Molecular Determinants of Lung Function Decline: A Multi- Level Analysis of Gene Expression

Background: Chronic obstructive pulmonary disease (COPD) is characterized by progressive lung function decline, commonly measured by forced expiratory volume in one second (FEV ₁ ). Uncovering the genetic basis of FEV ₁ decline is essential for understanding COPD pathophysiology and for developing therapies. We hypothesized that gene expression patterns in inflammatory pathways are associated with FEV ₁ decline. Methods: We analyzed whole blood RNA-sequencing data from the 5 (n = 4,147) and 10 year visits (n = 435) in the COPDGene Study. Gene expression was assessed in three analyses: cross-sectional associations with FEV ₁ at two separate time points, association between year 5 gene expression and FEV ₁ changes from year 5–10, and longitudinal changes in both gene expression and FEV ₁ . A gene signature derived from the 5-year visit was linked to FEV ₁ decline across three intervals (baseline to 5 years, 5 to 10 years, and baseline to 10 years) and tested for validation in the ECLIPSE study. Results: Distinct gene sets emerged in the three analyses (Cross-sectional: 961 genes; FEV ₁ Change: 179; Longitudinal: 532). Only two genes ( NOV and AC009404.2 ) overlapped across all analyses, while unique genes (e.g., MMP9 , IL1RL1 , and CHI3L1 ) were context-specific. Pathway analysis of genes from the longitudinal analysis highlighted oxidative stress and immune processes. A 20-gene signature was derived, including 17 genes positively and three negatively associated with FEV ₁ . These signatures were significantly associated with FEV ₁ -related traits in COPDGene and ECLIPSE. Conclusions: These findings reveal molecular markers of FEV ₁ decline, offering insights into COPD pathophysiology and potential therapeutic targets.