Abstract
Objective:
The objective of our study was to measure the effect of genetic variants of these two enzymes, UGT1A1 and SLCO1B1, in the bilirubin metabolic pathway on the degree of hyperbilirubinemia in a cohort of African-American (AA) infants from our well-baby nursery. In addition, a second objective was to document the types and frequencies of genetic variations of these enzymes in our cohort.
Study Design:
A prospective study of 180 AA infants from the Well Baby Nursery of an inner city community hospital, all of whose mothers were type O pos. Sixty infants were ABO-incompatible direct antiglobulin test (DAT) pos, 60 were ABO-incompatible DAT neg and 60 were type O+. Blood for carboxyhemoglobin (COHb) and variants of the enzymes uridine diphosphoglucuronosyltransferase 1A1 and hepatic solute carrier organic anion transporter 1B1 (SLCO1B1) was drawn at the time of the infants’ initial bilirubin, and the infants’ precise percentile on the Bhutani nomogram was calculated.
Results:
Variants in the two enzymes studied were quite common. In total, 21.1% were positive for a Gilbert phenotype, whereas an additional 42.4% were heterozygous for the *28 or *37 variant of UGT1A1. In total, 67.2% were homozygous for the *60 variant of the phenobarbital responsive enhancer module. In total, 41.1% were homozygous for the *1b variant of SLCO1B1, whereas an additional 12.7% were positive for the *4 variant of this gene. In total, 20.6% of infants had variations in both genes. Using logistic regression when COHbc was assessed with each of the different variants, only COHbc (P<0.0001 to 0.0004) was significantly associated with the level of hyperbilirubinemia as defined by the Bhutani nomogram.
Conclusion:
Although we have found quite a large number of genetic variants of the UGT1A1 and SLCO1B1 genes in the AA population, it does not appear that they have a significant impact on the incidence of hyperbilirubinemia among this group of infants.
Similar content being viewed by others
References
Slusher TM, Zipursky A, Bhutani VK . A global need for affordable neonatal jaundice technologies. Semin Perinatol 2011; 35: 185–191.
Kaplan M, Muraca M, Hammerman C, Rubaltelli FF, Vilei MT, Vreman HJ et al. Imbalance between production and conjugation of bilirubin: a fundamental concept in the mechanism of neonatal jaundice. Pediatrics 2002; 110: e47.
Watchko JF, Lin Z . Genetics of Neonatal Jaundice. In: Stevenson DK, Maisels MJ, Watchko JF (eds). Care of the Jaundiced Neonate. McGraw Hill: New York, NY, USA, 2012, pp 1–27.
American Academy of Pediatrics Subcommittee on hyperbilirubinemia. Management of in the newborn infant 35 or more weeks of gestation. Pediatrics 2004; 114: 297–316.
Bhutani VK, Johnson L, Sivieri EM . Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term infants. Pediatrics 1999; 13: 6–14.
Herschel M, Karrison T, Wen M, Caldarelli L, Baron B . Evaluation of the direct antiglobulin (Coombs) test for identifying newborns at risk for hemolysis as determined by end-tidal carbon monoxide concentration (ETCOc); and comparison of the Coombs test with ETCOc for detecting significant jaundice. J Perinatol 2002; 22: 341–347.
Christensen RD, Nussenzveig RH, Yaish HM, Henery E, Eggert LD, Agarwal AM . Causes of hemolysis in neonates with extreme hyperbilirubinemia. J Perinatol 2014; 34: 616–619.
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: 1146–1152.
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 USA 1998; 95: 8170–8174.
Huang MJ, Kus KE, Teng HC, Tang KS, Weng HW, Huang CS . Risk factors for severe hyperbilirubinemia in neonates. Pediatr Res 2004; 56: 682–689.
Watchko JF, Lin Z, Clark RH, Kelleher AS, Walker W, Spitzer AR . Complex multifactorial nature of significant hyperbilirubinemia in neonates. Pediatrics 2009; 124: e868–e877.
Schutzman DL, Gatien E, Ajayi S, Wong RJ . Carboxyhemoglobin levels as a predictor of risk for significant hyperbilirubinemia in African-American DAT+ infants. J Perinatol 2016; 36: 386–388.
Stevenson DK, Fanaroff AA, Maisels MJ, Young BWY, Wong RJ, Vreman HJ et al. Prediction of hyperbilirubinemia in near-term and term infants. Pediatrics 2001; 108: 31–39.
Tirona RG, Leake BF, Merino G, Kim RB . Polymorphisms in OATP-C: identification of multiple allelic varients associated with altered transport activity among European and African-Americans. J Biol Chem 2001; 276: 35669–35675.
Liu J, Long J, Zhang S, Fang X, Luo Y . The impact of SLCO1B1 genetic polymorphisms on neonatal hyperbilirubinemia: a systematic review with meta-analysis. J Pediatr (Rio J) 2013; 89: 434–443.
Kaniwa N, Kurosi 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; 3: 458–465.
Huang CS, Huang MJ, Lin MS, Teng HC, Tang KS . Genetic factors related to unconjugated hyperbilrubinemia amongst adults. Pharmacogenet Genomics 2005; 15: 43–50.
Kaplan M, Renbaum P, Vreman HJ, Wong RJ, Levy-Lahad E et al. Hammerman C (TA)n UGT 1A1 promoter polymorphism: a crucial factor in the physiology of jaundice in G-6-PD deficient neonates. Pediatr Res 2007; 61: 727–731.
Watchko JF, Lin Z . Exploring the genetic architecture of neonatal hyperbilirubinemia. Semin Fetal Neonatal Med 2010; 15: 169–175.
Wickremasinghe AC, Kuzniewicz MW, Newman TB . Black race is not protective against hazardous bilirubin levels. J Pediatr 2013; 162: 1068–1069.
Johnson L, Bhutani VK, Karp K, Sivieri EM, Shapiro SM . Clinical report from the pilot USA Kernicterus Registry (1992 to 2004). J Perinatol 2009; 29: S25–S45.
Acknowledgements
This study was supported in part by a grant from The Albert Einstein Society of the Einstein Healthcare Network. We would like to acknowledge the help of Solomon Samuel with statistical analyses.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Schutzman, D., Baudhuin, L., Gatien, E. et al. Effect of genetic variants of bilirubin metabolism on the degree of hyperbilirubinemia in African-American newborns. J Perinatol 37, 432–435 (2017). https://doi.org/10.1038/jp.2016.232
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/jp.2016.232
- Springer Nature America, Inc.
This article is cited by
-
Heme oxygenase-1 genetic variants and the conundrum of hyperbilirubinemia in African-American newborns
Journal of Perinatology (2018)