sun J. Association of neonatal hyperbilirubinemia with UGT1A1 gene polymorphisms: a meta-analysis. Med Sci Monitor. 2015; 21:3104-14.
17. 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.
18. Sato H, Uchida T, Toyota K, Kanno M, Hashimoto T, Watanabe M, 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;58:7-10.
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;47:137-41.
20. Ardan R. The profile of upper integument lip of Baduy and the nearby living Sundanese in South Banten, West Java, Indonesia. Dental J (Majalah Kedokteran Gigi). 2008; 41:118-22.
21. Zhang A, Xing Q, Qin S, Du J, Wang L, Yu L, et al. Intra-ethnic differences in genetic variants of the UGT-glucuronosyltransferase 1A1 gene in Chinese populations. Pharmacogenomics J. 2007;7:333.