Association of low-affinity FC gamma receptor 3B (FCGR3B) copy number variation with rheumatoid arthritis in Caucasian subjects

Abstract

Aim: There is increasing evidence that gene copy-number variation influences phenotypic variation. The low-affinity Fc receptor 3B (FCGR3B) is a copy-number polymorphic gene involved in the recruitment to sites of inflammation and activation of polymorphonuclear neutrophils (PMN). Given the importance of PMN in the pathophysiology of rheumatoid arthritis (RA), and recent evidence that low FCGR3B copy-number is a risk factor for systemic but not organ-specific autoimmune disease, we hypothesised that FCGR3B gene dosage influences susceptibility to RA. Methods: We measured FCGR3B copy-number in 1749 RA cases from New Zealand (NZ) the United Kingdom (UK) and Holland, and a total of 1322 controls. All subjects were ancestrally Caucasian. Results: A copy number of less than 2 was a risk factor for RA in the two larger NZ and Netherlands cohorts (OR = 1.52 [0.99-2.31], p = 0.05; OR = 2.27 [1.56-3.30], p = 1.8 × 10-5, respectively). Meta-analysis with the UK cohort yielded strong evidence for association of CN <2 with RA (OR = 1.83 [1.40-2.38], p = 7.0 × 10-6). There was an inverse linear relationship between FCGR3B CN and risk of RA (p = 1 × 10-4). Conclusions: FCGR3B CN is inversely related to susceptibility to RA in the Caucasian cohorts examined in this study. This association is similar to that previously observed in systemic lupus erythematosus, suggesting overlap in pathophysiology of disease. Whether FCGR3B deletion is etiological or acts as a proxy marker for another biologically-relevant variant will require more detailed examination of genetic variation with the FCGR gene cluster.