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

Nature Genetics volume 39, pages 721–723 (2007)Cite this article

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 × 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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Acknowledgements

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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Author notes

  1. Manuela Fanciulli, Penny J Norsworthy and Enrico Petretto: These authors contributed equally to this work.

Authors and Affiliations

  1. Physiological Genomics and Medicine Group, UK Medical Research Council (MRC) Clinical Sciences Centre, Imperial College, London, W12 0NN, UK

    Manuela Fanciulli, Penny J Norsworthy, Enrico Petretto, Rong Dong & Timothy J Aitman

  2. Division of Immunity and Infection, Renal Immunobiology, Medical School, University of Birmingham, Birmingham, B15 277, UK

    Lorraine Harper & Lavanya Kamesh

  3. Division of Medical Sciences, Medical School, University of Birmingham, Birmingham, B15 277, UK

    Joanne M Heward & Stephen C L Gough

  4. Division of Medicine, Section of Genomic Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK

    Adam de Smith, Alexandra I F Blakemore & Philippe Froguel

  5. Centre National de la Recherche Scientifique (CNRS), UMR 8090-Institute of Biology, Pasteur Institute, Lille, 59800, France

    Philippe Froguel

  6. Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK

    Catherine J Owen & Simon H S Pearce

  7. Department of Internal Medicine, Reference Center for Vasculitis and Systemic Sclerosis, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris-Descartes University 27, rue du Faubourg Saint-Jacques, Paris Cedex 14, 75679, France

    Luis Teixeira & Loic Guillevin

  8. Section of Molecular Genetics and Rheumatology, Imperial College London, London, W12 0NN, UK

    Deborah S Cunninghame Graham, Timothy J Vyse & Timothy J Aitman

  9. Renal Medicine, Imperial College London, London, W12 0NN, UK

    Charles D Pusey

  10. Department of Histopathology, Imperial College London, London, W12 0NN, UK

    H Terence Cook

Authors
  1. Manuela Fanciulli
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  4. Rong Dong
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  5. Lorraine Harper
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  11. Philippe Froguel
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  12. Catherine J Owen
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Contributions

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.

Corresponding author

Correspondence to Timothy J Aitman.

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Competing interests

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). https://doi.org/10.1038/ng2046

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