Bronchial gene expression signature associated with rate of subsequent FEV₁ decline in individuals with and at risk of COPD.

Abstract

COPD is characterised by progressive lung function decline. Leveraging prior work demonstrating bronchial airway COPD-associated gene expression alterations, we sought to determine if there are alterations associated with differences in the rate of FEV₁ decline. We examined gene expression among ever smokers with and without COPD who at baseline had bronchial brushings profiled by Affymetrix microarrays and had longitudinal lung function measurements (n=134; mean follow-up=6.38±2.48 years). Gene expression profiles associated with the rate of FEV₁ decline were identified by linear modelling. Expression differences in 171 genes were associated with rate of FEV₁ decline (false discovery rate <0.05). The FEV₁ decline signature was replicated in an independent dataset of bronchial biopsies from patients with COPD (n=46; p=0.018; mean follow-up=6.76±1.32 years). Genes elevated in individuals with more rapid FEV₁ decline are significantly enriched among the genes altered by modulation of XBP1 in two independent datasets (Gene Set Enrichment Analysis (GSEA) p<0.05) and are enriched in mucin-related genes (GSEA p<0.05). We have identified and replicated an airway gene expression signature associated with the rate of FEV₁ decline. Aspects of this signature are related to increased expression of XBP1-regulated genes, a transcription factor involved in the unfolded protein response, and genes related to mucin production. Collectively, these data suggest that molecular processes related to the rate of FEV₁ decline can be detected in airway epithelium, identify a possible indicator of FEV₁ decline and make it possible to detect, in an early phase, ever smokers with and without COPD most at risk of rapid FEV₁ decline.