Stratification of pre-COPD by lung volume indices creates distinct proteomic profiles in COPDGene cohort

<bold>Rationale-</bold> Among tobacco-exposed persons with preserved spirometry (<bold>TEPS</bold>), TLC and FRC/TLC stratification can identify lung volume-based phenotypes with distinct radiographic features and clinical trajectories. <bold>Objective-</bold> Determine the biological underpinnings of the observed lung volume-based phenotypes in TEPS. <bold>Methods-</bold> We examined peripheral blood proteomic data (SomaScan) for mutually exclusive subgroups of TEPS with high TLC but not high FRC/TLC (TLC^high) <italic>vs.</italic> those with high FRC/TLC but not high TLC (FRC/TLC^high) in the COPDGene cohort, as described by Zeng et al. <italic>ERJ Open Res 2023</italic>, with adjustment for covariates and performed pathway enrichment analysis. <bold>Results-</bold> Compared to the TLC^high group (n=610), 50 proteins were upregulated and 70 were downregulated in the FRC/TLC^high group (n=610) (FDR<0.05). Several immunomodulatory mediators related to COPD were differentially expressed including sRAGE, CCL15, CCL16, CCL23, CCL25, SIGLEC-9 & ICAM-1 (<bold>Fig.</bold>). The differential expressions of the proteins implied involvement of multiple pro-inflammatory pathways including immune cell signaling, trafficking, and activation, as well as secretory, hyperplastic, and apoptotic pathways likely involved in COPD pathogenesis. <bold>Discussion-</bold> Lung volume-based stratification by FRC/TLC <italic>vs.</italic> TLC appears to distinguish biological endotypes in pre-COPD and may be a promising approach for understanding COPD heterogeneity in early disease. <fig><object-id>erj;64/suppl_68/PA4837/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig>