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A transcriptomics study of hereditary angioedema attacks

  • Author Footnotes
    ∗ G. Castellano, C. Divella, and F. Sallustio contributed equally to this work.
    Giuseppe Castellano
    Correspondence
    Corresponding author: Giuseppe Castellano, MD, PhD, Nephrology Unit, Department of Emergency and Organ Transplantation, University “Aldo Moro,” Piazza G. Cesare 11, 70124 Bari, Italy.
    Footnotes
    ∗ G. Castellano, C. Divella, and F. Sallustio contributed equally to this work.
    Affiliations
    Nephrology Unit, Department of Emergency and Organ Transplantation, University “Aldo Moro,” and the Center for Diagnosis and Treatment of Hereditary Angioedema, Bari, Italy
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  • Author Footnotes
    ∗ G. Castellano, C. Divella, and F. Sallustio contributed equally to this work.
    Chiara Divella
    Footnotes
    ∗ G. Castellano, C. Divella, and F. Sallustio contributed equally to this work.
    Affiliations
    Nephrology Unit, Department of Emergency and Organ Transplantation, University “Aldo Moro,” and the Center for Diagnosis and Treatment of Hereditary Angioedema, Bari, Italy
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  • Author Footnotes
    ∗ G. Castellano, C. Divella, and F. Sallustio contributed equally to this work.
    Fabio Sallustio
    Footnotes
    ∗ G. Castellano, C. Divella, and F. Sallustio contributed equally to this work.
    Affiliations
    Nephrology Unit, Department of Emergency and Organ Transplantation, University “Aldo Moro,” and the Center for Diagnosis and Treatment of Hereditary Angioedema, Bari, Italy

    Department of Basic Medical Sciences, Neuroscience and Sense Organs, University “Aldo Moro,” Bari, Italy
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  • Vincenzo Montinaro
    Affiliations
    Nephrology Unit, Department of Emergency and Organ Transplantation, University “Aldo Moro,” and the Center for Diagnosis and Treatment of Hereditary Angioedema, Bari, Italy
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  • Claudia Curci
    Affiliations
    Nephrology Unit, Department of Emergency and Organ Transplantation, University “Aldo Moro,” and the Center for Diagnosis and Treatment of Hereditary Angioedema, Bari, Italy
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  • Andrea Zanichelli
    Affiliations
    Department of Biomedical and Clinical Sciences, Luigi Sacco Hospital, University of Milan, Milan, Italy
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  • Erika Bonanni
    Affiliations
    Department of Biomedical and Clinical Sciences, Luigi Sacco Hospital, University of Milan, Milan, Italy
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  • Chiara Suffritti
    Affiliations
    Department of Biomedical and Clinical Sciences, Luigi Sacco Hospital, University of Milan, Milan, Italy
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  • Sonia Caccia
    Affiliations
    Department of Biomedical and Clinical Sciences, Luigi Sacco Hospital, University of Milan, Milan, Italy
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  • Fleur Bossi
    Affiliations
    Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy
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  • Anna Gallone
    Affiliations
    Department of Basic Medical Sciences, Neuroscience and Sense Organs, University “Aldo Moro,” Bari, Italy
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  • Author Footnotes
    ‡ F. P. Schena, L. Gesualdo, and M. Cicardi contributed equally to this work as senior authors.
    Francesco Paolo Schena
    Footnotes
    ‡ F. P. Schena, L. Gesualdo, and M. Cicardi contributed equally to this work as senior authors.
    Affiliations
    University of Bari and Fondazione Schena, Valenzano, Bari, Italy
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  • Author Footnotes
    ‡ F. P. Schena, L. Gesualdo, and M. Cicardi contributed equally to this work as senior authors.
    Loreto Gesualdo
    Footnotes
    ‡ F. P. Schena, L. Gesualdo, and M. Cicardi contributed equally to this work as senior authors.
    Affiliations
    Nephrology Unit, Department of Emergency and Organ Transplantation, University “Aldo Moro,” and the Center for Diagnosis and Treatment of Hereditary Angioedema, Bari, Italy
    Search for articles by this author
  • Author Footnotes
    ‡ F. P. Schena, L. Gesualdo, and M. Cicardi contributed equally to this work as senior authors.
    Marco Cicardi
    Footnotes
    ‡ F. P. Schena, L. Gesualdo, and M. Cicardi contributed equally to this work as senior authors.
    Affiliations
    Department of Biomedical and Clinical Sciences, Luigi Sacco Hospital, University of Milan, Milan, Italy
    Search for articles by this author
  • Author Footnotes
    ∗ G. Castellano, C. Divella, and F. Sallustio contributed equally to this work.
    ‡ F. P. Schena, L. Gesualdo, and M. Cicardi contributed equally to this work as senior authors.

      Background

      Hereditary angioedema (HAE) caused by C1-inhibitor deficiency is a lifelong illness characterized by recurrent acute attacks of localized skin or mucosal edema. Activation of the kallikrein/bradykinin pathway at the endothelial cell level has a relevant pathogenetic role in acute HAE attacks. Moreover, other pathways are involved given the variable clinical expression of the disease in different patients.

      Objective

      We sought to explore the involvement of other putative genes in edema formation.

      Methods

      We performed a PBMC microarray gene expression analysis on RNA isolated from patients with HAE during an acute attack and compared them with the transcriptomic profile of the same patients in the remission phase.

      Results

      Gene expression analysis identified 23 genes significantly modulated during acute attacks that are involved primarily in the natural killer cell signaling and leukocyte extravasation signaling pathways. Gene set enrichment analysis showed a significant activation of relevant biological processes, such as response to external stimuli and protein processing (q < 0.05), suggesting involvement of PBMCs during acute HAE attacks. Upregulation of 2 genes, those encoding adrenomedullin and cellular receptor for urokinase plasminogen activator (uPAR), which occurs during an acute attack, was confirmed in PBMCs of 20 additional patients with HAE by using real-time PCR. Finally, in vitro studies demonstrated the involvement of uPAR in the generation of bradykinin and endothelial leakage.

      Conclusions

      Our study demonstrates the increase in levels of adrenomedullin and uPAR in PBMCs during an acute HAE attack. Activation of these genes usually involved in regulation of vascular tone and in inflammatory response might have a pathogenic role by amplifying bradykinin production and edema formation in patients with HAE.

      Key words

      Abbreviations used:

      ADM (Adrenomedullin), C1-INH (C1 inhibitor protein), FC (Fold change), FDR (False discovery rate), GSEA (Gene set enrichment analysis), HAE (Hereditary angioedema), HAE-A (HAE caused by C1-INH deficiency during the acute attack), HAE-R (HAE caused by C1-INH deficiency during the remission phase), HS (Healthy subject), uPA (Urokinase plasminogen activator), uPAR (Cellular receptor for urokinase plasminogen activator)
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