Association of Neuregulin Levels and Neuregulin-1 Polymorphism with Short-term Morbidities in Preterm Neonates

Document Type : Original Article

Authors

1 Department of Pediatrics, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia

2 Department of Clinical Pathology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia

3 Department of Pediatrics, Faculty of Medicine, Universitas Padjajaran, Bandung, Indonesia

Abstract

Background: Premature birth is linked to neonatal morbidity and mortality worldwide. Neuregulin (NRG) is a trophic factor from the growth factor (GF) of a transmembrane polypeptide, encoded by four different genes, including NRG-1 which acts as an endogenous protector in fetal development. Decreased levels of NRG-1 affect several organs. The relationship between NRG-1 polymorphism and the outcome of neonatal development has been widely studied. There are no studies that have assessed NRG-1 levels and NRG-1 rs35753505 C/T polymorphism in preterm neonates, as well as its association with short-term morbidities in Indonesia.
Methods: This cross-sectional study was conducted on preterm neonates with the gestational age of 32-36 weeks in Medan, North Sumatera, Indonesia, from December 2017 to December 2018. It aimed to evaluate the association of NRG-1 levels and NRG1 polymorphism with short-term morbidities. Samples were obtained from cord blood specimens. Enzyme-linked immunosorbent assay (ELISA) was used to determine NRG-1 levels, and NRG-1 polymorphism was sequenced by polymerase chain reaction (PCR). Observations in preterm neonates were made during the first 72 h to assess short-term morbidities.
Results: During the study period, 48 cord blood specimens from preterm neonates were found eligible for analysis. Preterm neonates with low NRG-1 levels had a 10-times higher risk of developing short-term morbidities. The presence of CC and CT genotypes increased the risk of developing short-term morbidities 13.33 times (P=0.003) and 6.19 times (P=0.019), respectively. The presence of the C allele in subjects' genotype increased the risk of short-term morbidities 4.04 times (P=0.001), compared to those with T allele.
Conclusion: As evidenced by the obtained results, preterm neonates with low NRG-1 levels had a higher risk of developing short-term morbidities. Furthermore, there was a significant association between NRG-1 rs35753505 C/T polymorphism and short-term morbidities.
 
 

Keywords

References

  1. World Health Organization. Born too soon: the global action report on preterm birth. Geneva: World Health Organization; 2012. P. 19-26.
  2. Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012; 379(9832):2162-72.
  3. Blencowe H, Cousens S, Oestergaard M, Chou D, Oestergaard M, Say L, et al. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health. 2013; 10(1):S2.
  4. Ananth CV, Vintzileos AM. Epidemiology of preterm birth and its clinical subtypes. J Matern Fetal Neonatal Med. 2006; 19(12):773-82.
  5. Kumar V, Shearer JC, Kumar A, Darmstadt GL. Neonatal hypothermia in low resource settings: a review. J Perinatol. 2009; 29(6):401-2.
  6. Thompson BT, Chambers RC, Liu KD. Acute respiratory distress syndrome. N Engl J Med. 2017; 377(6):562-72.
  7. Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med. 2011; 364(3):255-64.
  8. Puntis JW. Nutritional support in the premature newborn. Postgrad Med J. 2006; 82(965):192-8.
  9. Stewart JE, Martin CR, Joselow MR. Follow up care of very low birth weight neonates. In: Cloherty JP, Eichenwald EC, Stark AR, editors. Manual of neonatal care. 6th ed. Philadelphia: Lippincot Williams and Wilkins; 2008. P. 159-63.
  10. Pearlman SA. Management of late preterm infant. In: Cunningham MD, Eyal FG, Tuttle DJ, editors. Neonatology management, procedures, on-call problems, diseases, and drugs. 7th ed. New York: McGraw-Hill Education; 2013. P. 169-72.
  11. Bany-Mohammed F. Sepsis. In: Gomella TL, Cunningham MD, Eyal FG, Tuttle DJ, editors. Neonatology management, procedures, on-call problems, diseases, and drugs. 7th ed. New York: McGraw-Hill Education; 2013. P. 865-74.
  12. Simonsen KA, Anderson-Berry AL, Delair SF, Davies HD. Early-onset neonatal sepsis. Clin Microbiol Rev. 2014; 27(1):21-47.
  13. Eyal FG. Anemia. In: Gomella TL, Cunningham MD, Eyal FG, Tuttle DJ, editors. Neonatology management, procedures, on-call problems, diseases, and drugs. 7th ed. New York: McGraw-Hill Education; 2013. P. 557-65.
  14. Strauss RG. Anaemia of prematurity: pathophysiology & treatment. Blood Rev. 2010; 24(6):221-5.
  15. Torpy JM, Lynm C, Glass RM. JAMA patient page. Premature neonates. JAMA. 2009; 301(21):2290.
  16. Bueter W, Dammann O, Zscheppang K, Korenbaum E, Dammann CE. ErB receptors in fetal endothelium- a potential linkage point for inflammation-associated neonatal disorders. Cytokine. 2006; 36(5-6):267-75.
  17. Falls DL. Neuregulins: functions, forms, and signaling strategies. Exp Cell Res. 2006; 284(1):14-30.
  18. Mei L, Xiong WC. Neuregulin 1 in neural development, synaptic plasticity and schizoprenia. Nat Rev Neurosci. 2008; 9(6):437-452.
  19. NRG1 gene. US National Library of Medicine. Available at: URL: https://ghr.nlm.nih.gov/gene/
    NRG1#synonyms    ; 2018.
  20. Nawar R, Asif H, Khan A, Ishtiaq H, Shad FK, Siddiqui S. Genetic polymorphism in NRG1 SNP rs35753505 gene is associated with schizophrenia in Pakistani patients. Int J Genetics. 2013; 5(2):142-8.
  21. Canto C, Pich S, Paz JC, Sanches R, Martinez V, Orpinell M, et al. Neuregulin increase mitochondrial oxidative capacity and insulin sensitivity in skeletal muscle cells. Diabetes. 2007; 56(9):2185-93.
  22. Eng L, Liu G. Polymorphisms as prognostic and pharmacogenetics factors in cancer: a 2013 update. Pharmacogenomics. 2013; 14(13):1659-67.
  23. Sripichai O, Fucharoen S. Genetic polymorphisms and implication for human diseases. J Med Assoc Thai. 2007; 90(2):394-8.
  24. Nicodemus KK, Law AJ, Luna A, Vakkalanka R, Straub RE, Kleinman JE, et al. A 5′ promoter region SNP in NRG1 is associated with schizophrenia risk and type III isoform expression. Mol Psychiatry. 2009; 14(8):741-3.
  25. Law AJ, Lipska BK, Weickert CS, Hyde TM, Straub RE, Hashimoto R, et al. Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease. Proc Natl Acad Sci U S A. 2006; 103(17):6747-52.
  26. Pleickhardt EP, Celandine A, Davis J, Chen M, Schurmann P, Dork T. Neuregulin 1 high-producer genotype is associated with a decreased risk of admission to the neonatal intensive care unit. Early Hum Dev. 2010; 86(5):299-304.
  27. Sheikh I, Ahmad E, Jamal M, Assidi M. Spontaneus preterm birth and single nucleotide gene polymorphisms: a recent update. BMC Genomic. 2016; 17(suppl 9):40-87.
  28. World Health Organization. WHO recommendations on interventions to improve preterm birth Geneva: World Health Organization; 2015. P. 41.
  29. Pignotti MS, Donzelli G. Preterm babies at a glance. J Clin Neonatol. 2015; 4(2):75-81.
  30. Cunningham GC, Leveno KJ, Bloom SL. Caesarean delivery and peripartum hysterectomy. Williams obstetrics. 24th ed. New York: McGraw Hill; 2014. P. 587.
  31. Li C, Liang Z, Blom MS, Wang Q, Shen X, Zhang H, et al. Temporal trends of preterm birth in Shenzen, China: a retrospective study. Reprod Health. 2018; 15(1):47.
  32. Wen S, Smith G, Yang Q, Walker M. Epidemiology of preterm birth and neonatal outcome. Semin Fetal Neonatal Med. 2004; 9(6):429-35.
  33. Stoll BJ, Chapman IA. The high risk infant. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BM, editors. Nelson textbook of pediatrics. 18th ed. New York: Elsevier Health Sciences; 2007. P. 671-98.
  34. Kaczmarczyk K, Wiszomirska I, Szturmowicz M, Magiera A, Btazkiewicz M. Are preterm-born survivors at risk of long-term respiratory disease? Ther Adv Respir Dis. 2017; 11(7):277-87.
  35. McIntosh AM, Job D, Lymer GKS, Maniega SM, Mckirdy J, Sussmann JED. The effect of a neuregulin 1 variant on white matter density and integrity. Mol Psychiatry. 2008; 13(11):1054-9.
  36. Damman O, Leviton A, Gressens P, Dammann E. Neuregulin 1: a potential endogenous protector
    in perinatatal brain white matter damage. Neonatology. 2008; 93(3):182-7.
  37. Moondra V, Sarma S, Buxton T, Safa R, Cote G, Storer T, et al. Serum neuregulin-1β as a biomarker of cardiovascular fitness. Open Biomark J. 2009; 2:1-5.
  38. HoffmannI, Bueter W, Zcheppang K, Brinkhaus M,
    Liese A, Riemke S, et al. Neuregulin 1, the fetal endothelium, and brain damage in preterm newborns. Brain Behav Immun. 2010; 24(5):784-91.
  39. Plunkett J, Doniger S, Orabona G, Morgan T, Haataja R, Haliman M, et al. An evolutionary genomic approach to identify genes involved in human birth timing. PLoS Genet. 2011; 7(4):e001365.
  40. Swaggart KA, Pavlicev M, Muglia LJ. Genomics of preterm birth. Cold Spring Harb Perspect Med. 2015; 5(2):a023127.
  41. Knickmeyer RC, Wang J, Zhu H, Geng X, Woolson S, Hamer RM, et al. Common variants in
    psychiatric risk genes predict brain structure at birth. Cereb Cortex. 2014; 24(5):1230-46.



 

Iranian Journal of Neonatology
Volume 12, Issue 4
October 2021
Pages 22-29

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