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Association between genetic variations in carbamoyl-phosphate synthetase gene and persistent neonatal pulmonary hypertension

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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.

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Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request. The study data was not presented as an abstract or poster.

Code availability

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Abbreviations

PPHN:

Persistent pulmonary hypertension of the new-borns

NO:

Nitric oxide

CPS-I:

Carbamoyl phosphate synthetase-I

PVR:

Pulmonary vascular resistance

PAH:

Pulmonary arterial hypertension

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Authors and Affiliations

  1. Department of Clinical Pathology-Hematology and Ain Shams Medical Research Institute (MASRI), Faculty of Medicine, Ain Shams University, Cairo, 11566, Egypt

    Nashwa El-Khazragy

  2. Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt

    Mohamed El Barbary & Dina Rabie

  3. Department of Pediatrics, Faculty of Medicine, Misr University for Science and Technology, Cairo, Egypt

    Hala Fouad

  4. Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt

    Abdallah Abdelgawad

Authors
  1. Nashwa El-Khazragy
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  2. Mohamed El Barbary
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  3. Hala Fouad
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  4. Abdallah Abdelgawad
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  5. Dina Rabie
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by AA and DR. The first draft of the manuscript was written by NE and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Nashwa El-Khazragy.

Ethics declarations

Ethics approval

The case–control study was carried out at the pediatric department after approval from the Local Ethics Committee of Faculty of Medicine, Ain Shams University (FMASU MS 82/2020).

Consent to participate

Written informed consent was obtained from all neonates’ parents. All the methods were conducted following the relevant guidelines, regulations, and Declaration of Helsinki.

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Competing interests

The authors declare no competing interests.

Additional information

Communicated by Daniele De Luca

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El-Khazragy, N., El Barbary, M., Fouad, H. et al. Association between genetic variations in carbamoyl-phosphate synthetase gene and persistent neonatal pulmonary hypertension. Eur J Pediatr 180, 2831–2838 (2021). https://doi.org/10.1007/s00431-021-04053-8

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  • DOI: https://doi.org/10.1007/s00431-021-04053-8

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