Lookup NU author(s): Professor John Isaacs
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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.
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
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.
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