title: Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells.
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.
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Abramson Research Center Suite 1216, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: K.G. Jebsen Inflammation Research Centre, Division of Cancer Medicine, Surgery and Transplantation, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, 0424 Oslo, Norway.
authors.forename: Silje F
authors.initials: SF
authors.lastname: Jørgensen
authors.affiliation: 1] Center for Applied Genomics, Children's Hospital of Philadelphia, Abramson Research Center Suite 1216, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA [2] Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: S Melkorka
authors.initials: SM
authors.lastname: Maggadottir
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Abramson Research Center Suite 1216, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Bakay
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Warnatz
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Abramson Research Center Suite 1216, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Glessner
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Abramson Research Center Suite 1216, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Pandey
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Salzer
authors.affiliation: Clinic for Immunology and Rheumatology, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Reinhold E
authors.initials: RE
authors.lastname: Schmidt
authors.affiliation: Division of Pediatric Allergy and Immunology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Perez
authors.affiliation: Department of Medicine, Institute of Immunology, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Resnick
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Sigune
authors.initials: S
authors.lastname: Goldacker
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Mary
authors.initials: M
authors.lastname: Buchta
authors.affiliation: Clinic for Immunology and Rheumatology, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Witte
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, SE-17176 Stockholm, Sweden.
authors.forename: Leonid
authors.identifier: 0000000329505670
authors.initials: L
authors.lastname: Padyukov
authors.affiliation: 1] Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway [2] Department of Immunology and Transfusion Medicine, St Olavs Hospital, NO-7006 Trondheim, Norway.
authors.forename: Vibeke
authors.initials: V
authors.lastname: Videm
authors.affiliation: 1] K.G. Jebsen Inflammation Research Centre, Division of Cancer Medicine, Surgery and Transplantation, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, 0424 Oslo, Norway [2] Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Trine
authors.initials: T
authors.lastname: Folseraas
authors.affiliation: Clinic for Immunology and Rheumatology, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Faranaz
authors.initials: F
authors.lastname: Atschekzei
authors.affiliation: 1] Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, 48105 USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Rajan P
authors.initials: RP
authors.lastname: Nair
authors.affiliation: 1] Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany [2] Department of Neurology, MRI, Technische Universität München, 81675 München, Germany [3] SyNergy Munich Cluster for Systems Neurology, Ismaninger Str. 22, 81675 München, Germany [4] Stanford Center for Sleep Sciences and Medicine, 3165 Porter Drive, Palo Alto, CA 94301, USA.
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
authors.affiliation: 1] Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany [2] Research Unit of Molecular Epidemiology, German Research Center for Environmental Health, 85764 Neuherberg, Germany [3] Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany [2] Department of Genomics, Life and Brain Center, University of Bonn, 53127 Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Department of Hepatology and Gastroenterology, Charité, Campus Mitte, 14163 Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Büning
authors.affiliation: University Hospital Munich-Grosshadern, Department of Medicine II, Marchioninistr. 15, D-81377 Munich, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Brand
authors.affiliation: 1] Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA [2] Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia,Pennsylvania 19104, USA.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Sullivan
authors.affiliation: Section of Immunology, Allergy and Rheumatology, Department of Pediatric Medicine, Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.affiliation: 1] K.G. Jebsen Inflammation Research Centre, Division of Cancer Medicine, Surgery and Transplantation, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, 0424 Oslo, Norway [2] Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, 0424 Oslo, Norway.
authors.forename: Børre
authors.initials: B
authors.lastname: Fevang
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Institute of Epidemiology and Biobank Popgen, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.affiliation: 1] K.G. Jebsen Inflammation Research Centre, Division of Cancer Medicine, Surgery and Transplantation, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, 0424 Oslo, Norway [2] Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, 0424 Oslo, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.affiliation: Department of Clinical Immunology, Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Chapel
authors.affiliation: Department of Medicine, Institute of Immunology, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cunningham-Rundles
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: 1] K.G. Jebsen Inflammation Research Centre, Division of Cancer Medicine, Surgery and Transplantation, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, 0424 Oslo, Norway [2] Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, 0424 Oslo, Norway [3] Institute of Clinical Medicine, University of Oslo, 0424 Oslo, Norway.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.affiliation: 1] Center for Applied Genomics, Children's Hospital of Philadelphia, Abramson Research Center Suite 1216, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA [2] Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA [3] The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska University Hospital, Huddinge, SE-14186 Stockholm, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Hammarström
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany.
authors.forename: Eva
authors.identifier: 0000000329143382
authors.initials: E
authors.lastname: Ellinghaus
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D017074:Common Variable Immunodeficiency / Q000453:epidemiology / Q000235:genetics*; D005060:Europe / Q000453:epidemiology; D005786:Gene Expression Regulation / Q000502:physiology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D016015:Logistic Models; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D013154:Spleen / Q000166:cytology; D014481:United States / Q000453:epidemiology
chemical_list: C522505:CLEC16A protein, human; C000591253:CLEC16A protein, mouse; D037181:Lectins, C-Type; D009004:Monosaccharide Transport Proteins