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

Abstract

Aim Pulmonary hypertension (PH) develops in 25–40% of bronchopulmonary dysplasia (BPD) patients, substantially increasing mortality. We have previously found that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) production, is elevated in patients with BPD-associated PH. ADMA is metabolized by NG,NG- dimethylarginine dimethylaminohydrolase (DDAH). Presently, we test the hypothesis that there are single nucleotide polymorphisms (SNPs) in DDAH1 and/or DDAH2 associated with the development of PH in BPD patients. Methods BPD patients were enrolled (n=98) at Nationwide Children’s Hospital. Clinical characteristics and 36 SNPs in DDAH1 and DDAH2 were compared between BPD-associated PH patients (cases) and BPD-alone patients (controls). Results In BPD patients, 25 (26%) had echocardiographic evidence of PH (cases). In this cohort, DDAH1 wildtype rs480414 was 92% sensitive and 53% specific for PH in BPD, and the DDAH1 SNP rs480414 decreased the risk of PH in an additive model of inheritance (OR=0.39; 95% CI [0.18–0.88], p=0.01). Conclusion The rs480414 SNP in DDAH1 may be protective against the development of PH in patients with BPD. Furthermore, the DDAH1 rs480414 may be a useful biomarker in developing predictive models for PH in patients 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 ).…”

“…Eleven prevalences were derived from studies that reported a well‐defined time of PH‐assessment . Fourteen prevalences were derived from studies that did not report a well‐defined time point of assessment of PH …”

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

“…Furthermore, lymphocytes harvested from patients with the arginase‐1 SNP had greater levels of NO production . We have also described that patients with BPD and PH have differential expression of a SNP in the dimethylarginine dimethylaminohydrolase‐1 (DDAH‐1) gene compared to patients with BPD alone . Furthermore, we found higher plasma levels of asymmetric dimethylarginine (ADMA) in infants that went on to develop BPD with PH than in those with BPD alone .…”