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


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 × 10−8), microscopic polyangiitis (P = 2.9 × 10−4) and Wegener's granulomatosis in two independent cohorts from the UK (P = 3 × 10−3) and France (P = 1.1 × 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.

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Figure 1: Distribution of FCGR3B copy number in different groups of affected individuals (filled bars) versus unaffected controls (open bars).

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We thank C. Neuwirth and Y. Tan (Clinical Sciences Centre); A. Wong (Imperial College); J. Cedric and M. Delpech (INSERM U567); M. Marre (INSERM U695) and B. Balkau (INSERM U780-IFR69) for their role in collecting patients and controls. We thank A. Tsalenko, A. Scheffer, N. Sampas, P. Tsang and L. Bruhn from Agilent Laboratories for contributions to the array comparative genomic hybridization results. We acknowledge intramural funding from the Clinical Sciences Centre (to T.J.A.) and support from the Wellcome Trust Cardiovascular Functional Genomics award (T.J.A.), from the FP6 EURATools (European Union contract number LSHG-CT-2005-019015) award (T.J.A.), from the UK MRC (T.J.A., H.T.C.) and from a Wellcome Trust Senior Fellowship (T.J.V.). We acknowledge use of genotype data from the British 1958 Birth Cohort DNA collection, funded by the UK Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02.

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M.F., E.P., H.T.C., T.J.V. and T.J.A. designed the study. M.F., P.J.N. and R.D. performed PCR-based experiments. A.d.S., A.I.F.B. and P.F. performed oligonucleotide array comparative genomic hybridization analysis. M.F. and E.P. performed statistical and data analysis. L.H., L.K., J.M.H., S.C.L.G., P.F., C.J.O., S.H.S.P., L.T., L.G., D.S.G.G., C.D.P. and T.J.V. provided material and contributed to the collection of the case-control studies. The manuscript was written by M.F., E.P., H.T.C., T.J.V. and T.J.A.

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Correspondence to Timothy J Aitman.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Semiquantitative PCR. (PDF 220 kb)

Supplementary Fig. 2

Comparison between quantitative PCR and oligonucleotide array comparative genomic hybridization assays for copy number quantification at FCGR3B. (PDF 83 kb)

Supplementary Table 1

Descriptive characteristics of case-control cohorts. (PDF 90 kb)

Supplementary Table 2

Primer sequences. (PDF 51 kb)

Supplementary Methods (PDF 109 kb)

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Fanciulli, M., Norsworthy, P., Petretto, E. et al. FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nat Genet 39, 721–723 (2007).

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