Circulating MicroRNAs: Association with Lung Function in Asthma

BACKGROUND: MicroRNAs are key transcriptional and network regulators previously associated with asthma susceptibility. However, their role in relation to asthma severity has not been delineated. OBJECTIVE: We hypothesized that circulating microRNAs could serve as biomarkers of changes in lung function in asthma patients. METHODS: We isolated microRNAs from serum samples obtained at randomization for 160 participants of the Childhood Asthma Management Program. Using a TaqMan microRNA array containing 754 microRNA primers, we tested for the presence of known asthma microRNAs, and assessed the association of the individual microRNAs with lung function as measured by FEV(1)/FVC, FEV(1)% and FVC%. We further tested the subset of FEV(1)/FVC microRNAs for sex-specific and lung developmental associations. RESULTS: Of the 108 well-detected circulating microRNAs, 74 (68.5%) had previously been linked to asthma susceptibility. We found 22 (20.3%), 4 (3.7%) and 8 (7.4%) microRNAs to be associated with FEV(1)/FVC, FEV(1)% and FVC%, respectively. 8 (of 22) FEV(1)/FVC, 3 (of 4) FEV(1)% and 1 (of 8) FVC% microRNAs had functionally validated target genes that have been linked via genome wide association studies to asthma and FEV1 change. Among the 22 FEV(1)/FVC microRNAs, 9 (40.9%) remain associated with FEV(1)/FVC in boys alone in a sex-stratified analysis (compared with 3 FEV(1)/FVC microRNAs in girls alone), 7 (31.8%) were associated with fetal lung development, and 3 (13.6%) in both. Ontology analyses revealed enrichment for pathways integral to asthma, including PPAR signaling, G-protein coupled signaling, actin and myosin binding, and respiratory system development. CONCLUSIONS: Circulating microRNAs reflect asthma biology and are associated with lung function differences in asthmatics. They may represent biomarkers of asthma severity.