PMID- 25891430
OWN - NLM
STAT- MEDLINE
DCOM- 20160229
LR  - 20240323
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 6
DP  - 2015 Apr 20
TI  - Association of CLEC16A with human common variable immunodeficiency disorder and 
      role in murine B cells.
PG  - 6804
LID - 10.1038/ncomms7804 [doi]
AB  - 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 x 
      10(-9)) and confirm the previously reported human leukocyte antigen (HLA) 
      associations on chromosome 6p21 (rs1049225, P=4.8 x 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.
FAU - Li, Jin
AU  - Li J
AD  - Center for Applied Genomics, Children's Hospital of Philadelphia, Abramson 
      Research Center Suite 1216, 3615 Civic Center Boulevard, Philadelphia, 
      Pennsylvania 19104, USA.
FAU - Jorgensen, Silje F
AU  - Jorgensen SF
AD  - 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.
FAU - Maggadottir, S Melkorka
AU  - Maggadottir SM
AD  - 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.
FAU - Bakay, Marina
AU  - Bakay M
AD  - Center for Applied Genomics, Children's Hospital of Philadelphia, Abramson 
      Research Center Suite 1216, 3615 Civic Center Boulevard, Philadelphia, 
      Pennsylvania 19104, USA.
FAU - Warnatz, Klaus
AU  - Warnatz K
AD  - Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, 
      University of Freiburg, 79106 Freiburg, Germany.
FAU - Glessner, Joseph
AU  - Glessner J
AD  - Center for Applied Genomics, Children's Hospital of Philadelphia, Abramson 
      Research Center Suite 1216, 3615 Civic Center Boulevard, Philadelphia, 
      Pennsylvania 19104, USA.
FAU - Pandey, Rahul
AU  - Pandey R
AD  - Center for Applied Genomics, Children's Hospital of Philadelphia, Abramson 
      Research Center Suite 1216, 3615 Civic Center Boulevard, Philadelphia, 
      Pennsylvania 19104, USA.
FAU - Salzer, Ulrich
AU  - Salzer U
AD  - Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, 
      University of Freiburg, 79106 Freiburg, Germany.
FAU - Schmidt, Reinhold E
AU  - Schmidt RE
AD  - Clinic for Immunology and Rheumatology, Hannover Medical School, D-30625 
      Hannover, Germany.
FAU - Perez, Elena
AU  - Perez E
AD  - Division of Pediatric Allergy and Immunology, University of Miami Miller School 
      of Medicine, Miami, Florida 33136, USA.
FAU - Resnick, Elena
AU  - Resnick E
AD  - Department of Medicine, Institute of Immunology, Mount Sinai School of Medicine, 
      New York, New York 10029, USA.
FAU - Goldacker, Sigune
AU  - Goldacker S
AD  - Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, 
      University of Freiburg, 79106 Freiburg, Germany.
FAU - Buchta, Mary
AU  - Buchta M
AD  - Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, 
      University of Freiburg, 79106 Freiburg, Germany.
FAU - Witte, Torsten
AU  - Witte T
AD  - Clinic for Immunology and Rheumatology, Hannover Medical School, D-30625 
      Hannover, Germany.
FAU - Padyukov, Leonid
AU  - Padyukov L
AUID- ORCID: 0000000329505670
AD  - Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska 
      University Hospital Solna, SE-17176 Stockholm, Sweden.
FAU - Videm, Vibeke
AU  - Videm V
AD  - 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.
FAU - Folseraas, Trine
AU  - Folseraas T
AD  - 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.
FAU - Atschekzei, Faranaz
AU  - Atschekzei F
AD  - Clinic for Immunology and Rheumatology, Hannover Medical School, D-30625 
      Hannover, Germany.
FAU - Elder, James T
AU  - Elder JT
AD  - 1] Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109, 
      USA [2] Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, 48105 USA.
FAU - Nair, Rajan P
AU  - Nair RP
AD  - Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109, 
      USA.
FAU - Winkelmann, Juliane
AU  - Winkelmann J
AD  - 1] Institute of Human Genetics, Helmholtz Center Munich, German Research Center 
      for Environmental Health, 85764 Neuherberg, Germany [2] Department of Neurology, 
      MRI, Technische Universitat Munchen, 81675 Munchen, Germany [3] SyNergy Munich 
      Cluster for Systems Neurology, Ismaninger Str. 22, 81675 Munchen, Germany [4] 
      Stanford Center for Sleep Sciences and Medicine, 3165 Porter Drive, Palo Alto, CA 
      94301, USA.
FAU - Gieger, Christian
AU  - Gieger C
AD  - 1] Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen, 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 Munchen - 
      German Research Center for Environmental Health, 85764 Neuherberg, Germany.
FAU - Nothen, Markus M
AU  - Nothen MM
AD  - 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.
FAU - Buning, Carsten
AU  - Buning C
AD  - Department of Hepatology and Gastroenterology, Charite, Campus Mitte, 14163 
      Berlin, Germany.
FAU - Brand, Stephan
AU  - Brand S
AD  - University Hospital Munich-Grosshadern, Department of Medicine II, 
      Marchioninistr. 15, D-81377 Munich, Germany.
FAU - Sullivan, Kathleen E
AU  - Sullivan KE
AD  - 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.
FAU - Orange, Jordan S
AU  - Orange JS
AD  - Section of Immunology, Allergy and Rheumatology, Department of Pediatric 
      Medicine, Texas Children's Hospital, Houston, Texas 77030, USA.
FAU - Fevang, Borre
AU  - Fevang B
AD  - 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.
FAU - Schreiber, Stefan
AU  - Schreiber S
AD  - Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 
      Kiel, Germany.
FAU - Lieb, Wolfgang
AU  - Lieb W
AD  - Institute of Epidemiology and Biobank Popgen, Christian-Albrechts-University of 
      Kiel, 24105 Kiel, Germany.
FAU - Aukrust, Pal
AU  - Aukrust P
AD  - 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.
FAU - Chapel, Helen
AU  - Chapel H
AD  - Department of Clinical Immunology, Nuffield Department of Medicine, University of 
      Oxford, Oxford OX3 9DU, UK.
FAU - Cunningham-Rundles, Charlotte
AU  - Cunningham-Rundles C
AD  - Department of Medicine, Institute of Immunology, Mount Sinai School of Medicine, 
      New York, New York 10029, USA.
FAU - Franke, Andre
AU  - Franke A
AD  - Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 
      Kiel, Germany.
FAU - Karlsen, Tom H
AU  - Karlsen TH
AD  - 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.
FAU - Grimbacher, Bodo
AU  - Grimbacher B
AD  - Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, 
      University of Freiburg, 79106 Freiburg, Germany.
FAU - Hakonarson, Hakon
AU  - Hakonarson H
AD  - 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.
FAU - Hammarstrom, Lennart
AU  - Hammarstrom L
AD  - Division of Clinical Immunology and Transfusion Medicine, Department of 
      Laboratory Medicine, Karolinska University Hospital, Huddinge, SE-14186 
      Stockholm, Sweden.
FAU - Ellinghaus, Eva
AU  - Ellinghaus E
AUID- ORCID: 0000000329143382
AD  - Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 
      Kiel, Germany.
LA  - eng
GR  - R01 AR042742/AR/NIAMS NIH HHS/United States
GR  - U01HG006830/HG/NHGRI NIH HHS/United States
GR  - DP3 DK085708/DK/NIDDK NIH HHS/United States
GR  - U24 AI086037/AI/NIAID NIH HHS/United States
GR  - P01 AI061093/AI/NIAID NIH HHS/United States
GR  - R18 AI048693/AI/NIAID NIH HHS/United States
GR  - R01 AR065183/AR/NIAMS NIH HHS/United States
GR  - U01 HG006830/HG/NHGRI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150420
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (CLEC16A protein, human)
RN  - 0 (CLEC16A protein, mouse)
RN  - 0 (Lectins, C-Type)
RN  - 0 (Monosaccharide Transport Proteins)
SB  - IM
MH  - Animals
MH  - B-Lymphocytes/*metabolism
MH  - Case-Control Studies
MH  - Cells, Cultured
MH  - Common Variable Immunodeficiency/epidemiology/*genetics
MH  - Europe/epidemiology
MH  - Gene Expression Regulation/physiology
MH  - Genetic Predisposition to Disease
MH  - Genome-Wide Association Study
MH  - Humans
MH  - Lectins, C-Type/genetics/*metabolism
MH  - Logistic Models
MH  - Mice
MH  - Monosaccharide Transport Proteins/genetics/*metabolism
MH  - Odds Ratio
MH  - Polymorphism, Single Nucleotide
MH  - Spleen/cytology
MH  - United States/epidemiology
PMC - PMC4444044
MID - NIHMS669415
COIS- COMPETING FINANCIAL INTREST The authors declare no competing interest.
EDAT- 2015/04/22 06:00
MHDA- 2016/03/02 06:00
PMCR- 2015/10/20
CRDT- 2015/04/21 06:00
PHST- 2014/06/20 00:00 [received]
PHST- 2015/03/03 00:00 [accepted]
PHST- 2015/04/21 06:00 [entrez]
PHST- 2015/04/22 06:00 [pubmed]
PHST- 2016/03/02 06:00 [medline]
PHST- 2015/10/20 00:00 [pmc-release]
AID - ncomms7804 [pii]
AID - 10.1038/ncomms7804 [doi]
PST - epublish
SO  - Nat Commun. 2015 Apr 20;6:6804. doi: 10.1038/ncomms7804.