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

Nataly Manjarrez-Orduño; Emiliano Marasco; Sharon A. Chung; Matthew S. Katz; Jenna F. Kiridly; Kim R. Simpfendorfer; Jan Freudenberg; David H. Ballard; Emil Nashi; Thomas J. Hopkins; Deborah S. Cunninghame Graham; Annette T. Lee; Marieke J.H. Coenen; Barbara Franke; Dorine W. Swinkels; Robert R. Graham; Robert P. Kimberly; Patrick M. Gaffney; Timothy J. Vyse; Timothy W. Behrens; Lindsey A. Criswell; Betty Diamond; Peter K. Gregersen

doi:10.1038/ng.2439

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

Nataly Manjarrez-Orduño
, Emiliano Marasco
, Sharon A. Chung
, Matthew S. Katz
, Jenna F. Kiridly
, Kim R. Simpfendorfer
, Jan Freudenberg
, David H. Ballard
, Emil Nashi
, Thomas J. Hopkins
, Deborah S. Cunninghame Graham
, Annette T. Lee
, Marieke J.H. Coenen
, Barbara Franke
, Dorine W. Swinkels
, Robert R. Graham
, Robert P. Kimberly
, Patrick M. Gaffney
, Timothy J. Vyse
, Timothy W. Behrens

Lindsey A. Criswell, Betty Diamond, Peter K. Gregersen

Research output: Contribution to journal › Article › peer-review

105 Scopus citations

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.

Original language	English
Pages (from-to)	1227-1230
Number of pages	4
Journal	Nature Genetics
Volume	44
Issue number	11
DOIs	https://doi.org/10.1038/ng.2439
State	Published - Nov 2012
Externally published	Yes

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Manjarrez-Orduño, N., Marasco, E., Chung, S. A., Katz, M. S., Kiridly, J. F., Simpfendorfer, K. R., Freudenberg, J., Ballard, D. H., Nashi, E., Hopkins, T. J., Cunninghame Graham, D. S., Lee, A. T., Coenen, M. J. H., Franke, B., Swinkels, D. W., Graham, R. R., Kimberly, R. P., Gaffney, P. M., Vyse, T. J., ... Gregersen, P. K. (2012). CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation. Nature Genetics, 44(11), 1227-1230. https://doi.org/10.1038/ng.2439

@article{ef49313427d3425ab4cc4e87d4562b02,

title = "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.",

author = "Nataly Manjarrez-Ordu{\~n}o and Emiliano Marasco and Chung, \{Sharon A.\} and Katz, \{Matthew S.\} and Kiridly, \{Jenna F.\} and Simpfendorfer, \{Kim R.\} and Jan Freudenberg and Ballard, \{David H.\} and Emil Nashi and Hopkins, \{Thomas J.\} and \{Cunninghame Graham\}, \{Deborah S.\} and Lee, \{Annette T.\} and Coenen, \{Marieke J.H.\} and Barbara Franke and Swinkels, \{Dorine W.\} and Graham, \{Robert R.\} and Kimberly, \{Robert P.\} and Gaffney, \{Patrick M.\} and Vyse, \{Timothy J.\} and Behrens, \{Timothy W.\} and Criswell, \{Lindsey A.\} and Betty Diamond and Gregersen, \{Peter K.\}",

note = "Funding Information: 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.).",

year = "2012",

month = nov,

doi = "10.1038/ng.2439",

language = "English",

volume = "44",

pages = "1227--1230",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "11",

}

Manjarrez-Orduño, N, Marasco, E, Chung, SA, Katz, MS, Kiridly, JF, Simpfendorfer, KR, Freudenberg, J, Ballard, DH, Nashi, E, Hopkins, TJ, Cunninghame Graham, DS, Lee, AT, Coenen, MJH, Franke, B, Swinkels, DW, Graham, RR, Kimberly, RP, Gaffney, PM, Vyse, TJ, Behrens, TW, Criswell, LA, Diamond, B & Gregersen, PK 2012, 'CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation', Nature Genetics, vol. 44, no. 11, pp. 1227-1230. https://doi.org/10.1038/ng.2439

TY - JOUR

T1 - CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation

AU - Manjarrez-Orduño, Nataly

AU - Marasco, Emiliano

AU - Chung, Sharon A.

AU - Katz, Matthew S.

AU - Kiridly, Jenna F.

AU - Simpfendorfer, Kim R.

AU - Freudenberg, Jan

AU - Ballard, David H.

AU - Nashi, Emil

AU - Hopkins, Thomas J.

AU - Cunninghame Graham, Deborah S.

AU - Lee, Annette T.

AU - Coenen, Marieke J.H.

AU - Franke, Barbara

AU - Swinkels, Dorine W.

AU - Graham, Robert R.

AU - Kimberly, Robert P.

AU - Gaffney, Patrick M.

AU - Vyse, Timothy J.

AU - Behrens, Timothy W.

AU - Criswell, Lindsey A.

AU - Diamond, Betty

AU - Gregersen, Peter K.

N1 - Funding Information: 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.).

PY - 2012/11

Y1 - 2012/11

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84868208900

U2 - 10.1038/ng.2439

DO - 10.1038/ng.2439

M3 - Article

C2 - 23042117

AN - SCOPUS:84868208900

SN - 1061-4036

VL - 44

SP - 1227

EP - 1230

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

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

Abstract

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