Altered expression of miR-193b-3p, miR-202-5p and miR-331-3p in SEO-COPD lung tissue

Severe early onset (SEO-)COPD represents the most severe form of COPD that manifests at an early age. The molecular drivers of this subset of COPD are largely unclear. We previously identified a SEO-COPD gene signature related to B-cell immunity and extracellular matrix (ECM). Here we investigated differential miRNA expression to provide further insight in the molecular drivers of SEO-COPD. Small RNA sequencing was used to determine differential miRNA expression in peripheral lung tissue of SEO-COPD (n=18) and control (n=31) subjects. miRNAs that were also different between common COPD (n=21) and control were excluded. Differential miRNA expression was correlated with target gene expression obtained from matched RNAseq data, and pathway enrichment was assessed among the inversely correlated targets. We identified 3 SEO-COPD specific miRNAs; miR-193b-3p and miR-202-5p with higher and miR-331-3p with lower expression in SEO-COPD compared to control. MiR-193b-3p had 35 inversely correlated targets enriched for pathways related to vesicular transport and lysosomal activity, including gamma secretase-related genes NCSTN and APH1A. MiR-331-3p had 41 inversely correlated targets enriched for ECM pathways, including COL6A1, COL6A2 and ELN. miR-202-5p had no inversely correlated targets. Based on their target gene functions we propose a role for miR-193b-3p in altered vesical and lysosomal activity, and a regulatory role for miR-331-3p in aberrant ECM repair in SEO-COPD. By directly connecting differential miRNA expression to target gene expression we generated important new insights into the potential involvement of these miRNAs in SEO-COPD pathogenesis.