Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake

Abstract

Copy number (CN) variation (CNV) has been shown to be common in regions of the genome coding for immune-related genes, and thus impacts upon polygenic autoimmunity. Low CN of FCGR3B has recently been associated with systemic lupus erythematosus (SLE). FcγRIIIb is a glycosylphosphatidylinositol-linked, low affinity receptor for IgG found predominantly on human neutrophils. We present novel data demonstrating that both in a family with FcγRIIIb-deficiency and in the normal population, FCGR3B CNV correlates with protein expression, with neutrophil uptake of and adherence to immune complexes, and with soluble serum FcγRIIIb. Reduced FcγRIIIb expression is thus likely to contribute to the impaired clearance of immune complexes, which is a feature of SLE, explaining the association between low FCGR3B CNV and SLE that we have confirmed in a Caucasian population. In contrast, antineutrophil cytoplasmic antibody–associated systemic vasculitis (AASV), a disease not associated with immune complex deposition, is associated with high FCGR3B CN. Thus, we define a role for FCGR3B CNV in immune complex clearance, a function that may explain why low FCGR3B CNV is associated with SLE, but not AASV. This is the first report of an association between disease-related gene CNV and variation in protein expression and function that may contribute to autoimmune disease susceptibility.

Evidence that deletion at FCGR3B is a risk factor for systemic sclerosis

“…It has been hypothesised that the primary effect of deletion in the FCGR3B gene is a reduced uptake of IgG complexes, leading to tissue deposition of IC. 5,6,12,15 Our results, however, suggest that this may not be the only explanation for the observed associations. Although SLE and SSc are characterised by the presence of autoantibodies, the absence of IgG deposits in SSc is one of the major differences between SLE and SSc.…”

“…This is the first report in SSc and is consistent with the association reported for SLE, where published ORs range from 1.47 to 1.65. [7][8][9][10][11][12][13] Although the P value is modest (0.007), this likely represents genuine association given the prior evidence supporting a role for FCGR3B deletion in SSc. Membranebound FcgR3B is involved in the adherence of neutrophils to endothelial cells at sites of infection as well as in IC uptake.…”

“…14 ) The FCGR3B CN allele distribution among the controls (CNo2 ¼ 7.6%, CN 2 ¼ 82.6% and CN42 ¼ 9.8%) is similar to that observed in other healthy Caucasian populations as determined by multiplex ligand-dependent probe amplification or paralog ratio testing (CNo2 ¼ 6.7-7.8%, CN 2 ¼ 81.1-82.2% and CN42 ¼ 9.4-11.8%). 8,12,13,15,16 The influence of possessing o2 copies of FCGR3B on SSc risk was tested under the hypothesis that any association of FCGR3B with disease would be similar to that evident in SLE, where CNo2 is a risk factor. [5][6][7][8][9][10] There was significant evidence that possessing fewer than two copies of FCGR3B is a risk factor for SSc (odds ratio (OR) ¼ 1.55 (1.13-2.14), P ¼ 0.007) ( We tested for association between FCGR3B CNo2 and limited cutaneous or diffuse cutaneous SSc, and the presence or absence of anti-topoisomerase I and anti-centromere antibodies.…”

“…6,7 In particular, CNo2 has been reported to be a risk factor for SLE in a number of studies. [7][8][9][10][11][12][13] Given the evidence for shared genetic susceptibility between SSc and SLE, we hypothesised that copy-number variation in FCGR3B has a role in the pathology of SSc. In order to evaluate this hypothesis, we tested for association between FCGR3B gene dosage and SSc in a Caucasian case-control sample set under the specific hypothesis that deletion of FCGR3B is a risk factor in comparison with diploid and increased CN.…”

Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese

“…19 Recently, it has been found that low copy number variation of FCGRIIIB confers SLE susceptibility to patients of European origin but not to Hong Kong Chinese. 20 A major allele being a risk allele in the case of BLK is not surprising, but it may mean that the allele poses more risk to Asians on the population level. Because Asians have higher disease prevalence and more severe disease manifestations than Caucasians, it is likely that Asians may have higher genetic load than Caucasians in terms of susceptibility to the disease.…”