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Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells

Author

Listed:
  • Jin Li

    (Center for Applied Genomics, Children’s Hospital of Philadelphia, Abramson Research Center Suite 1216, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA)

  • Silje F. Jørgensen

    (K.G. Jebsen Inflammation Research Centre, Surgery and Transplantation, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet)

  • S Melkorka Maggadottir

    (Center for Applied Genomics, Children’s Hospital of Philadelphia, Abramson Research Center Suite 1216, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA
    The Children’s Hospital of Philadelphia)

  • Marina Bakay

    (Center for Applied Genomics, Children’s Hospital of Philadelphia, Abramson Research Center Suite 1216, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA)

  • Klaus Warnatz

    (Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, University of Freiburg)

  • Joseph Glessner

    (Center for Applied Genomics, Children’s Hospital of Philadelphia, Abramson Research Center Suite 1216, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA)

  • Rahul Pandey

    (Center for Applied Genomics, Children’s Hospital of Philadelphia, Abramson Research Center Suite 1216, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA)

  • Ulrich Salzer

    (Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, University of Freiburg)

  • Reinhold E. Schmidt

    (Clinic for Immunology and Rheumatology, Hannover Medical School)

  • Elena Perez

    (University of Miami Miller School of Medicine)

  • Elena Resnick

    (Institute of Immunology, Mount Sinai School of Medicine)

  • Sigune Goldacker

    (Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, University of Freiburg)

  • Mary Buchta

    (Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, University of Freiburg)

  • Torsten Witte

    (Clinic for Immunology and Rheumatology, Hannover Medical School)

  • Leonid Padyukov

    (Rheumatology Unit, Karolinska Institutet and Karolinska University Hospital Solna)

  • Vibeke Videm

    (Children's and Women’s Health, Norwegian University of Science and Technology
    St Olavs Hospital)

  • Trine Folseraas

    (K.G. Jebsen Inflammation Research Centre, Surgery and Transplantation, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet
    Norwegian PSC Research Center, Surgery and Transplantation, Oslo University Hospital)

  • Faranaz Atschekzei

    (Clinic for Immunology and Rheumatology, Hannover Medical School)

  • James T. Elder

    (University of Michigan
    Ann Arbor Veterans Affairs Hospital)

  • Rajan P. Nair

    (University of Michigan)

  • Juliane Winkelmann

    (Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health
    MRI, Technische Universität München
    SyNergy Munich Cluster for Systems Neurology
    Stanford Center for Sleep Sciences and Medicine)

  • Christian Gieger

    (Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
    Research Unit of Molecular Epidemiology, German Research Center for Environmental Health
    Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health)

  • Markus M. Nöthen

    (Institute of Human Genetics, University of Bonn
    Life and Brain Center, University of Bonn)

  • Carsten Büning

    (Charité, Campus Mitte)

  • Stephan Brand

    (University Hospital Munich-Grosshadern)

  • Kathleen E. Sullivan

    (The Children’s Hospital of Philadelphia
    The Perelman School of Medicine, University of Pennsylvania)

  • Jordan S. Orange

    (Section of Immunology, Allergy and Rheumatology, Texas Children’s Hospital)

  • Børre Fevang

    (K.G. Jebsen Inflammation Research Centre, Surgery and Transplantation, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet
    Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet)

  • Stefan Schreiber

    (Institute of Clinical Molecular Biology, Christian-Albrechts-University)

  • Wolfgang Lieb

    (Institute of Epidemiology and Biobank Popgen, Christian-Albrechts-University of Kiel)

  • Pål Aukrust

    (K.G. Jebsen Inflammation Research Centre, Surgery and Transplantation, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet
    Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet)

  • Helen Chapel

    (University of Oxford)

  • Charlotte Cunningham-Rundles

    (Institute of Immunology, Mount Sinai School of Medicine)

  • Andre Franke

    (Institute of Clinical Molecular Biology, Christian-Albrechts-University)

  • Tom H. Karlsen

    (K.G. Jebsen Inflammation Research Centre, Surgery and Transplantation, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet
    Norwegian PSC Research Center, Surgery and Transplantation, Oslo University Hospital
    Institute of Clinical Medicine, University of Oslo)

  • Bodo Grimbacher

    (Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, University of Freiburg)

  • Hakon Hakonarson

    (Center for Applied Genomics, Children’s Hospital of Philadelphia, Abramson Research Center Suite 1216, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA
    The Children’s Hospital of Philadelphia
    The Perelman School of Medicine, University of Pennsylvania)

  • Lennart Hammarström

    (Karolinska University Hospital)

  • Eva Ellinghaus

    (Institute of Clinical Molecular Biology, Christian-Albrechts-University)

Abstract

Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10,999 controls across 123,127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P=2.0 × 10−9) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P=4.8 × 10−16). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition.

Suggested Citation

  • Jin Li & Silje F. Jørgensen & S Melkorka Maggadottir & Marina Bakay & Klaus Warnatz & Joseph Glessner & Rahul Pandey & Ulrich Salzer & Reinhold E. Schmidt & Elena Perez & Elena Resnick & Sigune Goldac, 2015. "Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells," Nature Communications, Nature, vol. 6(1), pages 1-7, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7804
    DOI: 10.1038/ncomms7804
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