Arginase I gene single-nucleotide polymorphism is associated with decreased risk of pulmonary hypertension in bronchopulmonary dysplasia

Abstract

Aim To test the hypothesis that there are single-nucleotide polymorphisms (SNPs) in genes of the l-arginine/nitric oxide pathway associated with pulmonary hypertension (PH) in neonates with bronchopulmonary dysplasia (BPD). Methods Neonates with BPD were enrolled (n = 140) and clinical characteristics compared between case (BPD + PH) and control (BPD) groups. DNA was isolated from blood leucocytes and assayed for 17 SNPs in l-arginine/nitric oxide pathway genes by Sequenom massarray. Genes included carbamoyl-phosphate synthetase, ornithine transcarbamylase, argininosuccinate synthase, nitric oxide synthase and arginase. SNPs were selected from the National Center for Biotechnology Information database for their putative functionality. Calculated minor allele frequencies (MAF) of cases and controls were compared using χ2 and logistic regression. Results Of the 140 patients with BPD, 26% had echocardiographic evidence of PH. Ventilation days were longer for cases than controls (mean 31 vs. 15 days, p < 0.05). Of the 17 SNPs, rs2781666 in arginase I gene was less common in cases (MAF = 0.23) than controls (MAF = 0.37, p = 0.04). The odds of PH decreased by 43% (p = 0.047) for each copy of the SNP minor allele in arginase I gene in patients with BPD. Conclusion Arginase I SNP (rs2781666) may be associated with protection against pulmonary hypertension in preterm neonates with BPD.

Identification of gaps in the current knowledge on pulmonary hypertension in extremely preterm infants: A systematic review and meta‐analysis

“…We included two articles by scanning the reference lists. Finally, 25 articles, 16 retrospective and 9 prospective studies, were eligible for inclusion in the study . The flow chart of this excluding process is given in Figure .…”

“…The results of the assessment of the risk of bias are shown in Table . Eight studies that were included provided clearly defined objectives, study populations, and outcome measures . However, 17 of the 25 included studies had a retrospective design and included a selected study population .…”

“…Four studies reported on a study population of extremely preterm infants with and without BPD, whereas 16 studies reported selectively on infants with BPD and seven studies reported selectively on a study population of infants with moderate/severe BPD . In nine studies the study population partly overlapped with other included studies (Table ) . Seven studies were excluded because they failed to report a clear definition of the outcome of interest (Table ).…”

A single nucleotide polymorphism in the dimethylarginine dimethylaminohydrolase gene is associated with lower risk of pulmonary hypertension in bronchopulmonary dysplasia

“…BPD was defined according to the NICHD consensus statement as a supplemental oxygen requirement at 28 days of life (2). Some of the patients enrolled in the current study have been enrolled in previous research studies (11, 18). Enrollment, clinical data abstraction, and specimen collection were completed through the Ohio Perinatal Research Network (OPRN) and Perinatal Research Repository (PRR) at The Research Institute at NCH, Columbus, Ohio, USA.…”

Arginase and α‐smooth muscle actin induction after hyperoxic exposure in a mouse model of bronchopulmonary dysplasia

“…Arginase hydrolyzes L‐arginine to L‐ornithine and urea, and L‐ornithine can be further metabolized by either ornithine decarboxylase (ODC) to produce polyamines or by ornithine aminotransferase (OAT) to produce L‐proline important for both endothelial and smooth muscle cell proliferation indicative of vascular remodelling in pulmonary hypertension . Recently, our group demonstrated in infants with BPD, differential expression of a single nucleotide polymorphism (SNP) in the arginase‐1 gene between those patients with BPD and those with BPD and PH. Furthermore, lymphocytes harvested from patients with the arginase‐1 SNP had greater levels of NO production .…”