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.

Modulation of the diet and gastrointestinal microbiota normalizes systemic inflammation and β-cell chemokine expression associated with autoimmune diabetes susceptibility

“…The ileal and cecal communities of DR+/+ ND and F+/+ ND rats were most similar, yet the peripheral inflammatory state was higher in DR+/+ rats, as measured by plasma cytokine levels (IL-1a, IL-4, IL-13, IL-18) and plasma induced transcription analysis. This result is consistent with the BB rat lineage possessing genetic variation that influences immune responsiveness and possibly increased intestinal permeability [ 86 , 87 ] as is suggested by the measurement of higher HMGB1-independent plasma TLR4 reporter activity in DR+/+ rats. Previously, we reported that the susceptibility of DR+/+ rats to KRV triggered diabetes declines with age and is coincident with the temporal acquisition of an IL-10- and TGF-β-mediated immunoregulated state [ 15 ].…”

Innate inflammation in type 1 diabetes

“…Consistent with the existence of additional genetic modifiers of immune function is the recent report that BB rats possess a single nucleotide substitution in the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene (a gene also associated with human T1D susceptibility) that results in T-cell hyper-responsiveness (75). Another source of inflammation could be intestinal hyper-permeability, possibly mediated by genetic variation and/or the composition of the intestinal microbiome, which could promote translocation of bacteria and/or PRR ligands and a heightened systemic innate inflammatory state.…”

Genomic Scans of Zygotic Disequilibrium and Epistatic SNPs in HapMap Phase III Populations

“…Fig 6 lists 19 networks of the interactions among three or more genes on individual chromosomes. For instance, the interactions among genes MAGI3 (rs1230658), PHTF1(rs1936398) and PTPN22 (rs1217410) on Chr 1 are evident, which is associated with Type 1 diabetes [ 41 , 42 ]. Part of ZRANB3 gene (213 bp; rs6742030) on Chr 2 is antisense to spliced RAB3GAP1 gene (rs7422031; d = -0.0483±0.0075; r 2 d<0 = 0.6047±0.5590) according to the information from http://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/ .…”