title: A functional polymorphism of Ptpn22 is associated with type 1 diabetes in the BioBreeding rat.
abstract: The R620W variant of PTPN22 is one of the major genetic risk factors for several autoimmune disorders including type 1 diabetes (T1D) in humans. In the BioBreeding T1D-prone (BBDP) rat, a single nucleotide polymorphism in Ptpn22 results in an A629T substitution immediately C-terminal to the aliphatic residues central to the Ptpn22-C-terminal Src kinase interaction. This variant exhibits a 50% decrease in C-terminal Src kinase binding affinity and contributes to T cell hyperresponsiveness. Examination of BBDP sublines congenic for the Iddm26.2 locus that includes Ptpn22 has not only shown an expansion of activated CD4(+)25(+) T lymphocytes in animals homozygous for the BBDP allele, consistent with enhanced TCR-mediated signaling, but also a decrease in their proportion of peripheral Foxp3(+) regulatory T cells. Furthermore, clinical assessment of both an F2(BBDP × ACI.1u.Lyp) cohort and Iddm26.2 congenic BBDP sublines has revealed an association of Ptpn22 with T1D. Specifically, in both cases, T1D risk is significantly greater in BBDP Ptpn22 homozygous and heterozygous animals. These findings are consistent with a role for rat Ptpn22 allelic variation within Iddm26.2 in the regulation of T cell responses, and subsequently the risk for development of T1D.
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada;
authors.forename: Janice
authors.initials: J
authors.lastname: Sarmiento
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada;
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wallis
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada;
authors.forename: Terri
authors.initials: T
authors.lastname: Ning
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada;
authors.forename: Leili
authors.initials: L
authors.lastname: Marandi
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada;
authors.forename: Gary
authors.initials: G
authors.lastname: Chao
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada;
authors.forename: André
authors.initials: A
authors.lastname: Veillette
authors.affiliation: Department of Clinical Sciences, Lund University, 20502 Malmö, Sweden;
authors.forename: Åke
authors.initials: Å
authors.lastname: Lernmark
authors.affiliation: Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario M5T 3M7, Canada; and Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada; philippe.poussier@sri.utoronto.ca.
authors.forename: Philippe
authors.initials: P
authors.lastname: Poussier
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D003433:Crosses, Genetic; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics* / Q000276:immunology; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
chemical_list: D011948:Receptors, Antigen, T-Cell; C000590795:PTPN22 protein, rat; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22