Proteomic biomarkers of emphysema-predominant and non-emphysema-predominant chronic obstructive pulmonary disease
Yuhang Zhang, Peter J. Castaldi, Russell P. Bowler, Katherine Pratte, Gregory L. Kinney, Kendra A. Young, Heena Rijhwani, Sharon M. Lutz, Craig P. Hersh, Michael H. Cho, Jarrett D. Morrow, Edwin K. Silverman
Abstract
BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a complex and heterogeneous disease. Emphysema-predominant and non-emphysema predominant COPD are two major disease subtypes capturing important aspects of COPD heterogeneity. Molecular differences between these COPD subtypes are unknown. METHODS: We assessed plasma proteomic associations (using SomaScan) with emphysema-predominant vs. non-emphysema predominant COPD subtypes in COPDGene; replication of significant associations was performed in SPIROMICS. We performed pathway analyses on COPD subtype plasma proteomic associations and used weighted gene correlation network analysis to find COPD subtype-associated protein correlation networks. We tested previously reported COPD genetic variants for association with COPD subtypes and COPD subtype-associated proteomic biomarkers. FINDINGS: One hundred and twenty-four proteins were significantly associated with COPD subtypes in COPDGene, with 64 proteins (65 SOMAmers) validated in SPIROMICS. Higher correlations were observed between proteomic biomarkers with greater expression levels in non-emphysema predominant participants with COPD. Cell adhesion, collagen-containing extracellular matrix, and epithelial mesenchymal transition were biological pathways enriched for COPD subtype proteomic associations. One COPD subtype-associated correlation network module was identified, including highly connected proteomic biomarkers like PXDN and EFNA2. We observed significant genetic effects on COPD subtypes for rs2579762 in LRMDA and on COPD subtype-associated proteomic biomarkers including sRAGE and Ganglioside GM2 Activator. INTERPRETATION: We identified and replicated multiple plasma proteomic biomarkers associated with emphysema-predominant vs. non-emphysema predominant COPD. Pathway analyses, correlation-based network analyses, and genetic association analyses of these proteins may provide insight into the molecular heterogeneity of COPD. FUNDING: National Heart, Lung, and Blood Institute (NIH).