Association of variation in Fcgamma receptor 3B gene copy number with rheumatoid arthritis in Caucasian samples

Abstract

Objective: There is increasing evidence that variation in gene copy number (CN) influences clinical phenotype. The low-affinity Fcgamma 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 x 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 x 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.

Figure 1

Distribution of Fcγ receptor 3B copy number (CN) as a continuous variable in the three case and control cohorts. Data are shown without removal of samples. Boxes and lines encompass samples within 1 and 2 SD from the mean, respectively. Mean (SD) values for the six sample sets are (from left to right): 2.23 (0.45), 2.04 (0.39), 2.18 (0.25), 1.89 (0.20), 2.14 (0.24) and 1.92 (0.26).

Figure 2

Meta-analysis of the association between low Fcγ receptor 3B (FCGR3B) copy number and rheumatoid arthritis for the four sample sets using Metan (STATA Version 7.0) with a fixed Mantel–Haenszel pooling model. FCGR3B CN of 0–1 was designated as the minor allele and copy number ≥2 as the major allele.