Bronchopulmonary Dysplasia‐associated Pulmonary Hypertension and Mutations in the DDAH1 Gene

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Pulmonary hypertension (PH) is the most common comorbidity in bronchopulmonary dysplasia (BPD). Nitric oxide (NO) is produced by endothelial NO synthase (eNOS) in pulmonary endothelial cells and is a potent vasodilator. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of eNOS. Our group has recently published that ADMA levels are elevated in patients with BPD‐associated PH. ADMA is degraded by the enzyme Nᴳ,Nᴳ‐ dimethylarginine dimethylaminohydrolase (DDAH). We tested the hypothesis that there are single nucleotide polymorphisms (SNPs) in DDAH1 associated with PH in BPD. Neonates diagnosed with BPD were enrolled at Nationwide Children's Hospital. DNA was assayed for 34 SNPs in DDAH1. Calculated minor allele frequency (MAF) for cases and controls were compared using chi‐square. Assuming recessive inheritance, logistic regression was used to estimate the odds ratio. Among 157 patients with BPD, 53 (34%) also had echocardiographic evidence of PH. Gestational age, birth weight, gender, and ethnicity were not different between groups. DDAH1 rs11161637 SNP had a significantly (p=0.04) lower MAF in cases than in controls (0.25 vs. 0.34). DDAH1 rs11161637 was associated with a decreased risk (OR=0.27) of PH in this BPD cohort, although this did not reach statistical significance (p‐value=0.06). These results indicate that rs11161637 SNP of DDAH1 may be protective against the development of PH in patients with BPD. We speculate that the DDAH1 SNP may be a useful biomarker in developing predictive models for PH in patients with BPD.