A functional single nucleotide polymorphism in PTPN22 contributes to diabetes susceptibility in the BioBreeding Rat (49.4)

Abstract

Abstract The C1858T polymorphism in the Ptpn22 gene is associated with increased susceptibility to several autoimmune disorders including Type 1 Diabetes (T1D). This produces a gain-of-function R620W variant with diminished binding affinity to Csk, which, like PTPN22 is an inhibitor of antigen receptor signaling. In the T1D-prone BioBreeding (BB) rat, this gene is located in the Iddm3 locus on chromosome 2, making it a likely candidate gene. Sequencing revealed a non-synonymous SNP causing an A629T substitution C-terminal to the PTPN22 P1 domain that binds to Csk. Co-immunoprecipitations examining the PTPN22-Csk interaction have shown a 2-fold reduction in binding affinity of the BB compared to the ACI variant. Importantly, a genome-wide segregation analysis of an F2(BBxACI.1u.lyp) cohort revealed the dominant effect of the BB allele to confer a 3-fold increased T1D risk compared to the allele carried by the T1D-resistant ACI strain. Homozygosity for the BB allele is also associated with phenotypes indicative of immune dysregulation including increased proportions of activated CD4 T cells in the periphery. Reminiscent of the phenotypes observed in T1D patients carrying the R620W variant, BB-derived T and B cells exhibit hyporesponsiveness to antigen receptor engagement, with a concomitant decrease in IL-2 production by CD4 T cells. Banting and Best Diabetes Centre, Genome Canada, Ontario Research Foundation and CIHR