title: Confirmation of association of FCGR3B but not FCGR3A copy number with susceptibility to autoantibody positive rheumatoid arthritis.
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.
authors.affiliation: NIHR-Leeds Musculoskeletal Biomedical Research Unit and Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.
authors.forename: James I
authors.initials: JI
authors.lastname: Robinson
authors.forename: Ian M
authors.initials: IM
authors.lastname: Carr
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Cooper
authors.forename: Lubna H
authors.initials: LH
authors.lastname: Rashid
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Martin
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.forename: John D
authors.initials: JD
authors.lastname: Isaacs
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Wilson
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Barrett
authors.forename: Ann W
authors.initials: AW
authors.lastname: Morgan
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology*; D016022:Case-Control Studies; D058851:GPI-Linked Proteins / Q000235:genetics; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D006801:Humans; D008957:Models, Genetic; D009504:Neutrophils / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D044465:White People / Q000235:genetics
chemical_list: D001323:Autoantibodies; C499173:FCGR2B protein, human; C496124:FCGR3A protein, human; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D017452:Receptors, IgG