Extracellular Vesicle-Encapsulated microRNAs and Respiratory Health Among American Indian Participants in the Strong Heart Study

Abstract

American Indian populations have experienced marked disparities in respiratory disease burden. Extracellular vesicle-encapsulated microRNAs (EV-miRNAs) are a novel class of biomarkers that may improve recognition of lung damage in indigenous populations in the United States. Are plasma EV-miRNAs viable biomarkers of respiratory health in American Indian populations? The Strong Heart Study is a prospective cohort study that enrolled American Indian patients aged 45 to 74 years. EV-miRNA expression was measured in plasma (1993-1995). Respiratory health outcomes, including prebronchodilator FEV1, FVC, and respiratory symptom burden, were ascertained in the same study visit. Club cell secretory protein (CC-16), an antiinflammatory pneumoprotein implicated in COPD pathogenesis, was measured in serum. Linear and logistic regression were used for statistical analyses. Biological pathway analyses were used to elucidate gene targets of significant EV-miRNAs. Among 853 American Indian adults, three EV-miRNAs were associated with FEV1, four EV-miRNAs were associated with FVC, and one EV-miRNA was associated with FEV1/FVC (P< .05). Increased miR-1294 expression was associated with higher odds of airflow limitation (OR, 1.29; 95%CI, 1.07-1.55), whereas increased expression of miR-1294 (OR, 1.32; 95%CI, 1.07-1.63) and miR-532-5p (OR, 1.57; 95%CI, 1.02-2.40) was associated with higher odds of restriction. Increased miR-451a expression was associated with lower odds of exertional dyspnea (OR, 0.71; 95%CI, 0.59-0.85). Twenty-two EV-miRNAs were associated with serum CC-16 levels (q< 0.05), suggesting that EV-miRNAs may play a role in the pathway linking CC-16 to COPD pathogenesis. A pathway analysis showed key EV-miRNAs targeted biological pathways that modulate inflammation, immunity, and structural integrity in the lungs. Circulating EV-miRNAs are novel mechanistic biomarkers of respiratory health and may facilitate the early detection and treatment of lung damage in American Indian populations that have been disproportionately affected by chronic lung diseases.