Circulating MicroRNAs and Treatment Response in Childhood Asthma

作者：Jiang Li, Ronald Allan M. Panganiban, Alvin T. Kho, Michael J. McGeachie, Leanna Farnam, Robert Chase, Scott T. Weiss, Quan Lu, Kelan G. Tantisira · 发表于：American Journal of Respiratory and Critical Care Medicine · 年份：2020 · DOI：10.1164/rccm.201907-1454oc · 被引用次数：69 · 研究领域：MicroRNA in disease regulation、Asthma and respiratory diseases、Cancer-related molecular mechanisms research

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 FEV1% (prebronchodilator FEV1 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 FEV1% 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 ...