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

BACKGROUND: Persistent 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. METHODS: We 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. RESULTS: Three 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. CONCLUSIONS: This study suggests an association (P < 0.05) between SNPs in CPS1 and PPHN. These findings warrant further replication in larger cohorts of patients.