FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity

Abstract

Naturally occurring variation in gene copy number is increasingly recognized as a heritable source of susceptibility to genetically complex diseases. Here we report strong association between FCGR3B copy number and risk of systemic lupus erythematosus (P = 2.7 x 10(-8)), microscopic polyangiitis (P = 2.9 x 10(-4)) and Wegener's granulomatosis in two independent cohorts from the UK (P = 3 x 10(-3)) and France (P = 1.1 x 10(-4)). We did not observe this association in the organ-specific Graves' disease or Addison's disease. Our findings suggest that low FCGR3B copy number, and in particular complete FCGR3B deficiency, has a key role in the development of systemic autoimmunity.

Figure 1

Distribution of FCGR3B copy number in different groups of affected individuals (filled bars) versus unaffected controls (open bars). (a) SLE with nephritis. (b) SLE without nephritis. (c) Wegener’s granulomatosis (UK). (d) Wegener’s granulomatosis (France). (e) Microscopic polyangiitis. (f) Graves’ disease. (g) Addison’s disease. A nonparametric Mann-Whitney U test was applied to assess association with gene copy number at FCGR3B. Two-tailed P values for significance were estimated by 100,000 Monte Carlo simulations. n, number of subjects in each group.