Neonatal Hyperbilirubinemia and Organic Anion Transporting Polypeptide-2 Gene Mutations

ABSTRACT

The aim of this study was to investigate the genotypic distribution of organic anion transporting polypeptide 2 (OATP-2) gene mutations and the relationship with hyperbilirubinemia of unknown etiology. Polymerase chain reaction, restriction fragment length polymorphism, and agarose gel electrophoresis techniques were used for detection of OATP-2 gene mutations in 155 newborn infants: 37 with unexplained hyperbilirubinemia, 65 with explained hyperbilirubinemia, and 53 without hyperbilirubinemia. In the OATP-2 gene, we identified A→G transitions at nucleotide positions 388 and 411 and observed six polymorphic forms. The 388/411–411 mutation was the most common form (43%) in subjects with hyperbilirubinemia of unknown etiology. Male sex [odds ratio (OR): 3.08] and two polymorphic forms of the OATP-2 gene [the 388/411–411 A→G mutation (OR: 3.6) and the 388–411 mutation (OR: 2.4)] increased the risk of neonatal hyperbilirubinemia. In male infants with the 388 A→G mutation of the OATP-2 gene, the levels of unconjugated bilirubin in plasma were significantly increased compared with those observed in females. The polymorphic forms of 388 nucleotide of the OATP-2 gene were identified as risk factors for hyperbilirubinemia of unknown etiology.

KEYWORDS

Newborn - organic anion transporting polypeptide 2 gene - polymorphism - nonphysiological hyperbilirubinemia

REFERENCES

• 1 Blackmon L R, Fanaroff A A, Raju T NK. National Institute of Child Health and Human Development . Research on prevention of bilirubin-induced brain injury and kernicterus: National Institute of Child Health and Human Development conference executive summary. 2003.  Pediatrics. 2004;  114 229-233
• 2 Sarıcı S U, Serdar M A, Korkmaz A et al.. Incidence, course, and prediction of hyperbilirubinemia in near-term and term newborns.  Pediatrics. 2004;  113 775-780
• 3 Watchko J F, Daood M J, Biniwale M. Understanding neonatal hyperbilirubinaemia in the era of genomics.  Semin Neonatol. 2002;  7 143-152
• 4 Watchko J F, Lin Z, Clark R H, Kelleher A S, Walker M V, Spitzer A R. Complex multifactorial nature of significant hyperbilirubinemia in neonates. Pediatric Hyperbilirubinemia Study Group. Pediatrics 2009; 124 e 868–877. Available at: http://pediatrics.aappublications.org/cgi/content/full/124/5/e868 (accessed January 20, 2010)
• 5 Ritter J K, Crawford J M, Owens I S. Cloning of two human liver bilirubin UDP-glucuronosyltransferase cDNAs with expression in COS-1 cells.  J Biol Chem. 1991;  266 1043-1047
• 6 Bosma P J, Chowdhury J R, Huang T J et al.. Mechanisms of inherited deficiencies of multiple UDP-glucuronosyltransferase isoforms in two patients with Crigler-Najjar syndrome, type I.  FASEB J. 1992;  6 2859-2863
• 7 Bosma P J, Chowdhury J R, Bakker C et al.. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome.  N Engl J Med. 1995;  333 1171-1175
• 8 Agrawal S K, Kumar P, Rathi R et al.. UGT1A1 gene polymorphisms in North Indian neonates presenting with unconjugated hyperbilirubinemia.  Pediatr Res. 2009;  65 675-680
• 9 Huang M J, Kua K E, Teng H C, Tang K S, Weng H W, Huang C S. Risk factors for severe hyperbilirubinemia in neonates.  Pediatr Res. 2004;  56 682-689
• 10 Prachukthum S, Nunnarumit P, Pienvichit P et al.. Genetic polymorphisms in Thai neonates with hyperbilirubinemia.  Acta Paediatr. 2009;  98 1106-1110
• 11 Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics.  Br J Pharmacol. 2009;  158 693-705
• 12 Cui Y, König J, Leier I, Buchholz U, Keppler D. Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6.  J Biol Chem. 2001;  276 9626-9630
• 13 Niemi M. Role of OATP transporters in the disposition of drugs.  Pharmacogenomics. 2007;  8 787-802
• 14 Kılıc I, Cakaloz I, Atalay E. Frequency of UDP-glucuronosyltransferase 1 (UGT1A1) gene promoter polymorphisms in neonates with prolonged and pathological jaundice in the Denizli region of Turkey.  Int J Clin Pharmacol Ther. 2007;  45 475-476
• 15 Ulgenalp A, Duman N, Schaefer F V et al.. Analyses of polymorphism for UGT1*1 exon 1 promoter in neonates with pathologic and prolonged jaundice.  Biol Neonate. 2003;  83 258-262
• 16 Muslu N, Turhan A B, Eskandari G et al.. The frequency of UDP-glucuronosyltransferase 1A1 promoter region (TA)7 polymorphism in newborns and it's relation with jaundice.  J Trop Pediatr. 2007;  53 64-68
• 17 American Academy of Pediatrics Subcommittee on Hyperbilirubinemia . Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation.  Pediatrics. 2004;  114 297-316
• 18 Sambrook J, Russell D W. Molecular Cloning: A Laboratory Manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 2001
• 19 Ip S, Chung M, Kulig J American Academy of Pediatrics Subcommittee on Hyperbilirubinemia et al. An evidence-based review of important issues concerning neonatal hyperbilirubinemia.  Pediatrics. 2004;  114 e130-e153
• 20 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 Available at: http://pediatrics.aappublications.org/cgi/content/full/106/5/e59 (accessed December 20, 2010)
• 21 Atay E, Bozaykut A, Ipek I O. Glucose-6-phosphate dehydrogenase deficiency in neonatal indirect hyperbilirubinemia.  J Trop Pediatr. 2006;  52 56-58
• 22 Kocabay K, Yılmaz S, İlhan N et al.. The investigation of glucose-6-phosphate dehydrogenase deficiency in newborn hyperbilirubinemia with unknown etiology.  Turk J Med Res. 1995;  13 194-198
• 23 Keskin N, Ozdes I, Keskin A, Acikbas I, Bagci H. Incidence and molecular analysis of glucose-6-phosphate dehydrogenase deficiency in the province of Denizli, Turkey.  Med Sci Monit. 2002;  8 CR453-CR456
• 24 Luzzatto L, Poggi V. G6PD deficiency. In: Orkin S, Nathan D G, Ginsburg D, Look A T, Fisher D E, Lux S E, eds. Nathan and Oski's Hematology of Infancy and Childhood. Philadelphia: Saunders Elsevier; 2007: 883-907
• 25 Huang C S, Chang P F, Huang M J, Chen E S, Chen W C. Glucose-6-phosphate dehydrogenase deficiency, the UDP-glucuronosyl transferase 1A1 gene, and neonatal hyperbilirubinemia.  Gastroenterology. 2002;  123 127-133
• 26 Kadakol A, Ghosh S S, Sappal B S, Sharma G, Chowdhury J R, Chowdhury N R. Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype.  Hum Mutat. 2000;  16 297-306
• 27 Kaplan M, Hammerman C, Maisels M J. Bilirubin genetics for the nongeneticist: hereditary defects of neonatal bilirubin conjugation.  Pediatrics. 2003;  111 (4 Pt 1) 886-893
• 28 Monaghan G, Ryan M, Seddon R, Hume R, Burchell B. Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome.  Lancet. 1996;  347 578-581
• 29 Ergin H, Bican M, Atalay O E. A causal relationship between UDP-glucuronosyltransferase 1A1 promoter polymorphism and idiopathic hyperbilirubinemia in Turkish newborns.  Turk J Pediatr. 2010;  52 28-34
• 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;  24 313-316
• 31 Tirona R G, Leake B F, Merino G, Kim R B. Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans.  J Biol Chem. 2001;  276 35669-35675
• 32 Tamai I, Nezu J, Uchino H et al.. Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family.  Biochem Biophys Res Commun. 2000;  273 251-260
• 33 Nozawa T, Nakajima M, Tamai I et al.. Genetic polymorphisms of human organic anion transporters OATP-C (SLC21A6) and OATP-B (SLC21A9): allele frequencies in the Japanese population and functional analysis.  J Pharmacol Exp Ther. 2002;  302 804-813
• 34 Nishizato Y, Ieiri I, Suzuki H et al.. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics.  Clin Pharmacol Ther. 2003;  73 554-565
• 35 Wong F L, Boo N Y, Ainoon O, Wang M K. Variants of organic anion transporter polypeptide 2 gene are not risk factors associated with severe neonatal hyperbilirubinemia.  Malays J Pathol. 2009;  31 99-104
• 36 van de Steeg E, Wagenaar E, van der Kruijssen C M et al.. Organic anion transporting polypeptide 1a/1b-knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs.  J Clin Invest. 2010;  120 2942-2952