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