Skip to main content
Download PDF

UGT1A1 mutation association with increased bilirubin levels and severity of unconjugated hyperbilirubinemia in ABO incompatible newborns of China

BMC Pediatrics volume 21, Article number: 259 (2021) Cite this article

Abstract

Background

Neonatal hyperbilirubinemia causing jaundice is common in East Asian population. Uridine diphosphate glucuronosyltransferase isoenzyme (UGT1A1) glucuronidates bilirubin and converts the toxic form of bilirubin to its nontoxic form.

Method

A retrospective study was conducted to review clinical information of ABO hemolysis neonates (ABO HDN) admitted to the Department of Neonatology, referred for neonatal hyperbilirubinemia, in a large general hospital of southern China from 2011 to 2017. Variation status of UGT1A1 was determined by direct sequencing or genotype assays.

Result

Sixty-nine ABO HDNs were included into the final analysis. UGT1A1 c.211 G > A mutation (UGT1A1*6, p.Arg71Gly, rs4148323) was significantly associated with the increased bilirubin level in ABO HDNs, after adjusted by age, sex and feeding method (P = 0.019 for TBIL, P = 0.02 for IBIL). Moreover, heterozygous and/or homozygous UGT1A1 mutations in the coding sequence region were significantly associated with the increased risk of developing hazardous hyperbilirubinemia (as defined by TSB > 427 umol/L) as compared those with a normal UGT1A1 genotype (ORadj = 9.16, 95%CI 1.99–42.08, P = 0.002) in the study cohort.

Conclusion

UGT1A1 variant in coding region is actively involved in the pathogenesis of ABO hemolysis related neonatal hyperbilirubinemia. Genetic assessment of UGT1A1 may be useful for clinical diagnosis of neonatal unconjugated hyperbilirubinemia.

Peer Review reports

Background

Neonatal hyperbilirubinemia causing jaundice is a complex pediatric disorder affecting up to 80% of newborns worldwide [1, 2]. Although it is benign in the vast majority of infants, total serum bilirubin (TSB) may accumulate and reach very high levels in some cases. Once it reaches the hazardous threshold levels, certain brain regions can be irreversibly damaged [3,4,5].

In 2004, the American Academy of Pediatrics (AAP) guidelines listed the East Asia, including mainland China as a major risk factor for severe hyperbilirubinemia [6]. The incidence and severity of neonatal hyperbilirubinemia in Asians and American Indians are much higher, as compared to those in Caucasian and black populations. It has been suggested that the high incidence rate of hemolytic anemia, caused by ABO alloimmunization or glucose-6-phosphate dehydrogenase (G6PD) deficiency, may predispose these populations to neonatal hyperbilirubinemia. The overall risk dramatically increased for a TSB level of 20 mg/dL (342 mmol/L) [7].

Congenital variation of the bilirubin clearance rate in the liver is also the biological basis of neonatal hyperbilirubinemia risk in Asia. The key bilirubin metabolism gene, namely, the hepatic bilirubin conjugating isoenzyme UDP glucuronosyltransferase family 1 member A1 (UGT1A1) was classically described for Crigler-Najjar type I and II syndrome as well as Gilbert syndrome [8,9,10]. More and more evidence has shown that the genetic variation of UGT1A1 is also closely related to the incidence rate and severity of neonatal hyperbilirubinemia [10,11,12,13,14]. However, the innate variants of the UGT1A1 gene are under-diagnosed in neonates and under-recognized as a cause of severe hyperbilirubinemia clinically.

In our previous studies [14, 15], we have demonstrated the role of UGT1A1 in non-hemolytic unconjugated hyperbilirubinemia in Chinese newborns. Here, we aim to further explore the role of UGT1A1 variants in ABO hemolytic disease of newborns (ABO HDNs). We suspected that ABO HDNs that carried the gene variant for Gilbert’s syndrome may have a higher risk of developing severe hyperbilirubinemia. This study may enhance our understanding of the genetic basis of neonatal hyperbilirubinemia in Asia.

Methods

Participants and sample collection

This retrospective study was conducted in the pediatric center of Chaozhou Central Hospital affiliated to Southern Medical University, Chaozhou, China. All neonates enrolled in this study were admitted to the study center from 2011 to 2017. Demographic and clinical records and laboratory results were reviewed and collected by the ordering physicians from electronic medical records.

Information recorded included date of birth, gender, weight at birth, mode of delivery, gestational age, feeding mode, Apar score symptoms, signs, laboratory findings, medical records and underlying comorbidities. Laboratory tests including the TSB level, G6PD enzyme assay, and three serological tests for neonate hemolytic disease were specially recorded. Neonates without complete medical information were excluded from final analyzed.

The study group comprised infants of blood group A or B with a blood-group-O mother (ABO incompatible) suffering from neonatal hemolytic disease confirmed by seroimmunity antibody tests. Newborns with birth weight less than 2500 g and gestational age less than 37 weeks were excluded. In addition, the infants who had other risk factors for jaundice were also excluded: maternal diabetes, infection, Rh incompatibility-caused hemolytic disease, asphyxia, G6PD deficiency, hypothermia, drug treatment, cerebral hematoma, dehydration, metabolic diseases, hypothyroidism, liver disease, and major organ abnormalities. These conditions were determined by past and family history, as well as clinical and laboratory tests. The information was reviewed and retrieved from the electronic medical records.

All the laboratory tests were conducted by our clinical laboratory staff according to National Clinical Laboratory Procedures. The serum bilirubin level was measured using a commercial TBIL/IBIL assay kit (KEFANG biotech, China, Co, Ltd) by automatic biochemical analytic method. Three serological antibody tests were done using commercial three-cell panel (LIBO biotechology, China, Co, Ltd) by gel technique. Three tests including red blood cells direct antiglobulin test (direct Coombs test), free antibody test (free) and antibody release test were performed according to the manufacturer’s protocol.

Hyperbilirubinemia was diagnosed according to the updated clinical guidelines of the Chinese Medical Association for neonates [16]. Serological diagnostic criteria for ABO hemolysis were as follows: 1) confirmed cases were neonates with two positive results of the three tests or the result of antibody elution test proved to be positive; 2) suspected cases were neonates only positive for either direct Coombs test or serum free antibody test. Antibody elution test was the final confirmed diagnosis for neonatal hemolysis disease.

After clinical diagnosis, the EDTA anticoagulant whole blood samples were collected prospectively and stored at − 20 °C prior to UGT1A1 genotyping.

This study was initially approved by the Ethics Committee of Chaozhou Central Hospital in 2011 (No. 2011021), and then the second ethical approval was obtained in 2015 (No.2015001). As the patients data were analyzed anonymously, and the blood samples in this study were used after the clinical diagnosis (blood routine examination), a waiver of written consent was approved by the Ethics Committee of Chaozhou Central Hospital. Our group had the administrative permissions to access the data according to associated regulation by national health commission of P.R.China. Specially, clinical data were collected by pediatrician, laboratory data was reviewed by the clinical laboratory staff.

DNA extraction and UGT1A1 genotyping

Genomic DNA from peripheral blood specimens was extracted with FlexiGene DNA Kit (Qiagen Inc., Valencia, California). The DNA sequences of promoter, exons, and exon-intron boundaries of UGT1A1 were determined by polymerase chain reaction (PCR) and DNA sequencing as previously described [14]. The repetitive polymorphism of (TA)n in the promoter region was further confirmed by capillary electrophoresis, described in detail in our previous studies [14, 15].

Data analysis

Hardy-Weinberg equilibrium (HWE) was used to test the two common variants of UGT1A1 locus. Linkage disequilibrium (LD) analysis for the polymorphisms within UGT1A1 was performed, and the haplotypes were inferred using the web tool SNPStats (http://bioinfo.iconcologia.net/SNPStats), [17] as described in our previous studies [14, 15].

The differences of categorical variables between the two groups were compared by chi-square test or Fisher exact test. According to the UGT1A1 genotype, all infants were divided into two (wild type and mutant) or three groups (wild type, heterozygous mutant, and homozygous mutant). Independent group t-test was used to analyze the difference of continuous variables if the dataset was normally distributed; otherwise, the Mann-Whitney test was used.

After adjusting for known clinical risk factors for neonatal hyperbilirubinemia (including gender, breastfeeding, and age), a linear regression model was used to assess the association between specific polymorphisms or haplotypes of UGT1A1 and the TSB peak values prior to phototherapy. According to the AAP guidelines, all the infants were divided into the hazardous group (TSB ≥ 427 μmol/L), the severe group (TSB ≥ 342 μmol/L), and the non-severe group (TSB < 342 μmol/L). Then logistic regression was used to evaluate the association of the UGT1A1 gene variations with the severity of hyperbilirubinemia.

All statistical analyses were performed using the two-sided test by SPSS (version 16) and SNPstat, and P < 0.05 was considered as statistically significant.

Results

Clinical analysis

After excluding neonates with the conditions described above, a total of 69 full-term ABO HDNs infants were admitted to the hospital on the 3rd day (median) after birth (range, 1–10 days). They are all Han ethnicity from southern China. All the studied neonates presented with skin jaundice and higher TcB level. The average peak serum total serum bilirubin level (TBIL) was 335 μmol/L (123–652 μmol/L). Among 69 ABO HDNs, 31 cases had peak TSB ≥ 342 μmol/L, in which 15 neonates had TSB ≥ 427 μmol/L. All the neonates received phototherapy. Most of the neonates were discharged without complication, except for two infants with bilirubin encephalopathy symptoms, showing high-pitched cry, lethargy, and poor sucking, and loss of upward gaze. The MRI showed high T2 signal in the globus pallidus.

There were significant differences in the bilirubin levels, but no differences in average gestational age, birth weight, gender and feeding pattern between the two groups of neonates divided according to the c.211 genotypes of UGT1A1-- the most common UGT1A1 variant in Asian population (Table 1).

Table 1 Demographic and clinical features among the neonates with ABO hemolytic disease (ABO HDN) in UGT1A1 c. 211 G > A mutation group VS c.211 normal group (N = 69)
Full size table

UGT1A1 variant results

In addition to the two common variants of UGT1A1 gene, TA7 polymorphism (UGT1A1*28, rs8175347) in the promoter and c.211 G > A mutation (UGT1A1*6, p.Arg71Gly, rs4148323) in exon 1, another coding variant c.1091C > T (UGT1A1*73, p.Pro364Leu, rs34946978) was observed in the neonates. Specifically, heterozygote of TA7 promoter polymorphism (TA6/TA7) was detected in 9 neonates, with no homozygote for TA7 polymorphism (TA7/TA7) observed. The frequency of heterozygous (G/A) and homozygous (A/A) genotypes of c.211 G > A mutation were 0.275 (19/69) and 0.014 (1/69), respectively. Three cases were observed with heterozygous c.1091C > T mutation (Table 2).

Table 2 Minor allelic, genotypic, and haplotype distributions of UGT1A1 polymorphism in studied patients (N = 69)
Full size table

There was a strong pairwise LD between the UGT1A1 promoter polymorphism and exon mutation (|D|’ > 0.8), but none of the polymorphisms in our study had a statistically significant deviation in the HWE test. Haplotype analysis showed that the TA6GC (rs8175347-rs4148323-rs34946978) was the predominant haplotype among the study subjects (75.9%), (Table 2).

Co-inherited UGT1A1 variant on bilirubin levels in ABO HDNs

When analyzing the peak bilirubin levels according to UGT1A1 genotypes, the average peak bilirubin levels (TBIL and indirect serum bilirubin level (IBIL)) of ABO (+) neonates with both heterozygous and homozygous c.211 G > A coding mutation were higher as compared to those with normal UGT1A1 genotype (P = 0.03 for TBIL, P = 0.04 for IBIL), whereas direct serum bilirubin level (DBIL) showed no statistical difference among the three genotypes (Table 1, Fig. 1). No significant difference in bilirubin levels was observed in the presence of either heterozygous of TA7 promoter polymorphism or heterozygous of c.1091C > T mutation in the neonates.

Fig. 1
figure 1

Distribution of serum bilirubin levels among the subgroup of the ABO hemolytic disease neonates according to UGT1A1 c.211 genotypes

Full size image

After adjusting the potential covariance (age, gender, and feeding method), c.211 G > A mutation was still associated with the increased bilirubin levels (ORadj = 78.2, 95%CI 14.7–141.8, P = 0.019 for TBIL, ORadj = 73.3, 95%CI 12.8–133.7, P = 0.021 for IBIL) (Table 3). Moreover, haplotype association analysis showed that the TA6AC (rs887829-rs4148323- rs34946978) was significantly associated with increased bilirubin levels (ORadj = 84.0, 95%CI 23.2–144.8, P = 0.009 for TBIL, ORadj = 79.0, 95%CI 21.4–136.6, P = 0.009 for IBIL). Haplotype TA6GT also showed significant association with increased bilirubin levels (ORadj = 107.9, 95%CI 93.7–122.1, P < 0.001 for TBIL, ORadj = 107.0, 95%CI 93.6–120.4, P < 0.001 for IBIL) (Table 3).

Table 3 The associations between serum bilirubin level and different types of UGT1A1 mutation and genotypes adjusted by age, gender, and feeding practice: Linear regression analysis (N = 59a)
Full size table

Co-inherited UGT1A1 variant on severe hyperbilirubinemia risk in ABO HDNs

The incidence rates of hazardous and severe hyperbilirubinemia in the ABO HDNs were compared in different types of UGT1A1 genotype. Promoter polymorphism and exon mutations were analyzed, separately. Compound heterozygous mutations in the coding sequence were regarded as homozygous mutations. No statistical difference of severe hyperbilirubinemia incidence was found between ABO HDNs with and without the UGT1A1 mutation (P > 0.05). On the contrary, after adjusted by age, gender, and feeding method, ABO HDNs with heterozygous and/or homozygous mutations in the UGT1A1 coding sequence region had a relatively higher risk of developing hazardous hyperbilirubinemia than those with a normal UGT1A1 genotype (ORadj = 9.16, 95%CI 1.99–42.08, P = 0.002). Moreover, haplotype association analysis showed that TA6AC was significantly associated with a higher incidence of hazardous hyperbilirubinemia in ABO HDNs (ORadj = 9.41, 95%CI 1.80–49.26, P = 0.011) (Table 4).

Table 4 The associations between risk of severe neonatal hyperbilirubinemia and UGT1A1 coding sequence variants and different type of UGT1A1 haplotype in neonates with ABO hemolysis disease: multivariate logistic regression analysis (N = 59a)
Full size table

Discussion

Hyperbilirubinemia is a common disorder among infants. Infants in Asia, including China where hazardous hyperbilirubinemia is not rare [1, 18], are at a greater risk of developing hyperbilirubinemia. ABO incompatibility, one of the main causes of hemolytic disease in newborns [19], has been well documented to be associated with the incidence and severity of neonatal hyperbilirubinemia [7, 20]. It is estimated that 27% of newborns have ABO incompatibility in China, while only 15% worldwide [21]. Indeed, ABO hemolytic disease is regarded as an important factor in neonatal hyperbilirubinemia in East Asia [7].

The serum bilirubin level is a consequence of many factors, which may change the production and excretion of bilirubin. Currently, more and more attention has been paid to the contribution of genetic polymorphisms of the bilirubin clearance genes in the pathogenesis of hyperbilirubinemia. In this study, we demonstrated that UGT1A1 mutation and polymorphism play an active role in the pathogenesis of ABO hemolysis-related neonatal hyperbilirubinemia.

The UGT1A1 coding sequence variant c.211 G > A (UGT1A1*6, G71R), the main cause of Gilbert syndrome in East Asia, was also the predominant association factor with high TSB levels and neonatal hyperbilirubinemia risk in the Asian population without any additional icterogenic factors [14, 15, 22,23,24,25]. In this study, we further confirmed that both the occurrence rate and bilirubin levels of hyperbilirubinemia in the ABO HDNs were significantly higher in the presence of homozygous or heterozygous c.211 mutation. One recent study in Chinese neonates also reported the contribution of c.211 mutation to neonatal hyperbilirubinemia risk in ABO HDN patients [26]. However, a similar study in Turkish neonates failed to discern the association of c.211 variant with the increased hyperbilirubinemia risk in ABO HDNs [27]. The discrepancy may be due to the fact that the research subjects are from different races and different regions. Large-scale studies across different ethnic groups and regions are necessary to draw further conclusions.

The polymorphism of (TA)n repeat in the UGT1A1 promoter region has also been widely studied. TA7 is common in European and African populations, and it was proposed to be the genetic basis for Gilbert syndrome of Caucasians [28]. However, increasing studies in China and other countries reported that TA7 promoter polymorphism was not directly related to neonatal hyperbilirubinemia in most Asian regions [22]. More interestingly, several recent studies in Asian populations, including our previous studies, have shown that heterozygous of TA7 promoter may not cause neonatal hyperbilirubinemia, and may even have a protective effect [14, 15, 29,30,31]. In this study, we also observed that co-expression of TA6 allele, but not TA7, with the exon mutation (rs8175347-rs4148323-rs34946978: TA6AC/TA6GT) in UGT1A1 gene was associated with increased bilirubin levels and neonatal hyperbilirubinemia risk. This finding is contrary to previous studies in Caucasian populations and also inconsistent with the findings in Turkish neonates [27]. The reason for this contradictory effect of the UGT1A1promoter polymorphism in serum bilirubin level and neonatal hyperbilirubinemia risk is yet unknown.

Another coding sequence variants, UGT1A1*73(c.1091C > T, p.Pro364Leu, rs34946978), has also been reported to be linked to a significant decrease in UGT1A1 enzyme activity and the severity of Gilbert’s syndrome in both Caucasian and Asia populations [32, 33]. Although only the heterozygous c.1091C > T variant was identified in the present study, it has shown to increase bilirubin levels and hyperbilirubinemia risk in ABO HDNs in combination with other variant alleles of UGT1A1 genes (Table 3, Table 4).

There were several limitations in this study. Firstly, the size of the cohort was small, which may be the reason that some analyses could not reach statistical significance. Secondly, the newborns were all from one hospital in China. A larger multi-center study is necessary for future studies. Thirdly, it may not be comprehensive to analyze UGT1A1 alone. Evaluation of additional genes may also help to assess the genetic causes of unconjugated hyperbilirubinemia in newborns.

Conclusion

Our study demonstrated that UGT1A1 variants contributed to the increased bilirubin level and risk of developing hazardous neonatal hyperbilirubinemia in ABO HDNs. It is actively involved in the pathogenesis of ABO hemolysis-related unconjugated hyperbilirubinemia. This association may caution clinicians to assess UGT1A1 variations for neonates with ABO hemolysis, and may aid in the identification of high-risk population, which is important for management and intervention of hazardous hyperbilirubinemia.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ABO HDNs:

ABO hemolytic disease of newborns

UGT1A1:

Uridine diphosphoglucuronosyl transferase 1A1

TSB:

Total serum bilirubin level

TBIL:

Total serum bilirubin level

DBIL:

Direct serum bilirubin level

IBIL:

Indirect serum bilirubin level

References

  1. Kaplan M, Bromiker R, Hammerman C. Severe neonatal hyperbilirubinemia and kernicterus: are these still problems in the third millennium? Neonatology. 2011;100(4):354–62. https://doi.org/10.1159/000330055.

    Article  PubMed  Google Scholar 

  2. Keren R, Tremont K, Luan X, Cnaan A. Visual assessment of jaundice in term and late preterm infants. Arch Dis Child Fetal Neonatal Ed. 2009;94(5):F317–22. https://doi.org/10.1136/adc.2008.150714.

    Article  CAS  PubMed  Google Scholar 

  3. Newman TB, Escobar GJ, Gonzales VM, Armstrong MA, Gardner MN, Folck BF. Frequency of neonatal bilirubin testing and hyperbilirubinemia in a large health maintenance organization. Pediatrics. 1999;104(5 Pt 2):1198–203.

    CAS  PubMed  Google Scholar 

  4. Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. N Engl J Med. 2001;344(8):581–90. https://doi.org/10.1056/NEJM200102223440807.

    Article  CAS  PubMed  Google Scholar 

  5. Maisels MJ. Risk assessment and follow-up are the keys to preventing severe hyperbilirubinemia. J Pediatr. 2011;39:275–6.

    Google Scholar 

  6. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114(1):297–316. https://doi.org/10.1542/peds.114.1.297.

    Article  Google Scholar 

  7. Ho NK. Neonatal jaundice in Asia. Baillieres Clin Hematol. 1992;5(1):131–42. https://doi.org/10.1016/S0950-3536(11)80038-7.

    Article  CAS  Google Scholar 

  8. Watchko JF, Daood MJ, Biniwale M. Understanding neonatal hyperbilirubinaemia in the era of genomics. Semin Neonatol. 2002;7(2):143–52. https://doi.org/10.1053/siny.2002.0102.

    Article  PubMed  Google Scholar 

  9. 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(4):297–306. https://doi.org/10.1002/1098-1004(200010)16:4<297::AID-HUMU2>3.0.CO;2-Z.

    Article  CAS  PubMed  Google Scholar 

  10. Canu G, Minucci A, Zuppi C, Capoluongo E. Gilbert and Crigler Najjar syndromes: an update of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene mutation database. Blood Cells Mol Dis. 2013;50(4):273–80. https://doi.org/10.1016/j.bcmd.2013.01.003.

    Article  CAS  PubMed  Google Scholar 

  11. Huang MJ, Kua KE, Teng HC, Tang KS, Weng HW, Huang CS. Risk factors for severe hyperbilirubinemia in neonates. Pediatr Res. 2004;56(5):682–9. https://doi.org/10.1203/01.PDR.0000141846.37253.AF.

    Article  CAS  PubMed  Google Scholar 

  12. Christensen RD, Lambert DK, Henry E, Eggert LD, Yaish HM, Reading NS, et al. Unexplained extreme hyperbilirubinemia among neonates in a multihospital healthcare system. Blood Cells Mol Dis. 2013;50(2):105–9. https://doi.org/10.1016/j.bcmd.2012.10.004.

    Article  CAS  PubMed  Google Scholar 

  13. 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;162:1146–52, 1152.e1–2.

  14. Yang H, Wang Q, Zheng L, Zheng XB, Lin M, Zhan XF, et al. Clinical significance of UGT1A1 genetic analysis in Chinese neonates with severe hyperbilirubinemia. Pediatr Neonatol. 2016;57(4):310–7. https://doi.org/10.1016/j.pedneo.2015.08.008.

    Article  PubMed  Google Scholar 

  15. Yang H, Wang Q, Zheng L, Lin M, Zheng XB, Lin F, et al. Multiple genetic modifiers of bilirubin metabolism involvement in significant neonatal hyperbilirubinemia in patients of Chinese descent. PLoS One. 2015;10(7):e0132034. https://doi.org/10.1371/journal.pone.0132034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Editorial Board of Chinese Journal of Pediatrics; Subspecialty Group of Neonatology, The Society of Pediatrics, Chinese Medical Association. Experts consensus on principles for diagnosis and treatment of neonatal jaundice. Zhonghua Er Ke Za Zhi 2010; 48:685–686. [Article in Chinese].

  17. Solé X, Guinó E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 2006;22(15):1928–9. https://doi.org/10.1093/bioinformatics/btl268.

    Article  CAS  PubMed  Google Scholar 

  18. Subspecialty Group of Neonatology, Society of Pediatrics, Chinese Medical Association & Chinese Multicenter Study Coordination Group for Neonatal Bilirubin Encephalopathy. Clinical characteristics of bilirubin encephalopathy in Chinese newborn infants-a national multicenter survey. Zhonghua Er Ke Za Zhi 2012;50:331–5. [Article in Chinese].

  19. Chen Y, Wang HR, Zhou M, Li J. Correlation between serum IgG antibody titer of pregnant women with O blood type and hemolytic disease of newborn detected by micro-column gel agglutination assay: a meta-analysis. Maternal Child Health Care China. 2019;34:2646–8 [Article in Chinese].

    Google Scholar 

  20. Akanmu AS, Oyedeji OA, Adeyemo TA, Ogbenna AA. Estimating the risk of ABO hemolytic disease of the newborn in Lagos. J Blood Transfusion. 2015;2015:1–5. https://doi.org/10.1155/2015/560738.

    Article  Google Scholar 

  21. Cao H, Wu R, Han M, Caldwell PHY, Liu JP. Oral administration of Chinese herbal medicine during gestation period for preventing hemolytic disease of the newborn due to ABO incompatibility: a systematic review of randomized controlled trials. PLoS One. 2017;12(7):e0180746. https://doi.org/10.1371/journal.pone.0180746.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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(4):530–40. https://doi.org/10.1111/j.1442-200X.2011.03337.x.

    Article  CAS  PubMed  Google Scholar 

  23. Huang CS, Chang PF, Huang MJ, Chen ES, Hung KL, Tsou KI. Relationship between bilirubin UDPglucuronosyl transferase 1A1 gene and neonatal hyperbilirubinemia. Pediatr Res. 2002;52(4):601–5. https://doi.org/10.1203/00006450-200210000-00022.

    Article  CAS  PubMed  Google Scholar 

  24. Zhou YY, Lee LY, Ng SY, Hia CP, Low KT, Chong YS, et al. UGT1A1 haplotype mutation among Asians in Singapore. Neonatology. 2009;96(3):150–5. https://doi.org/10.1159/000209851.

    Article  CAS  PubMed  Google Scholar 

  25. Zhou Y, Wang SN, Li H, Zha W, Peng Q, Li S, et al. Quantitative trait analysis of polymorphisms in two bilirubin metabolism enzymes to physiologic bilirubin levels in Chinese newborns. J Pediatr. 2014;165(6):1154–60. https://doi.org/10.1016/j.jpeds.2014.08.041.

    Article  CAS  PubMed  Google Scholar 

  26. Yu Y, Du L, Chen A, Chen L. Study of Gilbert's syndrome-associated UGT1A1 polymorphism in jaundiced neonates of ABO incompatibility hemolysis disease. Am J Perinatol. 2019;37(06):652–8. https://doi.org/10.1055/s-0039-1688816.

    Article  PubMed  Google Scholar 

  27. 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):2658–64. https://doi.org/10.1080/14767058.2016.1261105.

    Article  CAS  PubMed  Google Scholar 

  28. Watchko JF, Lin Z. Exploring the genetic architecture of neonatal hyperbilirubinemia. Semin Fetal Neonatal Med. 2010;15(3):169–75. https://doi.org/10.1016/j.siny.2009.11.003.

    Article  PubMed  Google Scholar 

  29. Lin YJ, Tsao PN. 211 G to a variation of UGT1A1 and severe neonatal hyperbilirubinemia. Pediatr Neonatol. 2018;59(1):106–7. https://doi.org/10.1016/j.pedneo.2017.01.008.

    Article  PubMed  Google Scholar 

  30. Zhou Y, Wang SN, Li H, Zha W, Wang X, Liu Y, et al. Association of UGT1A1 variants and hyperbilirubinemia in breast-fed full-term Chinese infants. PLoS One. 2014;9(8):e104251. https://doi.org/10.1371/journal.pone.0104251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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(1):7–10. https://doi.org/10.1038/jhg.2012.116.

    Article  CAS  PubMed  Google Scholar 

  32. 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 for bilirubin UDP-glucuronosyltransferase 1 gene. World J Gastroenterol. 2006;12(14):2269–75. https://doi.org/10.3748/wjg.v12.i14.2269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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(6):539–44. https://doi.org/10.1097/00008571-200008000-00007.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not Applicable.

Funding

This study is funded by the Natural Science Foundation of Guangdong Province (2016A030307035) and Natural Science Foundation of China (81801509). The funder had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Author information

Author notes

  1. Hui Yang and Fen Lin contributed equally to this work.

Authors and Affiliations

  1. Department of Laboratory Medicine, School of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, People’s Republic of China

    Hui Yang

  2. Central Laboratory, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, Guangdong Province, People’s Republic of China

    Fen Lin, Lin Zhang, Jia-Xin Xu, Yong-Hao Wu & Jing-Ying Gu

  3. School of Food Engineering and Biotechnology, Hanshan Normal University, Chaozhou, Guangdong Province, People’s Republic of China

    Zi-kai Chen

  4. Department of Pediatrics, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, Guangdong Province, People’s Republic of China

    Yu-Bin Ma & Jian-Dong Li

  5. Lab for Respiratory Disease, People’s Hospital of Yangjiang, No. 42 Dongshan Road, Yangjiang, 529500, Guangdong Province, People’s Republic of China

    Li-Ye Yang

Authors
  1. Hui Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fen Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zi-kai Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jia-Xin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yong-Hao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jing-Ying Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yu-Bin Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jian-Dong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Li-Ye Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LYY conceptualized and designed the study, coordinated and supervised data collection, and reviewed and revised the manuscript. HY analyzed the data, drafted the initial manuscript, and revised the manuscript. FL collected the data, did the molecular analysis, and carried out the initial analyses. ZKC revised and polished the manuscript. LZ, JXX, YHW, JYG, YBM and JDL participated in the sample and data collection and performed the molecular analysis. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Li-Ye Yang.

Ethics declarations

Ethics approval and consent to participate

This study was initially approved by the Ethics Committee of Chaozhou Central Hospital in 2011 (No. 2011021), and then the second ethical approval was obtained in 2015 (No.2015001). As the patients data were analyzed anonymously, and the blood samples in this study were used after the clinical diagnosis (blood routine examination), and no extra cost was imposed on our participants. A waiver of written consent was approved by the Ethics Committee of Chaozhou Central Hospital. Our group had the administrative permissions to access the data according to associated regulation by national health commission of P.R.China. Specially, clinical data were collected by pediatrician, laboratory data was reviewed by the clinical laboratory staff.

Consent for publication

Not Applicable.

Competing interests

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, H., Lin, F., Chen, Zk. et al. UGT1A1 mutation association with increased bilirubin levels and severity of unconjugated hyperbilirubinemia in ABO incompatible newborns of China. BMC Pediatr 21, 259 (2021). https://doi.org/10.1186/s12887-021-02726-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12887-021-02726-9

BMC Pediatrics

ISSN: 1471-2431

Contact us