Abstract
Background
Pulmonary hypertension (PH) in patients with bronchopulmonary dysplasia (BPD) results from vasoconstriction and/or vascular remodeling, which can be regulated by mitogen-activated protein kinases (MAPKs). MAPKs are deactivated by dual-specificity phosphatases (DUSPs). We hypothesized that single-nucleotide polymorphisms (SNPs) in DUSP genes could be used to predict PH in BPD.
Methods
Preterm infants diagnosed with BPD (n = 188) were studied. PH was defined by echocardiographic criteria. Genomic DNA isolated from patient blood samples was analyzed for 31 SNPs in DUSP genes. Clinical characteristics and minor allele frequencies were compared between BPD-PH (cases) and BPD-without PH (control) groups. Biomarker models to predict PH in BPD using clinical and SNP data were tested by calculations of area under the ROC curve.
Results
In our BPD cohort, 32% (n = 61) had PH. Of the DUSP SNPs evaluated, DUSP1 SNP rs322351 was less common, and DUSP5 SNPs rs1042606 and rs3793892 were more common in cases than in controls. The best fit biomarker model combines clinical and DUSP genetic data with an area under the ROC curve of 0.76.
Conclusion
We identified three DUSP SNPs as potential BPD-PH biomarkers. Combining clinical and DUSP genetic data yields the most robust predictor for PH in BPD.
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Acknowledgements
The authors would like to thank the patients and their families for participating in this study and the research staff of the Ohio Perinatal Research Network (OPRN) and the Perinatal Research Respository (PRR). This work was supported in part by The Ohio State University College of Medicine Roessler Medical Student Research Scholarship awarded to L.L.C. This study was funded by an intramural grant from the Center for Clinical and Translational Research at The Research Institute, Nationwide Children’s Hospital (CTSA grant UL1TR001070) and an NIH grant (K08HL129080) from NHLBI.
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Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data: all authors. Drafting the article or revising it critically for important intellectual content: L.L.C., J.K.T. Final approval of the version to be published: all authors.
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Chen, L.L., Zmuda, E.J., Talavera, M.M. et al. Dual-specificity phosphatase (DUSP) genetic variants predict pulmonary hypertension in patients with bronchopulmonary dysplasia. Pediatr Res 87, 81–87 (2020). https://doi.org/10.1038/s41390-019-0502-9
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DOI: https://doi.org/10.1038/s41390-019-0502-9
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