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

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 Goldacker, Mary Buchta, Torsten Witte, Leonid Padyukov, Vibeke Videm, Trine Folseraas, Faranaz Atschekzei, James T. Elder, Rajan P. Nair, Juliane Winkelmann, Christian Gieger, Markus M. Nöthen, Carsten Büning, Stephan Brand, Kathleen E. Sullivan, Jordan S. Orange, Børre Fevang, Stefan Schreiber, Wolfgang Lieb, Pål Aukrust, Helen Chapel, Charlotte Cunningham-Rundles, Andre Franke, Tom H. Karlsen, Bodo Grimbacher, Hakon Hakonarson (), Lennart Hammarström and Eva Ellinghaus
Additional contact information
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
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
Trine Folseraas: K.G. Jebsen Inflammation Research Centre, Surgery and Transplantation, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet
Faranaz Atschekzei: Clinic for Immunology and Rheumatology, Hannover Medical School
James T. Elder: University of Michigan
Rajan P. Nair: University of Michigan
Juliane Winkelmann: Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health
Christian Gieger: Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
Markus M. Nöthen: Institute of Human Genetics, University of Bonn
Carsten Büning: Charité, Campus Mitte
Stephan Brand: University Hospital Munich-Grosshadern
Kathleen E. Sullivan: The Children’s Hospital of Philadelphia
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
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
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
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
Lennart Hammarström: Karolinska University Hospital
Eva Ellinghaus: Institute of Clinical Molecular Biology, Christian-Albrechts-University

Nature Communications, 2015, vol. 6, issue 1, 1-7

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7804

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