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

Nature Genetics 39, 721–723 (2007) | Download Citation

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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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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.

Author information

    • Manuela Fanciulli
    • , Penny J Norsworthy
    •  & Enrico Petretto

    These authors contributed equally to this work.

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. Renal Immunobiology, Division of Immunity and Infection, 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. Section of Genomic Medicine, Division of 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, 75679 Paris Cedex 14, 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

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Timothy J Aitman.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Semiquantitative PCR.

  2. 2.

    Supplementary Fig. 2

    Comparison between quantitative PCR and oligonucleotide array comparative genomic hybridization assays for copy number quantification at FCGR3B.

  3. 3.

    Supplementary Table 1

    Descriptive characteristics of case-control cohorts.

  4. 4.

    Supplementary Table 2

    Primer sequences.

  5. 5.

    Supplementary Methods

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DOI

https://doi.org/10.1038/ng2046

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