Iranian Journal of Neonatology

Iranian Journal of Neonatology

Clinical Significance of OATP2 Gene Variants in Iranian Neonates with Hyperbilirubinemia

Document Type : Original Article

Authors
Abbas Boskabadi 1
Gholamali Mamouri 1
Hassan Boskabadi 1
Nasim Pouralizadeh 2
Ali Moradi 3
Hassan Mehrad-Majd 4
1 Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
2 Department of Pediatrics, Faculty of Medicine, Neyshabur University of Medical Sciences, Neyshabur, Iran
3 Orthopedic Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
4 Cancer Molecular Pathology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
10.22038/ijn.2021.57052.2074
Abstract
Background: Neonatal hyperbilirubinemia is a life-threatening and multifactorial disorder affecting about 60%-80% of newborns during their first week of life. Various environmental and genetic factors can contribute to the occurrence of this problem. The present study aimed to investigate the relationship between the two organic anion transporter 2 (OATP2) gene polymorphisms (388A>G and 521T>C) and the risk of neonatal hyperbilirubinemia.
Methods: A total of 200 neonates, including 100 infants with pathological icterus without a specific cause as the case group and 100 healthy neonates as the control group, were included in this cross-sectional study. Using fresh blood DNA, allelic frequency and genotypic distribution of each variant were determined by polymerase chain reaction-restriction fragment length polymorphism method. The biochemical measurements were also performed for both groups.
Results: The two groups were similar in terms of gender, birth weight, gestational age, diet, and type of feeding. Allelic frequency and genotype distribution of the 388A>G and 521T>C polymorphisms did not show any significant association with hyperbilirubinemia both in crude and modified conditions (P>0.05). Moreover, no significant difference was observed between cases and controls in diplotypes and haplotypes analysis (P>0.05).
Conclusion: As evidenced by the obtained results, the neonates with hyperbilirubinemia were not different from healthy newborns in allelic frequency and genotypic distribution of the two variants of the OATP2 gene. It seems that these two polymorphisms are not correlated with the risk of hyperbilirubinemia in an Iranian neonatal population. Further studies with larger sample sizes are needed to confirm the results of this study.
 
 
Keywords
Neonatal hyperbilirubinemia
OATP2 gene
Polymorphism
388A>G
521T>C
  1. Mishra S, Agarwal R, Deorari AK, Paul VK. Jaundice in the newborns. Ind J Pediatr. 2008;75(2):157-63.
  2. 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;30;276(13):9626-30.
  3. Yu TC, Nguyen C, Ruiz N, Zhou S, Zhang X, Böing EA, et al. Prevalence and burden of illness of treated hemolytic neonatal hyperbilirubinemia in a privately insured population in the United States. BMC Pediatr. 2019;19(1):53-61.
  4. Farhat AS, Hafizi L, Pourhoseini Mt, Halimi F, Mohamadzadeh A, Saeidi R. Comparison of bilirubin level in term infants born by vaginal delivery and C/S. Iran J Neonat. 2016;7(4):45-9.
  5. Ullah S, Rahman K, Hedayati M. Hyperbilirubinemia in Neonates: Types, Causes, Clinical Examinations, Preventive Measures and Treatments: A Narrative Review Article. Iran J Pub Heal. 2016;45(5):558-68.
  6. Watchko JF, Lin Z, Clark RH, Kelleher AS, Walker MW, Spitzer AR. Complex multifactorial nature
    of significant hyperbilirubinemia in neonates. Pediatrics. 2009;124(5):e868-77.
  7. Olusanya BO, Osibanjo FB, Slusher TM. Risk factors for severe neonatal hyperbilirubinemia in low and middle-income countries: a systematic review and meta-analysis. PLoS One. 2015;10(2):e0117229.
  8. Büyükkale G, Turker G, Kasap M, Akpınar G, Arısoy E, Günlemez A, et al. Neonatal hyperbilirubinemia and organic anion transporting polypeptide-2 gene mutations. Am J Perinatol. 2011;28(8):619-26.
  9. Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. N Engl J Med. 2001;344(8
    ):581-90.
  10. Zahed Pasha Y, Alizadeh-Tabari S, Zahed Pasha E, Zamani M. Etiology and therapeutic management of neonatal jaundice in Iran: a systematic review and meta-analysis. 2020;16(5):480-93.
  11. Zardosht R, Shah Farhat A, Saeidi R, Parvin F. Assement Efficacy and Complication of the Distance between Phototherapy Lamps and Neonate’s Body Level on Serum Bilirubin Decrease and Phototherapy Complications in Neonatal Hyperbilirubinemia. Iran J Neonat. 2019;10(4):47-52.
  12. Najib KS, Saki F, Hemmati F, Inaloo S. Incidence,
    risk factors and causes of severe neonatal hyperbilirubinemia in the South of iran (fars province). Iran Red Cres Med J. 2013;15(3):260-3.
  13. Huang MJ, Kua KE, Teng HC, Tang KS, Weng HW, Huang CS. Risk factors for severe hyperbilirubinemia in neonates. Pedia Res. 2004;56(5):682-9.
  14. Mehrad-Majd H, Haerian MS, Akhtari J, Ravanshad Y, Azarfar A, Mamouri G. Effects of Gly71Arg mutation in UGT1A1 gene on neonatal hyperbilirubinemia: a systematic review and meta-analysis. J Matern Fetal Neonatal Med. 2019;32(10):1575-85.
  15. Wang P, Kim RB, Chowdhury JR, Wolkoff AW. The human organic anion transport protein SLC21A6 is not sufficient for bilirubin transport. J Biol Chem. 2003;278(23):20695-9.
  16. Wong F, Boo N, Othman A. Risk factors associated with unconjugated neonatal hyperbilirubinemia in Malaysian neonates. J Trop Pediatr. 2013;59(4):
    280-5.
  17. Wong FL, Boo NY, Ainoon O, Wang MK. Variants of organic anion transporter polypeptide 2 gene are not risk factors associated with severe neonatal hyperbilirubinemia. Malays J Pathol. 2009;31(2):
    99-104.
  18. Min J, Jie L, Caiyun Y, Ying L, Xuefang Y. Gene Mutation in Neonatal Jaundice - Mutations in UGT1A1 and OATP2 Genes. Indian J Pediatr. 2016;83(7):723-5.
  19. D'Silva S, Colah RB, Ghosh K, Mukherjee MB. Combined effects of the UGT1A1 and OATP2 gene polymorphisms as major risk factor for unconjugated hyperbilirubinemia in Indian neonates. 2014;547(1):18-22.
  20. Watchko JF, Daood MJ, Biniwale M. Understanding neonatal hyperbilirubinaemia in the era of genomics. Sem Neona. 2002;7(2):143-52.
  21. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114(1):297-316.
  22. van Es HH, Bout A, Liu J, Anderson L, Duncan AM, Bosma P, et al. Assignment of the human UDP glucuronosyltransferase gene (UGT1A1) to chromosome region 2q37. Cytog Cell Genet. 1993;63(2):114-6.
  23. Boskabadi H, Ashrafzadeh F, Azarkish F, Khakshour A. Complications of Neonatal Jaundice and the Predisposing Factors in‎ J Babol Uni Med Sci. 2015;17(9):7-13.
  24. Gaunt TR, Rodríguez S, Day IN. Cubic exact solutions for the estimation of pairwise haplotype frequencies: implications for linkage disequilibrium analyses and a web tool 'CubeX'. BMC Bioinform. 2007;8:428-431.
  25. Tirona RG, Leake BF, Merino G, Kim RB. Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J Biol Chem. 2001;276(38):35669-75.
  26. Amandito R, Rohsiswatmo R. SLCO1B1 c.388A > G variant incidence and the severity of hyperbilirubinemia in Indonesian neonates. BMC Pediatr. 2019;19(1):212.
  27. Prachukthum S, Nunnarumit P, Pienvichit P, Chuansumrit A, Songdej D, Kajanachumpol S, et al. Genetic polymorphisms in Thai neonates with hyperbilirubinemia. Acta Paediat. 2009;98(7):
    1106-10.
  28. Huang CS. Molecular genetics of unconjugated hyperbilirubinemia in Taiwanese. J Biomed Sci. 2005;12(3):445-50.
  29. Liu J, Long J, Zhang S, Fang X, Luo Y. Polymorphic variants of SLCO1B1 in neonatal hyperbilirubinemia in China. Ital J Pediatr. 2013;39:49-58.
  30. Fu WP, Liu Y. [Role of genetic factors in occurrence of neonatal jaundice in Guangxi region]. Zhonghua Er Ke Za Zhi. 2005;43(10):743-7.
  31. Pouralizadeh N, Maamouri G, Boskabadi A, Boskabadi H, Rafatpanah H, Moadi A, et al. Genetic association of UGT1A1 promoter c.-3279T> G, and c.-3156G> A variants with neonatal hyperbili-rubinemia in an Iranian Population. Iranian J Neonat. 2021;1:22-36.
  32. Rooki H, Haerian MS, Azimzadeh P, Mirhafez R, Ebrahimi M, Ferns G, et al. Associations between C1431T and Pro12Ala variants of PPARγ gene and their haplotypes with susceptibility to metabolic syndrome in an Iranian population. Molec Biol Repo. 2014;41(5):3127-33.

 

 

Iranian Journal of Neonatology
Volume 13, Issue 1
Winter 2022
Pages 30-35