Association Between Genetic Variations in Carbamoyl-phosphate Synthetase Gene and Persistent Neonatal Pulmonary Hypertension

Overview

Journal Eur J Pediatr

Specialty Pediatrics

Date 2021 Mar 27

PMID 33772623

Citations 3

Authors

Nashwa El-Khazragy

Mohamed El Barbary

Hala Fouad

Abdallah Abdelgawad

Dina Rabie

Affiliations

Soon will be listed here.

Abstract

Persistent pulmonary hypertension of the new-borns (PPHN) is one of the main etiologies of morbidity as well as mortality in neonates. Previous studies found that genetic polymorphisms in urea cycle enzymes are associated with PPHN. Few of the genetic polymorphisms in neonates have been recognized with PPHN. We aimed to find out the prevalence of the CPS-I gene polymorphism and to correlate the genotype with the serum nitric oxide (NO) levels in Egyptian neonates with idiopathic PPHN. We included neonates diagnosed with PPH (n = 150) while the control group included healthy neonates with matched age and sex (n = 100). The CPS-I gene polymorphism: A/C, trans-version substitution, rs4399666 genotype was identified using TaqMan-based quantitative PCR. The results revealed that the CPS-I A/C rs4399666 gene polymorphism and lower serum NO levels were significantly associated with idiopathic PPHN in neonates. In addition, serum NO level was significantly associated with an rs4366999 A/C variant gene in idiopathic PPHN (p = 0.001). Univariable regression analysis demonstrated that there was a significant association between CPS-I A/C rs4399666 CC and increased risk of PPHN (odd ratio, 95% CI of 1.8 (0.78 to 1.75), p-value = 0.04).Conclusion: We concluded that mutant CPS-I A/C rs4399666 minor variant especially the homozygous CC genotype is frequently distributed among the PPHN group. This demonstrates that the presence of mutant CPS-I rs4399666 does not necessarily predispose to the development of PPHN in neonates, but nonetheless, if the C allele is inherited in the homozygous CC genotype, it is associated with a higher risk of PPHN. What is Known: • Prior studies found that polymorphisms in urea cycle enzyme genes are associated with PPHN. • Association between CPS-1 gene polymorphisms is significantly associated with PPHN. What is New: • The prevalence of CPS-1, A/C trans-version substitution, rs4399666 gene polymorphism in Egyptian neonates presented with idiopathic PPHN. • Mutant CPS-I A/C rs4399666 especially the homozygous CC genotype is more frequently distributed among PPHN, and it is significantly associated with low serum nitric oxide level.

Citing Articles

Arginine metabolism is a biomarker of red blood cell and human aging.

Reisz J, Earley E, Nemkov T, Key A, Stephenson D, Keele G Aging Cell. 2024; 24(2):e14388.

PMID: 39478346 PMC: 11822668. DOI: 10.1111/acel.14388.

Genome-wide association study identifies WWC2 as a possible locus associated with persistent pulmonary hypertension of the newborn in the Thai population.

Nakwan N, Kunhapan P, Chaiyasung T, Satproedprai N, Singkhamanan K, Mahasirimongkol S Transl Pediatr. 2023; 12(1):1-12.

PMID: 36798934 PMC: 9926135. DOI: 10.21037/tp-22-280.

A nomogram prediction model for early death in patients with persistent pulmonary hypertension of the newborn.

Lin C, Mi J, Zhang Y, Duan S, Wu J, Li Y Front Cardiovasc Med. 2023; 9:1077339.

PMID: 36620618 PMC: 9813219. DOI: 10.3389/fcvm.2022.1077339.

Mechanisms of pulmonary vascular dysfunction in pulmonary hypertension and implications for novel therapies.

Christou H, Khalil R Am J Physiol Heart Circ Physiol. 2022; 322(5):H702-H724.

PMID: 35213243 PMC: 8977136. DOI: 10.1152/ajpheart.00021.2022.

References

Abman S . Recent advances in the pathogenesis and treatment of persistent pulmonary hypertension of the newborn. Neonatology. 2007; 91(4):283-90. DOI: 10.1159/000101343. View

Abman S, Hansmann G, Archer S, Ivy D, Adatia I, Chung W . Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation. 2015; 132(21):2037-99. DOI: 10.1161/CIR.0000000000000329. View

Tyson J, Wright L, Bauer C, KORONES S, Stevenson D, Verter J . Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics. 2000; 105(1 Pt 1):14-20. DOI: 10.1542/peds.105.1.14. View

Steurer M, Jelliffe-Pawlowski L, Baer R, Partridge J, Rogers E, Keller R . Persistent Pulmonary Hypertension of the Newborn in Late Preterm and Term Infants in California. Pediatrics. 2016; 139(1). DOI: 10.1542/peds.2016-1165. View

Lai M, Chu S, Lakshminrusimha S, Lin H . Beyond the inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Pediatr Neonatol. 2017; 59(1):15-23. DOI: 10.1016/j.pedneo.2016.09.011. View

Lipkin P, Davidson D, Spivak L, Straube R, Rhines J, Chang C . Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide. J Pediatr. 2002; 140(3):306-10. DOI: 10.1067/mpd.2002.122730. View

Hilgendorff A, Apitz C, Bonnet D, Hansmann G . Pulmonary hypertension associated with acute or chronic lung diseases in the preterm and term neonate and infant. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK. Heart. 2016; 102 Suppl 2:ii49-56. DOI: 10.1136/heartjnl-2015-308591. View

Byers H, Dagle J, Klein J, Ryckman K, McDonald E, Murray J . Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn. Pediatr Res. 2012; 71(2):162-7. PMC: 3718388. DOI: 10.1038/pr.2011.24. View

Catteruccia M, Verrigni D, Martinelli D, Torraco A, Agovino T, Bonafe L . Persistent pulmonary arterial hypertension in the newborn (PPHN): a frequent manifestation of TMEM70 defective patients. Mol Genet Metab. 2014; 111(3):353-359. DOI: 10.1016/j.ymgme.2014.01.001. View

10.

Vonk J, Postma D, Maarsingh H, Bruinenberg M, Koppelman G, Meurs H . Arginase 1 and arginase 2 variations associate with asthma, asthma severity and beta2 agonist and steroid response. Pharmacogenet Genomics. 2010; 20(3):179-86. DOI: 10.1097/FPC.0b013e328336c7fd. View

11.

Pearson D, Dawling S, Walsh W, Haines J, Christman B, Bazyk A . Neonatal pulmonary hypertension--urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. N Engl J Med. 2001; 344(24):1832-8. DOI: 10.1056/NEJM200106143442404. View

12.

Canter J, Summar M, Smith H, Rice G, Hall L, Ritchie M . Genetic variation in the mitochondrial enzyme carbamyl-phosphate synthetase I predisposes children to increased pulmonary artery pressure following surgical repair of congenital heart defects: a validated genetic association study. Mitochondrion. 2006; 7(3):204-10. PMC: 1929167. DOI: 10.1016/j.mito.2006.11.001. View

13.

Martinho S, Adao R, Leite-Moreira A, Bras-Silva C . Persistent Pulmonary Hypertension of the Newborn: Pathophysiological Mechanisms and Novel Therapeutic Approaches. Front Pediatr. 2020; 8:342. PMC: 7396717. DOI: 10.3389/fped.2020.00342. View

14.

Trittmann J, Nelin L, Zmuda E, Gastier-Foster J, Chen B, Backes C . Arginase I gene single-nucleotide polymorphism is associated with decreased risk of pulmonary hypertension in bronchopulmonary dysplasia. Acta Paediatr. 2014; 103(10):e439-43. PMC: 4180790. DOI: 10.1111/apa.12717. View

15.

Kaluarachchi D, Smith C, Klein J, Murray J, Dagle J, Ryckman K . Polymorphisms in urea cycle enzyme genes are associated with persistent pulmonary hypertension of the newborn. Pediatr Res. 2017; 83(1-1):142-147. PMC: 5811332. DOI: 10.1038/pr.2017.143. View

16.

Muktan D, Singh R, Bhatta N, Shah D . Neonatal mortality risk assessment using SNAPPE- II score in a neonatal intensive care unit. BMC Pediatr. 2019; 19(1):279. PMC: 6691535. DOI: 10.1186/s12887-019-1660-y. View

17.

Shi R, Lewis R, Panthee D . Filter paper-based spin column method for cost-efficient DNA or RNA purification. PLoS One. 2018; 13(12):e0203011. PMC: 6286138. DOI: 10.1371/journal.pone.0203011. View

18.

Kotsopoulos J, Tworoger S, De Vivo I, DeVivo I, Hankinson S, Hunter D . +331G/A variant in the progesterone receptor gene, postmenopausal hormone use and risk of breast cancer. Int J Cancer. 2009; 125(7):1685-91. PMC: 2736114. DOI: 10.1002/ijc.24477. View

19.

Faul F, Erdfelder E, Lang A, Buchner A . G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007; 39(2):175-91. DOI: 10.3758/bf03193146. View

20.

Liu X, Mei M, Chen X, Lu Y, Dong X, Hu L . Identification of genetic factors underlying persistent pulmonary hypertension of newborns in a cohort of Chinese neonates. Respir Res. 2019; 20(1):174. PMC: 6683566. DOI: 10.1186/s12931-019-1148-1. View