Abstract
BackgroundThe molecular basis of airway remodeling in chronic obstructive pulmonary disease remains poorly understood. We identified gene expression signatures associated with chest CT scan airway measures to understand molecular pathways associated with airway disease.MethodsIn 2,396 subjects in the COPDGene Study, we examined the relationship between quantitative CT airway phenotypes and blood transcriptomes to identify airway disease-specific genes and to define an airway wall thickness (AWT) gene set score. Multivariable regression analyses were performed to identify associations of the AWT score with clinical phenotypes, bronchial gene expression and genetic variants.ResultsType 1 interferon induced genes were consistently associated with airway wall thickness, Pi10, and wall area percent, with the strongest enrichment in airway wall thickness. A score derived from 18 genes whose expression was associated with AWT was associated with COPD-related phenotypes including reduced lung function (FEV1% predicted −3.4, p<0.05) and increased exacerbations (incidence rate ratio 1.6, p<0.05). The AWT score was reproducibly associated with airway wall thickness in bronchial samples from 23 subjects (beta 3.22, p<0.05). The blood AWT score was associated with genetic variant rs876039, an expression quantitative trait locus (eQTL) for IKZF1, a gene which regulates interferon signaling and is associated with inflammatory diseases.ConclusionA gene expression signature with interferon stimulated genes from peripheral blood and bronchial brushings is associated with CT airway wall thickness, lung function, and exacerbations. Shared genes and genetic associations suggest viral responses and/or autoimmune dysregulation as potential underlying mechanisms of airway disease in COPD.
Funder
National Heart, Lung, and Blood Institute
Publisher
European Respiratory Society (ERS)
Subject
Pulmonary and Respiratory Medicine
Cited by
8 articles.
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