Confirmation of association of FCGR3B but not FCGR3A copy number with susceptibility to autoantibody positive rheumatoid arthritis

Authors

  • James I. Robinson,

    1. NIHR—Leeds Musculoskeletal Biomedical Research Unit and Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK
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  • Ian M. Carr,

    1. NIHR—Leeds Musculoskeletal Biomedical Research Unit and Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK
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  • Dawn L. Cooper,

    1. NIHR—Leeds Musculoskeletal Biomedical Research Unit and Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK
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  • Lubna H. Rashid,

    1. NIHR—Leeds Musculoskeletal Biomedical Research Unit and Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK
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  • Stephen G. Martin,

    1. NIHR—Leeds Musculoskeletal Biomedical Research Unit and Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK
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  • Paul Emery,

    1. NIHR—Leeds Musculoskeletal Biomedical Research Unit and Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK
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  • John D. Isaacs,

    1. Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle Upon Tyne, UK
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  • Anne Barton,

    1. Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester, UK
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  • BRAGGSS,

    1. Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate, UK
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  • Anthony G. Wilson,

    1. Rheumatology Unit, Medical School, University of Sheffield, Sheffield, UK
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  • Jennifer H Barrett,

    1. NIHR—Leeds Musculoskeletal Biomedical Research Unit and Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK
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    • The authors wish it to be known that the last two authors should be regarded as joint last authors.

  • Ann W. Morgan

    Corresponding author
    1. NIHR—Leeds Musculoskeletal Biomedical Research Unit and Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK
    • Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St. James's University Hospital, Beckett Street, Leeds, West Yorkshire, LS9 7TF UK
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    • The authors wish it to be known that the last two authors should be regarded as joint last authors.


  • Communicated by Christopher Mathew

Abstract

The FCGR locus encoding the low-affinity Fcγ receptors (FcγR) for immunoglobulin G has largely been missed by genome-wide association studies due to complications with structural variation and segmental duplication. Recently identified copy number variants (CNVs) affecting FCGR3A and FCGR3B have been linked to a number of autoimmune disorders. We have developed and validated a novel quantitative sequence variant assay in combination with an adapted paralogue ratio test to examine independent CNVs carrying FCGR3A and FCGR3B in rheumatoid arthritis (RA) compared with healthy volunteers (n = 1,115 and 654, respectively). Implementation of a robust statistical analysis framework (CNVtools) allowed for systematic batch effects and for the inherent uncertainty of copy number assignment, thus avoiding two major sources of false positive results. Evidence for association with neither duplications nor deletions of FCGR3A was found; however, in line with previous studies, there was evidence of overrepresentation of FCGR3B deletions in RA (odds ratio [OR] 1.50, P = 0.028), which was more apparent in rheumatoid factor positive disease (OR 1.61, P = 0.011). The level of FcγRIIIb, encoded by FCGR3B, expression on neutrophils was shown to correlate with gene copy number. Thus, our results may highlight an important role for neutrophils in the pathogenesis of RA, potentially through reduced FcγRIIIb-mediated immune complex clearance. Hum Mutat 33:741–749, 2012. © 2012 Wiley Periodicals, Inc.

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