Circulating microRNAs Predict Longitudinal Asthma Control and Treatment Response

Background: GINA-based clinical assessment of asthma control provides limited insight into the molecular mechanisms driving disease progression and treatment response. Circulating microRNAs (miRNAs) are implicated in immune regulation and airway remodeling, but their relationship to longitudinal, treatment-specific asthma control is not well characterized. We aimed to identify treatment-specific miRNAs associated with longitudinal asthma control and evaluate their ability to discriminate well-controlled from uncontrolled asthma. Methods: Baseline serum miRNA sequencing data from 491 children in the Childhood Asthma Management Program (CAMP), a randomized trial of budesonide versus placebo, were analyzed, with GINA-based composite symptom scores assessed at baseline and 2, 4, 8, and 12 months. Cumulative link mixed models were fitted across 266 miRNAs to identify associations with longitudinal ordinal asthma control, adjusting for time, baseline status, and treatment. Random Forest classifiers were trained within each treatment group using Group K-Fold cross-validation. Pathway enrichment of validated miRNA targets was performed with DAVID. Results: In the budesonide group, hsa-miR-1224-5p was associated with lower symptom severity and hsa-miR-199a-3p|hsa-miR-199b-3p with higher severity; both associations persisted at 12 months. The placebo group showed a broader pattern, with ten miRNAs associated with symptoms. Random Forest classifiers achieved mean AUC of 0.776 (budesonide) and 0.714 (placebo) for 12-month control status. Budesonide-associated targets were enriched for glucocorticoid-responsive and MAPK/Ras signaling, while placebo-associated targets showed broad enrichment for general regulatory processes. Conclusion: Treatment-specific circulating miRNAs distinguish asthma control over time and implicate distinct signaling pathways, supporting their potential as complementary molecular markers for asthma monitoring in children.