Variation of two molecules that negatively regulate T cells, CTLA-4 and the tyrosine phosphatase LYP/PEP, are associated with susceptibility to human and NOD T1D.
The PTPN22 variant was strongly associated with T1D in cases vs controls (P=2 x 10(-7), OR=2.3, 95% CI=1.7-3.1) as well as in a transmission disequilibrium test in nuclear trio's (P=9 x 10(-9), OR=3.3, CI=2.1-5.0), RA (case/control: P=0.003, OR=1.8 CI =1.2-2.6), but not CD, in spite of a trend of increased homozygosity (P=0.05) and early age at onset (P=0.01).
We report that a recently described functional single-nucleotide polymorphism (rs2476601, encoding rs2476601" genes_norm="26191">R620W) in the intracellular tyrosine phosphatase (PTPN22) confers risk of four separate autoimmune phenotypes in these families: T1D, RA, SLE, and Hashimoto thyroiditis.
In addition, our results suggest a significant effect on T1D susceptibility for AC (Z score=2.30; p=0.02) and CTGGC (Z score=2.309, p=0.02) haplotypes of ZAP70 and PTPN22 genes, respectively.
Here, we analysed the effect of T1D-associated major HLA class II haplotypes and seven single nucleotide polymorphisms in six non-HLA genes [INS (rs689), PTPN22 (rs2476601), IL2RA (rs12722495 and rs2104286), PTPN2 (rs45450798), CTLA4 (rs3087243) and ERBB3 (rs2292239)] on peripheral blood Treg frequencies.
Recent studies demonstrated the association between the +1858T, -1123G>C variants of PTPN22 gene and type 1 diabetes mellitus in Caucasian and Japanese populations.
The -1123G > C SNP in the PTPN22 gene promoter and HLA DRB1*0405-DQB1*0401 might influence the concurrence of systemic and organ-specific ADs in patients with type 1 diabetes.
By comparison of a Danish population sample of 253 Caucasian children and adolescents with T1D and a control group consisted of 354 unrelated healthy blood donors, the present study provides evidence of an isolated association of the disease-associated PTPN22 1858T-allele with T1D to the female sex.
PTPN22rs2476601 is associated with JIA and numerous other autoimmune diseases, and has been reported to show female-specific association with type 1 diabetes.
The functional (R620W) variant of human PTPN22 (protein tyrosine phosphatase non-receptor 22) gene has been implicated in the risk to several autoimmune disorders, including type 1 diabetes, Graves' disease, rheumatoid arthritis and systemic lupus erythematosus.
Among the genetic variants associated with type 1 diabetes, the C1858T (Lyp) polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene alters the function of T cells but also of B cells in innate and adaptive immunity.
Genotype, allele, and phenotype distributions of the PTPN22 C1858T variant revealed similar frequencies in autoimmune diabetes with high GADA titer and juvenile-onset type 1 diabetes.
Polymorphisms in PTPN22 are associated with several autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and type 1 diabetes.
The PTPN22 +1858 allele and genotype distribution were markedly different between APS, type 1 diabetes [T1D; odds ratio (OR): 2.67; 95% confidence interval (CI): 1.52 to 4.68; P = 0.001], Graves disease (GD; OR: 1.94; 95% CI: 1.16 to 3.25; P = 0.011), and controls (OR: 3.31, 95% CI: 1.82 to 6.02; P < 0.001).