Airway gene expression in COPD is dynamic with inhaled corticosteroid treatment and reflects biological pathways associated with disease activity

Abstract

BackgroundA core feature of chronic obstructive pulmonary disease (COPD) is the accelerated decline in forced expiratory volume in one second (FEV1). The recent Groningen and Leiden Universities study of Corticosteroids in Obstructive Lung Disease (GLUCOLD) study suggested that particular phenotypes of COPD benefit from fluticasone±salmeterol by reducing the rate of FEV1 decline, yet the underlying mechanisms are unknown.MethodsWhole-genome gene expression profiling using the Affymetrix Gene ST array (V.1.0) was performed on 221 bronchial biopsies available from 89 COPD patients at baseline and after 6 and 30 months of fluticasone±salmeterol and placebo treatment in GLUCOLD.ResultsLinear mixed effects modelling revealed that the expression of 138 genes decreased, whereas the expression of 140 genes significantly upregulated after both 6 and 30 months of treatment with fluticasone±salmeterol versus placebo. A more pronounced treatment-induced change in the expression of 50 and 55 of these 278 genes was associated with a lower rate of decline in FEV1 and Saint George Respiratory Questionnaire, respectively. Genes decreasing with treatment were involved in pathways related to cell cycle, oxidative phosphorylation, epithelial cell signalling, p53 signalling and T cell signalling. Genes increasing with treatment were involved in pathways related to focal adhesion, gap junction and extracellular matrix deposition. Finally, the fluticasone-induced gene expression changes were enriched among genes that change in the airway epithelium in smokers with versus without COPD in an independent data set.ConclusionsThe present study suggests that gene expression in biological pathways of COPD is dynamic with treatment and reflects disease activity. This study opens the gate to targeted and molecular phenotype-driven therapy of COPD.

Asthma–COPD Overlap. Clinical Relevance of Genomic Signatures of Type 2 Inflammation in Chronic Obstructive Pulmonary Disease

“…We then studied the association of Th2 gene signatures with lung function in these cohorts. Finally, we determined whether a Th2 signature (T2S) score is associated with asthma-associated pathological features (e.g., lung tissue eosinophilia) and ICS responsiveness in a previously published randomized controlled trial of patients with COPD with no history of asthma (15).…”

Personalized Management of Chronic Obstructive Pulmonary Disease via Transcriptomic Profiling of the Airway and Lung

“…One of the more compelling findings of the airway gene expression study described above was the dynamic nature of the transcriptomic alterations post treatment with inhaled corticosteroids (34). Using Gene Set Enrichment Analysis (37), the 98-gene signature was found to be inversely correlated with genes that changed 30 months post treatment with fluticasone with or without salmeterol therapy within the GLUCOLD study, a cohort in which these therapies reduced the decline in lung function (19,34 (38). Together, these studies emphasize the key components of deriving and validating disease and disease subtype signatures, including the critical step of validation in samples from independent cohorts.…”

Clinical relevance of genomic signatures of type 2 inflammation in chronic obstructive pulmonary disease

“…Higher T2S scores correlated with increased airway wall eosinophil counts (p=0.003), blood eosinophil percentage (p=0.03), bronchodilator reversibility (p=0.01) and improvement in hyperinflation after corticosteroid treatment (p=0.019) in GLUCOLD. [4] Interestingly, from the same institute, Smolonska et al [7] recently performed genome-wide association studies for both asthma and COPD and could find no common single nucleotide polymorphisms that reached genome-wide significance. They did, however, suggest that although inflammatory processes differ in asthma and COPD, they are both mediated by the NF-kB pathway, and could therefore be driven by the same underlying genes.…”

“…[2] Tilley et al [3] reported on a 'COPD-like' small airway epithelial transcriptome; by identifying differentially expressed genes they could classify clinically healthy smokers into subgroups with lesser and greater responses to cigarette smoking. Following these results, whole-genome gene expression profiling done on bronchial biopsies from COPD patients treated with inhaled corticosteroids (ICS) in the GLUCOLD study, [4] showed that gene expression in biological pathways of COPD is dynamic with treatment and reflects disease activity.…”