Abstract
Rationale: Inhaled corticosteroids (ICS) are key treatments for controlling asthma and preventing asthma attacks. However, the responsiveness to ICS varies among individuals. MicroRNAs (miRNAs) have been lauded for their prognostic utility.Objectives: We hypothesized that circulating miRNAs obtained at baseline/prerandomization in the Childhood Asthma Management Program (CAMP) could serve as biomarkers and biologic mediators of ICS clinical response over the 4-year clinical trial period.Methods: We selected baseline serum samples from 462 CAMP subjects subsequently randomized to either ICS (budesonide) or placebo. Samples underwent small RNA sequencing, and read counts were normalized and filtered by depth and coverage. Linear regression was used to associate miRNAs with change in FEV(1)% (prebronchodilator FEV(1) as a percent predicted) over the 4-year treatment period in both main effects and interaction models. We validated the function of the top associated miRNAs by luciferase reporter assays of glucocorticoid-mediated transrepression and predicted response to ICS through logistic regression models.Measurements and Main Results: We identified 7 miRNAs significantly associated with FEV(1)% change (P ≤ 0.05) and 15 miRNAs with significant interaction (P ≤ 0.05) to ICS versus placebo treatments. We selected three miRNAs for functional validation, of which hsa-miR-155-5p and hsa-miR-532-5p were significantly associated with changes in dexamethasone-induced transrepression of NF-κB. Combined, these two miRNAs were predictive of ICS response over the course of the clinical trial, with an area under the receiver operating characteristic curve of 0.86.Conclusions: We identified two functional circulating miRNAs predictive of asthma ICS treatment response over time.