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.
authors.affiliation: Center for Autoimmune and Musculoskeletal Disorders, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish, Manhasset, New York, USA.
authors.forename: Nataly
authors.initials: N
authors.lastname: Manjarrez-Orduño
authors.forename: Emiliano
authors.initials: E
authors.lastname: Marasco
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Chung
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Katz
authors.forename: Jenna F
authors.initials: JF
authors.lastname: Kiridly
authors.forename: Kim R
authors.initials: KR
authors.lastname: Simpfendorfer
authors.forename: Jan
authors.initials: J
authors.lastname: Freudenberg
authors.forename: David H
authors.initials: DH
authors.lastname: Ballard
authors.forename: Emil
authors.initials: E
authors.lastname: Nashi
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hopkins
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Cunninghame Graham
authors.forename: Annette T
authors.initials: AT
authors.lastname: Lee
authors.forename: Marieke J H
authors.initials: MJ
authors.lastname: Coenen
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.forename: Dorine W
authors.initials: DW
authors.lastname: Swinkels
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.forename: Betty
authors.initials: B
authors.lastname: Diamond
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
mesh_terms: D000483:Alleles; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D000081247:CSK Tyrosine-Protein Kinase; D056726:Genetic Association Studies; D006801:Humans; D007438:Introns; D008180:Lupus Erythematosus, Systemic / Q000235:genetics; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics* / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000081247:CSK Tyrosine-Protein Kinase; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22