Abstract

The c-Src tyrosine kinase, Csk, physically interacts with the intracellular phosphatase Lyp (encoded by PTPN22) and can modify the activation state of downstream Src kinases, such as Lyn, in lymphocytes. We identified an association of CSK with systemic lupus erythematosus (SLE) and refined its location to the intronic polymorphism rs34933034 (odds ratio (OR) = 1.32; P = 1.04 × 10−9). The risk allele at this SNP is associated with increased CSK expression and augments inhibitory phosphorylation of Lyn. In carriers of the risk allele, there is increased B-cell receptor (BCR)-mediated activation of mature B cells, as well as higher concentrations of plasma immunoglobulin M (IgM), relative to individuals with the non-risk haplotype. Moreover, the fraction of transitional B cells is doubled in the cord blood of carriers of the risk allele, due to an expansion of late transitional cells in a stage targeted by selection mechanisms. This suggests that the Lyp-Csk complex increases susceptibility to lupus at multiple maturation and activation points in B cells.

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Acknowledgements

The authors thank the volunteers who participated in this study; the Genotype and Phenotype (GaP) registry; M. Keogh, M. DeFranco, C. Mason, C. Metz and the Biorepository at the Feinstein Institute for Medical Research (FIMR) for recruiting subjects and collecting samples; H. Borrero for technical assistance; and the Biostatistics Unit of the FIMR and M. Akerman for assistance. This work was supported by US National Institutes of Health (NIH) grant RC2AR059092; The Alliance for Lupus Research, a Kirkland Scholar Award and NIH/National Center for Research Resources (NCRR) grant 5 M01 RR-00079 (L.A.C.); P01 AR49084 and UL1 TR000165 (R.P.K.); and NIH/National Center for Advancing Translational Sciences grant KL2TR000143 and an American College of Rheumatology Physician Scientist Development Award (S.A.C.). The principal investigators of the Nijmegen Biomedical Study are L.A.L.M. Kiemeney, M. den Heijer, A.L.M. Verbeek, D.W. Swinkels and B. Franke. We thank the Lupus Family Registry and Repository (LFRR) investigators, J.B. Harley, K.L. Moser Sivils, M.H. Weisman and D.J. Wallace, funded by N01AR62277 (K.L.M.S. and J.B.H.).

Author information

Author notes

    • Emil Nashi

    Present address: Division of Clinical Immunology, McGill University Health Centre, Montreal, Quebec, Canada.

    • Betty Diamond
    •  & Peter K Gregersen

    These authors contributed equally to this work.

Affiliations

  1. Center for Autoimmune and Musculoskeletal Disorders, The Feinstein Institute for Medical Research, North Shore–Long Island Jewish (LIJ), Manhasset, New York, USA.

    • Nataly Manjarrez-Orduño
    • , Emiliano Marasco
    • , Emil Nashi
    •  & Betty Diamond
  2. Robert S Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, North Shore–LIJ, Manhasset, New York, USA.

    • Nataly Manjarrez-Orduño
    • , Matthew S Katz
    • , Jenna F Kiridly
    • , Kim R Simpfendorfer
    • , Jan Freudenberg
    • , David H Ballard
    • , Thomas J Hopkins
    • , Annette T Lee
    •  & Peter K Gregersen
  3. Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

    • Sharon A Chung
    •  & Lindsey A Criswell
  4. Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, School of Medicine, King's College London, London, UK.

    • Deborah S Cunninghame Graham
    •  & Timothy J Vyse
  5. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Marieke J H Coenen
    •  & Barbara Franke
  6. Department of Laboratory Medicine, Laboratory of Genetic Endocrine and Metabolic Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Dorine W Swinkels
  7. Deparment of Human Genetics, Genentech, South San Francisco, California, USA.

    • Robert R Graham
    •  & Timothy W Behrens
  8. Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • Robert P Kimberly
  9. Arthritis and Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.

    • Patrick M Gaffney

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Contributions

N.M.-O., B.D. and P.K.G. designed the study. N.M.-O., S.A.C., D.S.C.G., J.F., D.H.B., T.J.V., L.A.C. and A.T.L. performed genetic analysis. N.M.-O., E.M., J.F.K., M.S.K., K.R.S. and T.J.H. performed experiments. E.N. gave the initial insight into Csk. M.J.H.C., B.F., D.W.S., R.R.G., R.P.K., T.J.V., T.W.B., P.M.G. and L.A.C. provided samples. N.M.-O., B.D. and P.K.G. analyzed and interpreted the data and prepared the manuscript.

Competing interests

T.W.B. and R.R.G. are full-time employees of Genentech.

Corresponding authors

Correspondence to Betty Diamond or Peter K Gregersen.

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DOI

https://doi.org/10.1038/ng.2439

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