Background 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.
Methods 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.
Results 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).
Conclusion 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.
- respiratory measurement
- airway epithelium
Data availability statement
Data are available in a public, open access repository. The data are available on GEO as GSE37147.
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MEL and KS are joint senior authors.
MEL and KS contributed equally.
Contributors KS, AS and MEL conceived the idea. KS, AS, MEL, MvdB, AF and GO provided guidance during the analysis. EJB, AF and KC performed the computational analysis. WT, PSH, SL, MvdB and AF collected the original data. GL, XX and YOA profiled the data. EJB drafted the manuscript and all the authors read and provided feedback.
Funding National Institutes of Health/National Heart, Lung, and Blood Institute (R01HL095388 and R01HL118542-01) and Dutch Longfonds Foundation (18.104.22.168JO).
Competing interests GO reports unrelated personal fees from AstraZeneca and grants from Janssen Pharmaceuticals. PSH reports unrelated grants from Boehringer Ingelheim and Galapagos. MvdB reports unrelated research grants from GlaxoSmithKline, TEVA Pharmaceuticals and Chiesi. AS reports unrelated founder’s equity from Metera Pharmaceuticals as well as grants and personal fees from Janssen Research and Development. KS reports grants from CHEST Foundation, unrelated grants from Lungevity Foundation Early Detection Award and royalties from UpToDate. MEL reports unrelated founder’s equity from Metera Pharmaceuticals and unrelated grants from Janssen Research and Development. WT reports unrelated personal fees from Pfizer, GSK, Roche Diagnostics/Ventana, Merck Sharp Dohme, Novartis, Lilly Oncology, Boehringer Ingelheim, AstraZeneca, Bristol-Myers-Squibb and AbbVie. KS, MEL and AS have US patent 9,677,138 issued. EJB, KS, MEL and AS have a relevant patent pending (application no. 62/916,431).
Provenance and peer review Not commissioned; externally peer reviewed.
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