Objective There is increasing evidence that variation in gene copy number (CN) influences clinical phenotype. The low-affinity Fcγ receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment to sites of inflammation and activation of polymorphonuclear neutrophils (PMNs). Given recent evidence that low FCGR3B CN is a risk factor for systemic but not organ-specific autoimmune disease and the potential importance of PMN in the pathophysiology of rheumatoid arthritis (RA), the authors hypothesised that FCGR3B gene dosage influences susceptibility to RA.
Methods FCGR3B CN was measured in 643 cases of RA and 461 controls from New Zealand (NZ), with follow-up analysis in 768 cases and 702 controls from the Netherlands and 250 cases and 211 controls from the UK. All subjects were of Caucasian ancestry.
Results Significant evidence for an association between CN <2 and RA was observed in the Dutch cohort (OR 2.01 (95% CI 1.37 to 2.94), p=3×10−4) but not in the two smaller cohorts (OR 1.45 (95% CI 0.92 to 2.26), p=0.11 and OR 1.33 (95% CI 0.58 to 3.02), p=0.50 for the NZ and UK populations, respectively). The association was evident in a meta-analysis which included a previously published Caucasian sample set (OR 1.67 (95% CI 1.28 to 2.17), p=1.2×10−4).
Conclusions One possible mechanism to explain the association between reduced FCGR3B CN and RA is the reduced clearance of immune complex during inflammation. However, it is not known whether the association between RA and FCGR3B CN is aetiological or acts as a proxy marker for another biologically relevant variant. More detailed examination of genetic variation within the FCGR gene cluster is required.
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Funding This work was supported by the Health Research Council of New Zealand, Arthritis New Zealand and the NZ Child Health Research Foundation, Medical Research Council (UK) intramural funding from the Clinical Sciences Centre and Wellcome Trust project grant 083167. BZA was supported by a grant from the Netherlands Organization for Health Research and Development (ZonMw; grant number 016.096.121).
Competing interests None.
Ethics approval Ethical approval for the study in New Zealand was given by the MultiRegion (cases) and Lower South Ethics Committees (controls), in the UK by the local research ethics committees of Lewisham Hospital and Guy's and St Thomas' Hospitals and in The Netherlands by the local ethics committee. All subjects gave written informed consent.
Provenance and peer review Not commissioned; externally peer reviewed.