Identifying a gene expression signature of frequent COPD exacerbations in peripheral blood using network methods

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.

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“…Gene-based coexpression network analyses together with expression single nucleotide polymorphism (eSNP) provide a powerful framework by pinpointing GWAS loci for eSNPs and mapping these GWAS hit genes to relevant modules/interactome representing disease-driven functional pathways (13,70). Bunyavanich et al (70) report mitochondria module from CD41+ lymphocytes gene expression data, showing an effect of the GWAS hits.…”

“…In the absence of such genotype data, coexpression network analyses alone can further provide meaningful interactomes of genes associated to asthma symptoms. Morrow et al (13) report putative hub genes from top five modules mostly associated with COPD exacerbation, including IGHM, KLRD1, AFF3, GPR56, GBP1, and GBP5. These genes are proposed as potential key regulators of the underlying functional pathways of B-cell receptor signaling pathway, protein ubiquitination, and cell adhesion molecules (13).…”

“…GSEA does limit the discovery of critical regulators within the context of known pathways only. It is often accompanied by coexpression network analyses to perform unsupervised module detection and to identify enriched pathways in these modules to further guide the data inference (12,13,70).…”

“…Current paradigm of the asthma development involves intricate interactions between host genetics (8) and environmental stressors (9). Before and first few years of life is likely to be particularly critical period during which epigenetic (9,10), metabolomic (11), and transcriptomic (12)(13)(14) signaling mechanisms influence the robustness of the host's underlying immune susceptibility (15).…”

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“…To characterise this heterogeneity at the molecular level, several studies have already used a number of different systems approaches. 1) WGCNA and GSEA showed that a molecular signature composed of gene modules related to B-cell activity, NK-cell activity or viral infection cellular markers might be detectable in peripheral blood months following COPD exacerbations [90]. 2) XUE et al [91] used other network-centric procedures to reveal an unexpected loss of inflammatory signature in COPD patients, as well as an activation-independent core signature for human and murine macrophages.…”