Genetic Association Between a Lymphoid Tyrosine Phosphatase (PTPN22) and Type 1 Diabetes

Abstract

The lymphoid-specific phosphatase (LYP) encoded by PTPN22 is involved in preventing spontaneous T-cell activation by dephosphorylating and inactivating T-cell receptor-associated Csk kinase. We have genotyped 396 type 1 diabetic patients and 1,178 control subjects of Caucasian descent from north central Florida and report a strong association between type 1 diabetes and a polymorphism (R620W) in the PTPN22 gene. The homozygous genotype for the T allele encoding the 620W residue is associated with an increased risk for developing type 1 diabetes (odds ratio [OR] ‫؍‬ 3.4, P < 0.008), and the heterozygous genotype C/T had an OR of 1.7 (P ‫؍‬ 6 ؋ 10 ؊6 ). The C/C homozygous genotype is protective against type 1 diabetes (OR ‫؍‬ 0.5, P ‫؍‬ 6 ؋ 10 ؊6 ). Furthermore, transmission disequilibrium analysis of 410 affected sibpair and simplex families of Caucasian descent indicated that the type 1 diabetesassociated T allele is transmitted more often (57.2%) than randomly expected (P < 0.003). Together with previous reports of the association between PTPN22 and type 1 diabetes, as well as rheumatoid arthritis and systemic lupus erythematosus, these results provide compelling evidence that LYP is a critical player in multiple autoimmune disorders. Diabetes 54:906 -908, 2005

PTPN22 C1858T polymorphism in Colombian patients with autoimmune diseases

“…25 Similar to the above-summarized murine model, an increased germinal center formation is observed in autoimmune models of pSS, SLE, and T1D. 26,27 As previously shown by others, 11,[28][29][30][31][32][33] our results disclosed that T allele is a risk factor for T1D (OR ¼ 1.83), although this difference was in the threshold of significance (P ¼ 0.06).…”

From Markers to Molecular Mechanisms: Type 1 Diabetes in the Post-GWAS Era

“…Stimulation of peripheral blood mononuclear cells (PBMCs) from people at increased risk of T1D with an overlapping panel of synthetic peptides from the T1D-associated autoantigen glutamate decarboxylase (GAD) [27] identified a major determinant (amino acids 247-279) that had significant sequence similarity to the P2-C protein of Coxsackie B virus, which had been previously associated with the onset of T1D [28]. Furthermore, PBMC from individuals responding to GAD peptides also responded to a Coxsackie P2-C peptide (amino acids [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47]. Rudy et al (1995) [29] subsequently identified a 13 amino acid peptide of another T1D-associated autoantigen, proinsulin (amino acids [24][25][26][27][28][29][30][31][32][33][34][35][36] [30], which bears marked similarity to a peptide of GAD65 (amino acids 506-518).…”

“…A nonsynonymous SNP at position 1858 of PTPN22 was reported to be associated with T1D in many populations (OR for the heterozygous C/T genotype was 1.7) [40][41][42][43][44][45]. This C1858T SNP resulted in a missense mutation in people bearing the T1D risk allele that changed an arginine to a tryptophan at position 620 (R620W), resulting in the inability of LYP to bind its signaling molecule CSK [46], which increases phosphatase activity.…”

Finnish case–control and family studies support PTPN22 R620W polymorphism as a risk factor in rheumatoid arthritis, but suggest only minimal or no effect in juvenile idiopathic arthritis

“…The identification of PTPN22 1858 C/T as a putative disease risk allele in type 1 diabetes (T1D) [1][2][3][4][5][6] and subsequently RA [7][8][9] and other autoimmune diseases including SLE, 10,11 Graves disease 12 and JIA 9 has engendered considerable excitement. 13 PTPN22 also known as LYP (lymphocyte phosphatase) encodes a hematopoietic tissue-specific protein tyrosine phosphatase that is thought to inhibit T-cell activation through its association with the Csk tyrosine kinase.…”