MicroRNA Profiling to Inform Disease Classification, Severity, and Treatment Response in Pediatric Pulmonary Hypertension
Pediatric pulmonary hypertension is a heterogeneous disease associated with significant morbidity and mortality. MicroRNAs have been implicated as both pathologic drivers of disease and potential therapeutic targets in pediatric pulmonary hypertension. We sought to characterize the circulating microRNA profiles of a diverse array of pediatric pulmonary hypertension patients using high throughput sequencing technology. Peripheral blood samples were drawn from patients recruited at the time of a clinically indicated cardiac catheterization and microRNA sequencing followed by differential expression and target/pathway enrichment analyses were performed. Among 63 pediatric pulmonary hypertension patients, we identified specific microRNA signatures that uniquely classified patients by disease subtype, correlated with indicators of disease severity including invasive hemodynamic metrics, and changed over the course of treatment for pulmonary hypertension. These microRNA profiles include a number of specific microRNA molecules known to function in signaling pathways critical to pulmonary vascular biology and disease, including TGFß beta, VEGF, PI3K/Akt, cGMP-PKG, and HIF-1 signaling. Circulating levels of miR-122-5p, miR-124-3p, miR-204-5p, and miR-9-5p decreased over the course of treatment in a subset of patients who had multiple samples drawn during the study period. Our findings support the further investigation of specific microRNAs as mechanistic mediators, biomarkers, and therapeutic targets in pulmonary hypertension. Overall design: Peripheral blood samples were drawn from pediatric pulmonary hypertension patients and plasma was processed for RNA sequencing to identify circulating miRNA using the miRNeasy Advanced Kit (Qiagen). The QIAseq miRNA Quantification workflow of the CLC Genomics Server was used to map reads to miRBase version 22.