Polymorphisms in the Urea Cycle Enzyme Genes Are Associated with Persistent Pulmonary Hypertension of Newborn

Abstract

Background-Persistent pulmonary hypertension of the newborn (PPHN) is characterized by elevated pulmonary vascular resistance (PVR). Endogenous nitric oxide is critical for regulation of PVR . 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.Methods-Family based candidate gene analysis to study 48 single nucleotide polymorphisms in 6 UC enzyme genes. Genotyping was done on 94 infants with PPHN and their parents. We also performed a case-control analysis of 32 cases with PPHN and 64 controls to identify the association between amino acid levels on initial newborn screening and PPHN.Results-Three SNPs in carbamoyl phosphate synthetase 1 gene (CPS1) showed 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.Conclusions-This study suggests a potential association between SNPs in the CPS1 and PPHN. Tyrosine level was significantly lower and phenylalanine level was significantly higher in cases with PPHN. These findings warrant further replication in larger cohorts of patients.

Altered metabolites in newborns with persistent pulmonary hypertension

“…These differences are potentially due to different patient populations: While Montogmery et al studied preterm infants with BPD, Pearson et al, as well as the current study included term and nearterm infants with PPHN. Finally, Kaluarachchi et al 15 found trends toward lower arginine and citrulline levels in infants with PPHN, though these did not reach statistical significance. These are all relatively small case-control studies (up to 32 cases), and none adjusted for other metabolites.…”

“…Several prior studies suggest a link between PPHN and metabolism via the urea cycle; 12,15 endothelial cells generate the strong pulmonary vasodilator, nitric oxide (NO), from the precursor amino acid, L-arginine, supplied by the urea cycle (Fig. 3).…”

“…These are all relatively small case-control studies (up to 32 cases), and none adjusted for other metabolites. 12,14,15 In the urea cycle, ornithine is the product of arginine hydrolysis by arginase. 27 To our knowledge, there are no published data on the relationship of ornithine levels to PPHN, however, there is some evidence linking decreased ornithine levels to PH among adults with sickle cell disease.…”

“…We identified ten candidate metabolites (arginine, ornithine, citrulline, arginine to ornithine ratio, ornithine to citrulline ratio, tyrosine, phenylalanine, free carnitine, carnitine/(C16 + C18:1) ratio, and TSH) from the literature. [12][13][14][15][16][17][18][19] Metabolites were logtransformed. To avoid overfitting of the diagnostic model, the cohort of cases and controls was randomly divided into derivation (3/4 of cases with matched controls) and validation (1/4 of cases with matched controls) subsets.…”

“…13,14 Most recently, elevated phenylalanine and decreased tyrosine levels have been associated with PPHN. 15 In animal studies, there is a link between carnitine metabolism and pulmonary vascular disease. [16][17][18] Specifically, the disruption of carnitine homeostasis has been demonstrated in a lamb model of PH with increased pulmonary blood flow present in congenital heart disease (CHD).…”