Robinson, JI, Carr, IM, Cooper, DL et al. (9 more authors) (2012) Confirmation of association of FCGR3B but not FCGR3A copy number with susceptibility to autoantibody positive rheumatoid arthritis. Human Mutation, 33 (4). 741 - 749 . ISSN 1059-7794
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Keywords: | Arthritis, Rheumatoid, autoantibodies, case-control studies, European Continental Ancestry Group, GPI-Linked Proteins, gene dosage, genetic predisposition to disease, genetics, population, humans, models, genetic, Neutrophils, Receptors, IgG, reproducibility of results |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Musculoskeletal Disease (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Epidemiology and Biostatistics (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 10 Jun 2013 15:22 |
Last Modified: | 29 Mar 2018 17:39 |
Published Version: | http://dx.doi.org/10.1002/humu.22031 |
Status: | Published |
Publisher: | Wiley Blackwell |
Identification Number: | 10.1002/humu.22031 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:75648 |