Abstract
BackgroundExacerbations of chronic obstructive pulmonary disease (COPD), characterized by acute deterioration in symptoms, may be due to bacterial or viral infections, environmental exposures, or unknown factors. Exacerbation frequency may be a stable trait in COPD patients, which could imply genetic susceptibility. Observing the genes, networks, and pathways that are up- and down-regulated in COPD patients with differing susceptibility to exacerbations will help to elucidate the molecular signature and pathogenesis of COPD exacerbations.MethodsGene expression array and plasma biomarker data were obtained using whole-blood samples from subjects enrolled in the Treatment of Emphysema With a Gamma-Selective Retinoid Agonist (TESRA) study. Linear regression, weighted gene co-expression network analysis (WGCNA), and pathway analysis were used to identify signatures and network sub-modules associated with the number of exacerbations within the previous year; other COPD-related phenotypes were also investigated.ResultsIndividual genes were not found to be significantly associated with the number of exacerbations. However using network methods, a statistically significant gene module was identified, along with other modules showing moderate association. A diverse signature was observed across these modules using pathway analysis, marked by differences in B cell and NK cell activity, as well as cellular markers of viral infection. Within two modules, gene set enrichment analysis recapitulated the molecular signatures of two gene expression experiments; one involving sputum from asthma exacerbations and another involving viral lung infections. The plasma biomarker myeloperoxidase (MPO) was associated with the number of recent exacerbations.ConclusionA distinct signature of COPD exacerbations may be observed in peripheral blood months following the acute illness. While not predictive in this cross-sectional analysis, these results will be useful in uncovering the molecular pathogenesis of COPD exacerbations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-014-0072-y) contains supplementary material, which is available to authorized users.
Highlights
Exacerbations of chronic obstructive pulmonary disease (COPD), characterized by acute deterioration in symptoms, may be due to bacterial or viral infections, environmental exposures, or unknown factors
Despite the fact that gene expression data from lung tissues should provide greater sensitivity to detect the molecular signature of COPD exacerbations, COPD is a systemic disease, and blood is more accessible for genomics and biomarkers studies in large scale clinical trials and potentially in clinical practice than is lung tissue samples
Pathway analysis We examined enrichment of curated gene sets from the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases in the gene groups from association tests or the co-expression modules using a hypergeometric test in the R Bioconductor package GeneAnswers [22]
Summary
Exacerbations of chronic obstructive pulmonary disease (COPD), characterized by acute deterioration in symptoms, may be due to bacterial or viral infections, environmental exposures, or unknown factors. Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow obstruction accompanied by chronic inflammation. It is one of the leading causes of morbidity and mortality worldwide and is often caused by environmental exposure such as cigarette smoke [1]. COPD exacerbations, periods of acute deterioration, are a Morrow et al BMC Medical Genomics (2015) 8:1 supporting genetic susceptibility, and loci associated with COPD exacerbations have been identified [5,6]. Despite the fact that gene expression data from lung tissues should provide greater sensitivity to detect the molecular signature of COPD exacerbations, COPD is a systemic disease, and blood is more accessible for genomics and biomarkers studies in large scale clinical trials and potentially in clinical practice than is lung tissue samples. Gene expression in peripheral blood has been associated with COPD and related phenotypes [12]
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