Identification of biomarkers associated with clinical severity of chronic obstructive pulmonary disease.

We sought to identify the biomarkers related to the clinical severity of stage I to stage IV chronic obstructive pulmonary disease (COPD). Gene expression profiles from the blood samples of COPD patients at each of the four stages were acquired from the Gene Expression Omnibus Database (GEO, accession number: GSE54837). Genes showing expression changes among the different stages were sorted by soft clustering. We performed functional enrichment, protein-protein interaction (PPI), and miRNA regulatory network analyses for the differentially expressed genes. The biomarkers associated with the clinical classification of COPD were selected from logistic regression models and the relationships between TLR2 and inflammatory factors were verified in clinical blood samples by qPCR and ELISA. Gene clusters demonstrating continuously rising or falling changes in expression (clusters 1, 2, and 7 and clusters 5, 6, and 8, respectively) from stage I to IV were defined as upregulated and downregulated genes, respectively, and further analyzed. The upregulated genes were enriched in functions associated with defense, inflammatory, or immune responses. The downregulated genes were associated with lymphocyte activation and cell activation. TLR2, HMOX1, and CD79A were hub proteins in the integrated network of PPI and miRNA regulatory networks. TLR2 and CD79A were significantly correlated with clinical classifications. TLR2 was closely associated with inflammatory responses during COPD progression. Functions associated with inflammatory and immune responses as well as lymphocyte activation may play important roles in the progression of COPD from stage I to IV.