Genetic Determinants of Lung function Decline: A Multi-Level Analysis of Gene Expression

Background: Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation and FEV1 decline. Understanding the genetic basis of FEV1 change is vital for unraveling COPD pathophysiology and developing therapies. We hypothesized that gene expression in inflammatory pathways associates with FEV1 change in COPD.
Methods: RNA-sequencing data from 5- and 10-year follow-up visits in the COPDGene Study were used. We employed linear regression models (N=435) to assess gene expression and FEV1 associations at both population (cross-sectional) and individual (longitudinal) levels, using a p-value < 0.05. An FEV1 change gene signature was generated from RNA-seq data at the 5-year visit and longitudinal phenotype across three intervals (baseline to 5-year, N=3850; 5-year to 10-year, N=2043; baseline to 10-year, N=2035). Results: Distinct gene expression results were found for each approach (Cross-sectional: 500, Longitudinal: 316). Key genes implicated in lung function, such as MMP9, IL1RL1, ALOX5AP, and OPTN, were identified. The FEV1 change gene signature was associated with COPD progression, exacerbations, and chest CT measures of airway wall thickness and emphysema. Conclusions: These findings highlight key genes linked to FEV1 decline, offering insights into COPD's genetic underpinnings and potential therapeutic targets.