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Background: Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death and there is a huge unmet clinical need to identify disease biomarkers in peripheral blood. Compared to gene level differential expression approaches to identify gene signatures, network analyses provide a biologically intuitive approach which leverages the co-expression patterns in the transcriptome to identify modules of co-expressed genes.Methods: A weighted gene co-expression network analysis (WGCNA) was applied to peripheral blood transcriptome from 238 COPD subjects to discover co-expressed gene modules. We then determined the relationship between these modules and forced expiratory volume in 1 s (FEV1). In a second, independent cohort of 381 subjects, we determined the preservation of these modules and their relationship with FEV1. For those modules that were significantly related to FEV1, we determined the biological processes as well as the blood cell-specific gene expression that were over-represented using additional external datasets.Results: Using WGCNA, we identified 17 modules of co-expressed genes in the discovery cohort. Three of these modules were significantly correlated with FEV1 (FDR < 0.1). In the replication cohort, these modules were highly preserved and their FEV1 associations were reproducible (P < 0.05). Two of the three modules were negatively related to FEV1 and were enriched in IL8 and IL10 pathways and correlated with neutrophil-specific gene expression. The positively related module, on the other hand, was enriched in DNA transcription and translation and was strongly correlated to CD4+, CD8+ T cell-specific gene expression.Conclusions: Network based approaches are promising tools to identify potential biomarkers for COPD.Trial Registration: The ECLIPSE study was funded by GlaxoSmithKline, under ClinicalTrials.gov identifier NCT00292552 and GSK No. SCO104960. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death and there is a huge unmet clinical need to identify disease biomarkers in peripheral blood. Compared to gene level differential expression approaches to identify gene signatures, network analyses provide a biologically intuitive approach which leverages the co-expression patterns in the transcriptome to identify modules of co-expressed genes. Methods: A weighted gene co-expression network analysis (WGCNA) was applied to peripheral blood transcriptome from 238 COPD subjects to discover co-expressed gene modules. We then determined the relationship between these modules and forced expiratory volume in 1 s (FEV1). In a second, independent cohort of 381 subjects, we determined the preservation of these modules and their relationship with FEV1. For those modules that were significantly related to FEV1, we determined the biological processes as well as the blood cell-specific gene expression that were over-represented using additional external datasets. Results: Using WGCNA, we identified 17 modules of co-expressed genes in the discovery cohort. Three of these modules were significantly correlated with FEV1 (FDR < 0.1). In the replication cohort, these modules were highly preserved and their FEV1 associations were reproducible (P < 0.05). Two of the three modules were negatively related to FEV1 and were enriched in IL8 and IL10 pathways and correlated with neutrophil-specific gene expression. The positively related module, on the other hand, was enriched in DNA transcription and translation and was strongly correlated to CD4+, CD8+ T cell-specific gene expression. Conclusions: Network based approaches are promising tools to identify potential biomarkers for COPD. Trial registration The ECLIPSE study was funded by GlaxoSmithKline, under ClinicalTrials.gov identifier NCT00292552 and GSK No. SCO104960 Electronic supplementary material The online version of this article (doi:10.1186/s12931-017-0558-1) contains supplementary material, which is available to authorized users.

Background Extracellular ATP is a pro-inflammatory molecule released by damaged cells. Regulatory T cells (Treg) can suppress inflammation by hydrolysing this molecule via ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1), also termed as CD39. Multiple studies have reported differences in CD39+ Treg percentages in diseases such as multiple sclerosis, Hepatitis B and HIV-1. In addition, CD39 polymorphisms have been implicated in immunephenotypes such as susceptibility to inflammatory bowel disease and AIDS progression. However none of the studies published so far has linked disease-associated variants with differences in CD39 Treg surface expression. This study aims at identifying variants affecting CD39 expression on Treg and at evaluating their association with allergic rhinitis, a disease characterized by a strong Treg involvement. Methods Cohorts consisting of individuals of different ethnicities were employed to identify any association of CD39 variants to surface expression. Significant variant(s) were tested for disease association in a published GWAS cohort by one-locus and two-locus genetic analyses based on logistic models. Further functional characterization was performed using existing microarray data and quantitative RT-PCR on sorted cells. Results Our study shows that rs7071836, a promoter SNP in the CD39 gene region, affects the cell surface expression on Treg cells but not on other CD39+ leukocyte subsets. Epistasis analysis revealed that, in conjunction with a SNP upstream of the FAM134B gene (rs257174), it increased the risk of allergic rhinitis (P = 1.98 × 10-6). As a promoter SNP, rs257174 controlled the expression of the gene in monocytes but, notably, not in Treg cells. Whole blood transcriptome data of three large cohorts indicated an inverse relation in the expression of the two proteins. While this observation was in line with the epistasis data, it also implied that a functional link must exist. Exposure of monocytes to extracellular ATP resulted in an up-regulation of FAM134B gene expression, suggesting that extracellular ATP released from damaged cells represents the connection for the biological interaction of CD39 on Treg cells with FAM134B on monocytes. Conclusions The interplay between promoter SNPs of CD39 and FAM134B results in an intercellular epistasis which influences the risk of a complex inflammatory disease. [ABSTRACT FROM AUTHOR]

Abstract: In this study a proteomic approach was used to define the protein content of matched samples of afferent prenodal lymph and plasma derived from healthy volunteers. The analysis was performed using two analytical methodologies coupled with nanoliquid chromatography-tandem mass spectrometry: one-dimensional gel electrophoresis (1DEF nanoLC Orbitrap–ESI–MS/MS), and two-dimensional fluorescence difference-in-gel electrophoresis (2D-DIGE nanoLC–ESI–MS/MS). The 253 significantly identified proteins (p<0.05), obtained from the tandem mass spectrometry data, were further analyzed with pathway analysis (IPA) to define the functional signature of prenodal lymph and matched plasma. The 1DEF coupled with nanoLC–MS–MS revealed that the common proteome between the two biological fluids (144 out of 253 proteins) was dominated by complement activation and blood coagulation components, transporters and protease inhibitors. The enriched proteome of human lymph (72 proteins) consisted of products derived from the extracellular matrix, apoptosis and cellular catabolism. In contrast, the enriched proteome of human plasma (37 proteins) consisted of soluble molecules of the coagulation system and cell–cell signaling factors. The functional networks associated with both common and source-distinctive proteomes highlight the principal biological activity of these immunologically relevant body fluids. [Copyright &y& Elsevier]