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

Lookup NU author(s): Professor John Isaacs

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Abstract

The FCGR locus encoding the low-affinity Fc? receptors (Fc?R) 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 Fc?RIIIb, 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 Fc?RIIIb-mediated immune complex clearance. Hum Mutat 33:741749, 2012. (c) 2012 Wiley Periodicals, Inc.


Publication metadata

Author(s): Robinson JI, Carr IM, Cooper DL, Rashid LH, Martin SG, Emery P, Isaacs JD, Barton A, Wilson AG, Barrettt JH, Morgan AW, BRAGGSS

Publication type: Article

Publication status: Published

Journal: Human Mutation

Year: 2012

Volume: 33

Issue: 4

Pages: 741-749

Print publication date: 01/04/2012

Online publication date: 28/02/2012

Acceptance date: 17/01/2012

ISSN (print): 1059-7794

ISSN (electronic): 1098-1004

Publisher: John Wiley & Sons Ltd.

URL: http://dx.doi.org/10.1002/humu.22031

DOI: 10.1002/humu.22031


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