Research advances in neonatal hyperbilirubinemia and gene polymorphisms
HE Cui-Hong, QU Yi
Department of Pediatrics, West China Second University Hospital/Key Laboratory of Birth Defects and Related Diseases of Women and Children(Sichuan University), Ministry of Education, Chengdu 610041, China
Abstract：Hyperbilirubinemia is a prevalent disease in neonates and is also a main reason for hospitalization within the first week after birth, and this disease is mainly caused by the imbalance between production and elimination of bilirubin. Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), organic anion transporter polypeptide 2 (OATP2), heme oxygenase 1 (HO-1), and biliverdin reductase A (BLVRA) play crucial roles in the metabolism of bilirubin. More and more studies have revealed the association between the variation of the encoding genes for these enzymes and hyperbilirubinemia. This article reviews the research advances in the association between the gene polymorphisms of bilirubin metabolic enzymes and hyperbilirubinemia.
Kaplan M, Muraca M, Hammerman C, et al. Imbalance between production and conjugation of bilirubin:a fundamental concept in the mechanism of neonatal jaundice[J]. Pediatrics, 2002, 110(4):e47.
[2]
Mitra S, Rennie J. Neonatal jaundice:aetiology, diagnosis and treatment[J]. Br J Hosp Med (Lond), 2017, 78(12):699-704.
[3]
Lee SJ, Jee YH, Jung KJ, et al. Bilirubin and stroke risk using a Mendelian randomization design[J]. Stroke, 2017, 48(5):1154-1160.
[4]
Dani C, Poggi C, Pratesi S. Bilirubin and oxidative stress in term and preterm infants[J]. Free Radic Res, 2019, 53(1):2-7.
[5]
Jangi S, Otterbein L, Robson S. The molecular basis for the immunomodulatory activities of unconjugated bilirubin[J]. Int J Biochem Cell Biol, 2013, 45(12):2843-2851.
[6]
McGillivray A, Evans N. Severe neonatal jaundice:is it a rare event in Australia?[J]. J Paediatr Child Health, 2012, 48(9):801-807.
[7]
Olusanya B O, Kaplan M, Hansen T W R. Neonatal hyperbilirubinaemia:a global perspective[J]. Lancet Child Adolesc Health, 2018, 2(8):610-620.
[8]
Wu XJ, Zhong DN, Xie XZZ, et al. UGT1A1 gene mutations and neonatal hyperbilirubinemia in Guangxi Heiyi Zhuang and Han populations[J]. Pediatr Res, 2015, 78(5):585-588.
[9]
Yang H, Wang Q, Zheng L, et al. Multiple genetic modifiers of bilirubin metabolism involvement in significant neonatal hyperbilirubinemia in patients of Chinese descent[J]. PLoS One, 2015, 10(7):e0132034.
[10]
Guo XH, Sun YF, Cui M, et al. Analysis of uridine diphosphate glucuronosyl transferase 1A1 gene mutations in neonates with unconjugated hyperbilirubinemia[J]. Genet Mol Res, 2016, 15(2):gmr8373.
[11]
Liu W, Chang LW, Xie M, et al. Correlation between UGT1A1 polymorphism and neonatal hyperbilirubinemia of neonates in Wuhan[J]. J Huazhong Univ Sci Technolog Med Sci, 2017, 37(5):740-743.
[12]
Zhou Y, Wang SN, Li H, et al. Association of UGT1A1 variants and hyperbilirubinemia in breast-fed full-term Chinese infants[J]. PLoS One, 2014, 9(8):e104251.
[13]
Jiang M, Luo J, Yang C, et al. Gene mutation in neonatal jaundice-mutations in UGT1A1 and OATP2 genes[J]. Indian J Pediatr, 2016, 83(7):723-725.
[14]
Zhou J, Yang C, Zhu W, et al. Identification of genetic risk factors for neonatal hyperbilirubinemia in Fujian province, Southeastern China:a case-control study[J]. Biomed Res Int, 2018, 2018:7803175.
[15]
Yanagi T, Nakahara S, Maruo Y. Bilirubin uridine diphosphateglucuronosyltransferase polymorphism as a risk factor for prolonged hyperbilirubinemia in Japanese preterm infants[J]. J Pediatr, 2017, 190:159-162.
[16]
Halis H, Ergin H, Köseler A, et al. The role of UGT1A1 promoter polymorphism and exon-1 mutations in neonatal jaundice[J]. J Matern Fetal Neonatal Med, 2017, 30(22):2658-2664.
[17]
Mohammed AE, Behiry EG, El-Sadek AE, et al. Case-controlled study on indirect hyperbilirubinemia in exclusively breast fed neonates and mutations of the bilirubin uridine diphosphateglucuronyl transferase gene 1A1[J]. Ann Med Surg (Lond), 2016, 13:6-12.
[18]
Amandito R, Putradista R, Jikesya C, et al. UGT1A1 gene and neonatal hyperbilirubinemia:a preliminary study from Bengkulu, Indonesia[J]. BMC Res Notes, 2018, 11(1):172.
[19]
Wisnumurti DA, Sribudiani Y, Porsch RM, et al. UGT1A1 genetic variations and a haplotype associated with neonatal hyperbilirubinemia in Indonesian population[J]. Biomed Res Int, 2018, 2018:9425843.
[20]
Yu Z, Zhu K, Wang L, et al. Association of neonatal hyperbilirubinemia with UGT1A1 gene polymorphisms:a metaanalysis[J]. Med Sci Monit, 2015, 21:3104-3114.
[21]
Mehrad-Majd H, Haerian MS, Akhtari J, et al. Effects of Gly71Arg mutation in UGT1A1 gene on neonatal hyperbilirubinemia:a systematic review and meta-analysis[J]. J Matern Fetal Neonatal Med, 2019, 32(10):1575-1585.
[22]
Maruo Y, Morioka Y, Fujito H, et al. Bilirubin uridine diphosphate-glucuronosyltransferase variation is a genetic basis of breast milk jaundice[J]. J Pediatr, 2014, 165(1):36-41.
[23]
Sato H, Uchida T, Toyota K, et al. Association of neonatal hyperbilirubinemia in breast-fed infants with UGT1A1 or SLCOs polymorphisms[J]. J Hum Genet, 2015, 60(1):35-40.
[24]
Radoi VE, Ursu RI, Poenaru E, et al. Frequency of the UGT1A1*28 polymorphism in a Romanian cohort of Gilbert syndrome individuals[J]. J Gastrointestin Liver Dis, 2017, 26(1):25-28.
[25]
Mazur-Kominek K, Romanowski T, Bielawski K, et al. Association between uridin diphosphate glucuronosyltransferase 1 A 1(UGT1A1) gene polymorphism and neonatal hyperbilirubinemia[J]. Acta Biochim Pol, 2017, 64(2):351-356.
[26]
Yang H, Wang Q, Zheng L, et al. Clinical significance of UGT1A1 genetic analysis in Chinese neonates with severe hyperbilirubinemia[J]. Pediatr Neonatol, 2016, 57(4):310-317.
[27]
Travan L, Lega S, Crovella S, et al. Severe neonatal hyperbilirubinemia and UGT1A1 promoter polymorphism[J]. J Pediatr, 2014, 165(1):42-45.
[28]
Li H, Zhang P. UGT1A1*28 gene polymorphism was not associated with the risk of neonatal hyperbilirubinemia:a metaanalysis[J]. J Matern Fetal Neonatal Med, 2019:1-8.
[29]
Beutler E, Gelbart T, Demina A. Racial variability in the UDPglucuronosyltransferase 1(UGT1A1) promoter:a balanced polymorphism for regulation of bilirubin metabolism?[J]. Proc Natl Acad Sci U S A, 1998, 95(14):8170-8174.
[30]
Li Y, Buckley D, Wang S, et al. Genetic polymorphisms in the TATA box and upstream phenobarbital-responsive enhancer module of the UGT1A1 promoter have combined effects on UDP-glucuronosyltransferase 1A1 transcription mediated by constitutive androstane receptor, pregnane X receptor, or glucocorticoid receptor in human liver[J]. Drug Metab Dispos, 2009, 37(9):1978-1986.
[31]
D'Silva S, Colah RB, Ghosh K, et al. Combined effects of the UGT1A1 and OATP2 gene polymorphisms as major risk factor for unconjugated hyperbilirubinemia in Indian neonates[J]. Gene, 2014, 547(1):18-22.
[32]
Tomerak RH, Helal NF, Shaker OG, et al. Association between the specific UGT1A1 promoter sequence variant (c-3279T>G) and unconjugated neonatal hyperbilirubinemia[J]. J Trop Pediatr, 2016, 62(6):457-463.
[33]
Zubaida B, Cheema HA, Hashmi MA, et al. Spectrum of UGT1A1 variants in Pakistani children affected with inherited unconjugated hyperbilirubinemias[J]. Clin Biochem, 2019, 69:30-35.
[34]
Liu J, Long J, Zhang S, et al. The impact of SLCO1B1 genetic polymorphisms on neonatal hyperbilirubinemia:a systematic review with meta-analysis[J]. J Pediatr (Rio J), 2013, 89(5):434-443.
[35]
Li Y, Wu T, Chen L, et al. Associations between G6PD, OATP1B1 and BLVRA variants and susceptibility to neonatal hyperbilirubinaemia in a Chinese Han population[J]. J Paediatr Child Health, 2019, 55(9):1077-1083.
[36]
Schutzman DL, Baudhuin LM, Gatien E, et al. Effect of genetic variants of bilirubin metabolism on the degree of hyperbilirubinemia in African-American newborns[J]. J Perinatol, 2017, 37(4):432-435.
[37]
Amandito R, Rohsiswatmo R, Halim M, et al. SLCO1B1 c. 388 A> G variant incidence and the severity of hyperbilirubinemia in Indonesian neonates[J]. BMC Pediatr, 2019, 19(1):212.
[38]
Weng YH, Chiu YW, Cheng SW, et al. Risk assessment of gene variants for neonatal hyperbilirubinemia in Taiwan[J]. BMC Pediatr, 2016, 16(1):144.
[39]
Exner M, Minar E, Wagner O, et al. The role of heme oxygenase-1 promoter polymorphisms in human disease[J]. Free Radic Biol Med, 2004, 37(8):1097-1104.
[40]
Yamada N, Yamaya M, Okinaga S, et al. Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema[J]. Am J Hum Genet, 2000, 66(1):187-195.
[41]
Katayama Y, Yokota T, Zhao H, et al. Association of HMOX1 gene promoter polymorphisms with hyperbilirubinemia in the early neonatal period[J]. Pediatr Int, 2015, 57(4):645-649.
[42]
Zhou JF, Luo JY, Zhu WB, et al. Association between genetic polymorphism of heme oxygenase-1 promoter and neonatal hyperbilirubinemia:a meta-analysis[J]. J Matern Fetal Neonatal Med, 2019, 30:1-12.
[43]
Kaplan M, Renbaum P, Hammerman C, et al. Heme oxygenase-1 promoter polymorphisms and neonatal jaundice[J]. Neonatology, 2014, 106(4):323-329.
