Extracellular Vesicle-Encapsulated microRNAs as Novel Biomarkers of Lung Health.

Early detection of respiratory diseases is critical to facilitate delivery of disease-modifying interventions. Extracellular vesicle-enriched microRNAs (EV-miRNAs) may represent reliable markers of early lung injury. Evaluate associations of plasma EV-miRNAs with lung function. The prospective NAS (Normative Aging Study) collected plasma EV-miRNA measurements from 1996-2015 and spirometry every 3-5 years through 2019. Associations of EV-miRNAs with baseline lung function were modeled using linear regression. To complement the individual miRNA approach, unsupervised machine learning was used to identify clusters of participants with distinct EV-miRNA profiles. Associations of EV-miRNA profiles with multivariate latent longitudinal lung function trajectories were modeled using log binomial regression. Biological functions of significant EV-miRNAs were explored using pathway analyses. Results were replicated in an independent sample of NAS participants and in the HEALS (Health Effects of Arsenic Longitudinal Study). In the main cohort of 656 participants, 51 plasma EV-miRNAs were associated with baseline lung function (false discovery rate-adjusted value < 0.05), 28 of which were replicated in the independent NAS sample and/or in the HEALS cohort. A subset of participants with distinct EV-miRNA expression patterns had increased risk of declining lung function over time, which was replicated in the independent NAS sample. Significant EV-miRNAs were shown in pathway analyses to target biological pathways that regulate respiratory cellular immunity, the lung inflammatory response, and airway structural integrity. Plasma EV-miRNAs may represent a robust biomarker of subclinical lung injury and may facilitate early identification and treatment of patients at risk of developing overt lung disease.