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

. 2016 Apr;105(4):e170-5.

doi: 10.1111/apa.13296. Epub 2016 Jan 11.

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

Jennifer K Trittmann et al. Acta Paediatr. 2016 Apr.

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 metabolised by N(ᴳ) ,N(ᴳ) -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 wild-type 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.

Keywords: Neonate; Nitric oxide; Prematurity; Urea.

©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Arginine metabolism in the pulmonary vascular wall

Arginine metabolism occurs in endothelial cells with effects on vascular smooth muscle cells. L-arginine/NO pathway enzymes; carbamoyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (AS), argininosuccinate lyase (AL), arginase, nitric oxide synthase (NOS). Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NOS. Dimethylarginine dimethylaminohydrolase (DDAH) degrades ADMA to L-citrulline.

Figure 2
Figure 2. Genotype frequencies for the rs480414 SNP in the DDAH1 gene in BPD+PH patients

A is the minor allele (SNP), and G is the major allele (wildtype). The percentage of patients with BPD+PH for each genotype: AA [2/25 (8%)]; AG [6/25 (24%)]; GG [17/25 (68%)]. * BPD+PH different from BPD alone, p<0.01; # BPD+PH different from BPD alone, p<0.05.

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References

    1. Baker CD, Abman SH, Mourani PM. Pulmonary Hypertension in Preterm Infants with Bronchopulmonary Dysplasia. Pediatric allergy, immunology, and pulmonology. 2014;27:8–16. - PMC - PubMed
    1. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;163:1723–1729. - PubMed
    1. Strueby L, Thebaud B. Advances in bronchopulmonary dysplasia. Expert review of respiratory medicine. 2014;8:327–338. - PubMed
    1. Slaughter JL, Pakrashi T, Jones DE, South AP, Shah TA. Echocardiographic detection of pulmonary hypertension in extremely low birth weight infants with bronchopulmonary dysplasia requiring prolonged positive pressure ventilation. J Perinatol. 2011;31:635–640. - PubMed
    1. Khemani E, McElhinney DB, Rhein L, Andrade O, Lacro RV, Thomas KC, et al. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics. 2007;120:1260–1269. - PubMed

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