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CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation

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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Figure 1: Genetic structure of the CSK locus.
Figure 2: CSK expression varies in lymphocyte subsets and is associated with CSK genotype.
Figure 3: The CSK risk allele is associated with increased phosphorylation of Lyn at Tyr508 and enhanced activation of mature B cells.
Figure 4: The CSK risk allele is associated with expansion of transitional B cells in umbilical cord blood.

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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.).

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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.

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Correspondence to Betty Diamond or Peter K Gregersen.

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

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Manjarrez-Orduño, N., Marasco, E., Chung, S. et al. CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation. Nat Genet 44, 1227–1230 (2012). https://doi.org/10.1038/ng.2439

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