Polymorphisms in urea cycle enzyme genes are associated with persistent pulmonary hypertension of the newborn

Dinushan C Kaluarachchi; Caitlin J Smith; Jonathan M Klein; Jeffrey C Murray; John M Dagle; Kelli K Ryckman

doi:10.1038/pr.2017.143

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Polymorphisms in urea cycle enzyme genes are associated with persistent pulmonary hypertension of the newborn

Journal article

Open access

Peer reviewed

Polymorphisms in urea cycle enzyme genes are associated with persistent pulmonary hypertension of the newborn

Dinushan C Kaluarachchi, Caitlin J Smith, Jonathan M Klein, Jeffrey C Murray, John M Dagle and Kelli K Ryckman

Pediatric research, Vol.83(1-1), pp.142-147

01/2018

DOI: 10.1038/pr.2017.143

PMCID: PMC5811332

PMID: 28609431

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Abstract

BackgroundPersistent pulmonary hypertension of the newborn (PPHN) is characterized by elevated pulmonary vascular resistance. Endogenous nitric oxide is critical for regulation of pulmonary vascular resistance. Nitric oxide is generated from L-arginine, supplied by the urea cycle (UC). We hypothesized that polymorphisms in UC enzyme genes and low concentrations of UC intermediates are associated with PPHN.MethodsWe performed a family-based candidate gene analysis to study 48 single-nucleotide polymorphisms (SNPs) in six UC enzyme genes. Genotyping was carried out in 94 infants with PPHN and their parents. We also performed a case-control analysis of 32 cases with PPHN and 64 controls to identify an association between amino-acid levels on initial newborn screening and PPHN.ResultsThree SNPs (rs41272673, rs4399666, and rs2287599) in carbamoyl phosphate synthase 1 gene (CPS1) showed a significant association with PPHN (P=0.02). Tyrosine levels were significantly lower (P=0.003) and phenylalanine levels were significantly higher (P=0.01) in cases with PPHN. There was no difference in the arginine or citrulline levels between the two groups.ConclusionsThis study suggests an association (P<0.05) between SNPs in CPS1 and PPHN. These findings warrant further replication in larger cohorts of patients.

Haplotypes

Vascular Resistance

Nitric Oxide - chemistry

Humans

Genotype

Male

Persistent Fetal Circulation Syndrome - genetics

Case-Control Studies

Arginine - chemistry

Persistent Fetal Circulation Syndrome - diagnosis

Intensive Care, Neonatal

Models, Biological

Female

Heterozygote

Registries

Urea - metabolism

Polymorphism, Single Nucleotide

Infant, Newborn

Carbamoyl-Phosphate Synthase (Ammonia) - genetics

Details

Title: Subtitle: Polymorphisms in urea cycle enzyme genes are associated with persistent pulmonary hypertension of the newborn
Creators: Dinushan C Kaluarachchi - Department of Pediatrics, University of Iowa, Iowa City, Iowa
Caitlin J Smith - Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa
Jonathan M Klein - Department of Pediatrics, University of Iowa, Iowa City, Iowa
Jeffrey C Murray - Department of Pediatrics, University of Iowa, Iowa City, Iowa
John M Dagle - Department of Pediatrics, University of Iowa, Iowa City, Iowa
Kelli K Ryckman - Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa
Resource Type: Journal article
Publication Details: Pediatric research, Vol.83(1-1), pp.142-147
DOI: 10.1038/pr.2017.143
PMID: 28609431
PMCID: PMC5811332
NLM abbreviation: Pediatr Res
ISSN: 1530-0447
eISSN: 1530-0447
Publisher: United States
Grant note: R00 HD065786 / NICHD NIH HHS K99 HD065786 / NICHD NIH HHS
Language: English
Date published: 01/2018
Academic Unit: Anatomy and Cell Biology; International Programs; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Nursing; Public Policy Center (Archive); Biochemistry and Molecular Biology; Dental Research; Neonatology
Record Identifier: 9983995165802771

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