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A Functional Polymorphism of Ptpn22 Is Associated with Type 1 Diabetes in the BioBreeding Rat.

Sarmiento, Janice; Wallis, Robert H; Ning, Terri; Marandi, Leili; Chao, Gary; Veillette, André; Lernmark, Åke LU ; Paterson, Andrew D and Poussier, Philippe (2015) In Journal of Immunology 194(2). p.615-629
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... (More)
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. (Less)
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organization
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type
Contribution to journal
publication status
published
subject
in
Journal of Immunology
volume
194
issue
2
pages
615 - 629
publisher
American Association of Immunologists
external identifiers
  • pmid:25505293
  • wos:000347176700014
  • scopus:84920491698
ISSN
1550-6606
DOI
10.4049/jimmunol.1302689
language
English
LU publication?
yes
id
7bdce3b3-70e3-449a-8dd6-9aa949dfea71 (old id 4908289)
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http://www.ncbi.nlm.nih.gov/pubmed/25505293?dopt=Abstract
date added to LUP
2015-01-08 15:56:51
date last changed
2017-01-01 03:56:45
@article{7bdce3b3-70e3-449a-8dd6-9aa949dfea71,
  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.},
  author       = {Sarmiento, Janice and Wallis, Robert H and Ning, Terri and Marandi, Leili and Chao, Gary and Veillette, André and Lernmark, Åke and Paterson, Andrew D and Poussier, Philippe},
  issn         = {1550-6606},
  language     = {eng},
  number       = {2},
  pages        = {615--629},
  publisher    = {American Association of Immunologists},
  series       = {Journal of Immunology},
  title        = {A Functional Polymorphism of Ptpn22 Is Associated with Type 1 Diabetes in the BioBreeding Rat.},
  url          = {http://dx.doi.org/10.4049/jimmunol.1302689},
  volume       = {194},
  year         = {2015},
}