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¹ Cambridge Institute for Medical Research, ² Department of Medicine, ³ Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, University of Cambridge, CB2 0XY, England, UK
⁴ Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, LS9 7TF, England, UK
⁵ Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, Hong Kong, China
⁶ Division of Immunity and Infection and Wellcome Clinical Research Facility, The Medical School, University of Birmingham, Birmingham, B15 2TT, England, UK
⁷ School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, NR4 7TJ, England, UK
⁸ Department of Physiology, The Medical School, University of Birmingham, B15 2TT, England, UK

CORRESPONDENCE Kenneth G.C. Smith: kgcs2{at}cam.ac.uk

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). FcRIIIb 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 FcRIIIb-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 FcRIIIb. Reduced FcRIIIb 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.

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