{
  "abstract": "Objective Severe early-onset-chronic obstructive pulmonary disease (SEO-COPD) represents the most severe form of COPD that manifests at an earlier age than common COPD. We hypothesise that this is driven by a partially different disease pathogenesis and investigated whether SEO-COPD has a distinct gene and miRNA expression profile.Methods RNA and small RNA sequencing was performed on lung tissue from 18 SEO-COPD, 22 common COPD and 32 non-COPD control subjects. Differential gene expression analysis was performed to identify SEO-COPD-specific genes and miRNA signatures. This was followed by gene set enrichment analysis, pathway enrichment, genome-wide association studies catalog interrogation, expression quantitative trait loci (eQTL) analysis, immunohistochemical validation, mRNA-miRNA integration and cellular deconvolution.Results We identified 105 SEO-COPD specific genes and three SEO-COPD specific miRNAs. Pathway analysis showed enrichment of B-cell-mediated adaptive immunity, chemotaxis and extracellular matrix (ECM) pathways among genes upregulated in SEO-COPD, including the B-cell marker CD79A and ECM component FBLN1 as leading-edge genes. More CD79A-positive infiltrates were observed in SEO-COPD lung tissue compared with control. For 15 SEO-COPD genes, COPD- or lung function-associated single nucleotide polymorphisms were identified, while eQTLs were identified for six SEO-COPD-associated genes. mRNA-miRNA integration identified miR331-3p as a potential regulator of the ECM-related gene expression changes in SEO-COPD.Conclusions The identified lung tissue gene and miRNA expression profiles for SEO-COPD support the presence of a distinct pathogenetic phenotype of SEO-COPD characterised by B-cell-mediated immunity, ECM dysregulation as well as genetic pre-disposition.",
  "authors": [
    {
      "affiliations": [
        "Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands",
        "Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, Groningen, The Netherlands"
      ],
      "name": "Nicolaas Jacobus Bekker"
    },
    {
      "affiliations": [
        "Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands",
        "Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, Groningen, The Netherlands",
        "Respiratory Bioinformatics and Molecular Biology, University of Technology Sydney, Sydney, New South Wales, Australia"
      ],
      "name": "Johannes LL Van Nijnatten"
    },
    {
      "affiliations": [
        "Department of Analytical Biochemistry, University of Groningen, Groningen Research Institute of Pharmacy, Groningen, Groningen, The Netherlands"
      ],
      "name": "Peter L. Horvatovich"
    },
    {
      "affiliations": [
        "Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands"
      ],
      "name": "Justina C Wolters"
    },
    {
      "affiliations": [
        "Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, Groningen, The Netherlands",
        "European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, The Netherlands"
      ],
      "name": "Victor Guryev"
    },
    {
      "affiliations": [
        "Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, Groningen, The Netherlands",
        "Department of Pulmonary Diseases, University Medical Center Groningen, Groningen, The Netherlands"
      ],
      "name": "Tatiana Karp"
    },
    {
      "affiliations": [
        "Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands"
      ],
      "name": "Wierd Kooistra"
    },
    {
      "affiliations": [
        "Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands"
      ],
      "name": "Marjan Reinders-Luinge"
    },
    {
      "affiliations": [
        "Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands",
        "Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, Groningen, The Netherlands"
      ],
      "name": "Roy R Woldhuis"
    },
    {
      "affiliations": [
        "Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands",
        "Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, Groningen, The Netherlands"
      ],
      "name": "Wim Timens"
    },
    {
      "affiliations": [
        "Respiratory Bioinformatics and Molecular Biology, University of Technology Sydney, Sydney, New South Wales, Australia"
      ],
      "name": "Alen Faiz"
    },
    {
      "affiliations": [
        "Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, Groningen, The Netherlands",
        "Department of Pulmonary Diseases, University Medical Center Groningen, Groningen, The Netherlands"
      ],
      "name": "Maarten van den Berge"
    },
    {
      "affiliations": [
        "Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands",
        "Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, Groningen, The Netherlands"
      ],
      "name": "Corry-Anke Brandsma"
    }
  ],
  "title": "Identification of distinct gene and miRNA expression profiles in severe early-onset COPD providing novel insights in disease pathogenesis",
  "uid": "994b716f-2ba2-5274-8d8d-6c64b076933c"
}