A bronchial gene signature specific for severe COPD that is retained in the nose.

Introduction: A subset of COPD patients develops advanced disease with severe airflow obstruction, hyperinflation and extensive emphysema. We propose that the pathogenesis in these patients differs from mild-moderate COPD and is reflected by bronchial gene expression. The aim of the present study was to identify a unique bronchial epithelial gene signature for severe COPD patients.
Methods: We obtained RNA sequencing data from bronchial brushes from 123 ex-smokers with severe COPD, 23 with mild-moderate COPD and 23 non-COPD controls. We identified genes specific to severe COPD by comparing severe COPD to non-COPD controls, followed by removing genes that were also differentially expressed between mild-moderate COPD and non-COPD controls. Next, we performed a pathway analysis on these genes and evaluated whether this signature is retained in matched nasal brushings.
Results: We identified 219 genes uniquely differentially expressed in severe COPD. Interaction network analysis identified VEGFA and FN1 as the key genes with the most interactions. Genes were involved in extracellular matrix regulation, collagen binding and the immune response. Of interest were 10 genes ( VEGFA , DCN , SPARC , COL6A2 , MGP , CYR61 , ANXA6 , LGALS1 , C1QA and C1QB ) directly connected to fibronectin 1 ( FN1 ). Most of these genes were lower expressed in severe COPD and showed the same effect in nasal brushings.
Conclusions: We found a unique severe COPD bronchial gene signature with key roles for VEGFA and FN1 , which was retained in the upper airways. This supports the hypothesis that severe COPD, at least partly, comprises a different pathology and supports the potential for biomarker development based on nasal brushes in COPD.
Competing Interests: Conflict of interest: W. Timens declares consultancy payments to their institution from Merck Sharp & Dohme and Bristol Myers Squibb, in the 36 months prior to manuscript submission; as well as board membership of the Dutch Society of Pathology and membership of the Council for Research and Innovation of the Federation of Medical Specialists. Conflict of interest: D-J. Slebos declares grants or contracts to their institution from the following US companies in the 36 months prior to manuscript submission: PulmonX Corp., PneumRx/BTG/Boston Scientific, FreeFlowMedical, Nuvaira, PulmAir, GALA, CSA Medical and Apreo; consulting fees paid to their institution from PulmonX Corp., PneumRx/BTG/Boston Scientific, Nuvaira and Apreo; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from PulmonX Corp, PneumRx/BTG/Boston Scientific and Nuvaira; support for attending meeting and/or travel from PulmonX Corp., PneumRx/BTG/Boston Scientific and Nuvaira; and receipt by their institution of study material/devices from PulmonX Corp., PneumRx/BTG/Boston Scientific, FreeFlowMedical, Nuvaira, PulmAir, GALA and CSA Medical, all in the 36 months prior to manuscript submission. Conflict of interest: D.F. Choy is an employee of Genentech, Inc., a member of the Roche Group, and is a co-inventor, as part of that employment, for pending patents related to the diagnosis and treatment of chronic respiratory diseases. They also hold stocks and/or options in Roche. Conflict of interest: A. Chakrabarti is an employee of Genentech, Inc., a member of the Roche Group. Conflict of interest: M. Grimbaldeston is an employee of Genentech, Inc., a member of the Roche Group, and has received stock options. Conflict of interest: C.M. Rosenberger is an employee of Genentech, Inc., a member of the Roche Group, and has received support for attending conferences from their employer. They hold stocks and stock options in Roche. Conflict of interest: C-A. Brandsma declares a research grant from Genentech, related to the current manuscript. Conflict of interest: M. van den Berge declares a research grant from Genentech, related to the current manuscript. Conflict of interest: All other authors declare no competing interests.
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