title: Dissection of the FCGR3A association with RA: increased association in men and with autoantibody positive disease.
abstract: OBJECTIVE
  Genome-wide association studies in rheumatoid arthritis (RA) have failed to examine the FCGR gene cluster because of the confounding effects of segmental duplication. This study aimed to replicate previous candidate gene studies that had identified a significant association between the FCGR3A-158V allele and RA and then sought to estimate specific subgroup effects.
  
  
  METHODS
  FCGR3A-158F/V genotyping was undertaken in a UK Caucasian replication cohort comprising 2049 patients with RA and 1156 controls. Subgroup analyses assessing the magnitude of association according to gender and autoantibody (rheumatoid factor (RF) and cyclic citrullinated peptide (CCP)) status were undertaken in a pooled cohort of 2963 patients with RA and 1731 controls. Logistic regression was used to test for interaction between FCGR3A and HLA-DRB1 shared epitope (SE) alleles.
  
  
  RESULTS
  In the combined RA cohort, borderline association with homozygosity was found for the FCGR3A-158V allele (OR 1.2, p=0.05), which was stronger in men (OR 1.7, p=0.01). Stratification by autoantibody status showed an increased risk in RF and CCP positive RA. Analysis of the FCGR3A-158V and HLA-DRB1 SE interaction revealed roles for both genes in susceptibility to autoantibody positive RA, with no evidence of interaction.
  
  
  CONCLUSIONS
  FCGR3A is a risk factor for the development of autoantibody positive RA, particularly in men, with evidence of a multiplicative effect with HLA-DRB1 SE.
authors.affiliation: NIHR-Leeds Musculoskeletal Biomedical Research Unit, St James's University Hospital, Leeds Institute of Molecular Medicine, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: James I
authors.initials: JI
authors.lastname: Robinson
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Barrett
authors.forename: John C
authors.initials: JC
authors.lastname: Taylor
authors.forename: Marc
authors.initials: M
authors.lastname: Naven
authors.forename: Diane
authors.initials: D
authors.lastname: Corscadden
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Wilson
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.forename: John D
authors.initials: JD
authors.lastname: Isaacs
authors.forename: Ann W
authors.initials: AW
authors.lastname: Morgan
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology; D017452:Receptors, IgG / Q000235:genetics*; D012217:Rheumatoid Factor / Q000097:blood; D012737:Sex Factors; D055815:Young Adult
chemical_list: D001323:Autoantibodies; C496124:FCGR3A protein, human; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; D017452:Receptors, IgG; C487763:cyclic citrullinated peptide; D012217:Rheumatoid Factor