Protein Tyrosine Phosphatase Non-receptor 22 Gene Research Articles

Investigation of the Relationship between PTPN22 Polymorphisms and Lung Sarcoidosis: A cross sectional study

Objective: Sarcoidosis is a systemic granulomatous disease with an unknown etiology characterized by noncaseating granuloma formation. It most often affects the lungs. Protein tyrosine phosphatase non-receptor 22 (PTPN22) is a gene that acts as a negative regulator of T-cell activation. Polymorphisms of this gene are associated with multiple human autoimmune diseases. The aim of this study was to assess the relationship between PTPN22 polymorphisms and lung sarcoidosis in a selected population.
 Methods: The study included 64 patients with lung sarcoidosis and 30 healthy controls. Patients were genotyped to determine two single nucleotide polymorphisms (SNPs) using the polymerase chain reaction (PCR) method. Hardy–Weinberg equilibrium (HWE), an important tool for detecting genotyping errors, was tested. Direct counting was used to estimate genotype frequencies. Logistic regression analysis was performed to compare allele and genotype frequencies between the patient and control groups.
 Results: The results of the study showed no correlation between lung sarcoidosis and the tested two SNPs of the PTPN22 gene (rs2488457, rs1310182) (p>0.05). The categorization analysis according to the clinical features, laboratory, and radiographic characteristics showed no correlation between the tested polymorphism of PTPN22 and these characteristics (p>0.05). 
 Conclusion: The present study demonstrated that the studied two SNPs of the PTPN22 gene (rs2488457, rs1310182) were not correlated with lung sarcoidosis, suggesting that it might be different from other classic autoimmune disorders. There is a need for more studies to verify these results concerning lung sarcoidosis in other ethnic origins.

Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with unexplained recurrent pregnancy loss: A case-control study

Background Lymphoid-tyrosine-phosphatase which is encoded by the protein tyrosine phosphatase non-receptor 22 (PTPN22) gene plays a pivotal role in the regulation of immune responses by dephosphorylating several signaling intermediates of immune cells.ObjectiveSince a balanced immune response has been shown to be important during pregnancy, the purpose of this research was to compare the frequency of the PTPN22 C1858T polymorphism in women with unexplained recurrent pregnancy loss (URPL) vs. in a control group for the first time.Materials and MethodsGenomic DNA from 200 individuals with URPL and 200 individuals without URPL (the control group) at the infertility center in Yazd, Iran was isolated using the salting-out method. The PTPN22 C1858T polymorphism of the two groups was analyzed using polymerase chain reaction-restriction fragment length polymorphism. Genotype frequencies in the women with URPL and the fertile control group were compared using the Chi-square test.ResultsThere were significant differences in the frequency of the PTPN22 1858T polymorphism in the URPL individuals vs. the healthy controls, i.e. 32.0% and 21.5%, respectively (p = 0.01).ConclusionOur findings suggest that the PTPN22 1858T polymorphism could play a role in recurrent pregnancy loss. Therefore, genotyping of the mentioned polymorphism can help clinicians to predict the probable risk of URPL.

Moderating Role of TSHR and PTPN22 Gene Polymorphisms in Effects of Excessive Fluoride on Thyroid: a School-Based Cross-Sectional Study.

We aimed to investigate the relationship between the effects excessive of fluoride on thyroid health in children and the moderating role of thyroid stimulating hormone receptor (TSHR) or protein tyrosine phosphatase nonreceptor-22 (PTPN22) gene polymorphisms. Four hundred thirteen children (141 with dental fluorosis and 198 boys) were enrolled from both historical endemic and non-endemic areas of fluorosis in Tianjin, China. The fluoride exposure levels, thyroid health indicators, and TSHR (rs2268458) and PTPN22 (rs3765598) polymorphisms were examined. Multiple logistic models were applied to evaluate the relationship between dental fluorosis and thyroid abnormalities. Children over 9 year old with dental fluorosis have lower FT4 and TGAb levels and thyroid volume and higher TPOAb levels (all P < 0.05). In overall participants, children with dental fluorosis were more likely to have thyroid antibody single positive issues (adjusted P = 0.039) and less likely to have a goiter according to age or body surface area (age or BSA) (adjusted P = 0.003); In the TSHR (rs2268458) SNP = CC/CT or PTPN22 (rs3765598) SNP = CC subgroup, dental fluorosis may cause thyroid antibody single positive (adjusted P = 0.036; adjusted P = 0.002); in the TSHR (rs2268458) SNP = TT or PTPN22 (rs3765598) SNP = CC subgroup, dental fluorosis may protect children from goiter (age or BSA) (adjusted P = 0.018; adjusted P = 0.013). Excessive fluoride may induce thyroid antibody single positive and reduce goiter in children. Heterogeneity exists in the relationship between excessive fluoride and thyroid antibody single positive or goiter issues across children carrying different TSHR (rs2268458) or PTPN22 (rs3765598) genotypes.

PTPN22 gene polymorphism and susceptibility to rheumatoid arthritis (RA): Updated systematic review and meta-analysis.

Several genome-wide association studies have revealed a genetic background with respect to susceptibility to rheumatoid arthritis (RA). Although several individual case-control studies have evaluated the role of protein tyrosine phosphatase non-receptor 22 (PTPN22) gene rs2476601 single nucleotide polymorphism (SNP) in conferring a risk for RA, the results have been conflicting. Hence, this meta-analysis was aimed to provide a solution for this issue. To search for studies assessing the association between the PTPN22 gene rs2476601 SNP and the risk of RA, a systematic search was conducted in the main databases, including PubMed, Scopus and Web of Science, prior to December 2019. The odds ratio (OR) and corresponding 95% confidence interval (CI) was calculated to assess the possibility of association risk. The literature search identified 52 case-control studies. The pooled analysis detected significant positive association of rs2476601 in all genetic models, including dominant model (OR = 1.69, 95% CI = 1.55-1.84, P < 0.001), recessive model (OR = 2.50, 95% CI = 2.06-3.05, P < 0.001), allelic model (OR = 1.80, 95% CI = 1.60-2.2, P < 0.001), TT versus CC model (OR = 2.79, 95% CI = 2.28-3.41, P < 0.001) and CT versus CC model (OR = 1.59, 95% CI = 1.50-1.67, P < 0.001). Analyses based on population stratification indicated that rs2476601 SNP strongly increased the risk of RA in Caucasians and Africans under all genotype models. This meta-analysis reports that the PTPN22 gene rs2476601 SNP increases RA risk, especially in Caucasians and Africans.

Association between the functional PTPN22 G788A (R263Q) polymorphism and susceptibility to autoimmune diseases: A meta-analysis

This study explored whether the functional protein tyrosine phosphatase nonreceptor 22 (PTPN22) G788A (R263Q) polymorphism is associated with susceptibility to autoimmune diseases. A meta-analysis was conducted using 23 comparative studies with a total of 16,719 patients and 17,783 controls. The meta-analysis showed an association between the A allele of the PTPN22 G788A polymorphism and decreased risk of autoimmune diseases in all subjects (p &lt; 0.001). Analysis after stratification by ethnicity indicated that the PTPN22 788A allele was significantly associated with autoimmune diseases in Europeans (p &lt; 0.001) but not in Latin Americans. Meta-analysis by autoimmune disease type showed a significant negative association between the PTPN22 788A allele and systemic lupus erythematous (SLE) (p = 001), rheumatoid arthritis (RA) (p = 0.008), ulcerative colitis (UC) (p = 0.016), but not Crohn's disease (CD). A single study for each showed no association between the PTPN22 788A allele and systemic sclerosis, giant cell arteritis, Henoch-schonlein purpura, uveitis, and Grave's disease. This meta-analysis demonstrates that the PTPN22 G788A polymorphism confers protection against SLE, RA, and UC, supporting evidence of association of the PTPN22 gene with a subgroup of autoimmune diseases.

Association Study of the PTPN22 Gene Polymorphisms with Systemic Lupus Erythematosus in Lorestan Province of Iran

Background: The protein tyrosine phosphatase non-receptor 22 (PTPN22) gene encodes the lymphoid protein tyrosine phosphatase. Recent studies demonstrated the association between the +1858C > T, -1123G > C variants of PTPN22 gene, and different autoimmune diseases. The current study aimed at examining the association between the polymorphism of PTPN22 gene and systemic lupus erythematosus (SLE) in the Southwest of Iran. Methods: The current study included 120 patients with SLE and 120 healthy volunteers as a control group. Genomic DNA was extracted and the genotyping was performed based on the PCR-restriction fragment length polymorphism (PCR-RFLP) method. Results: Frequency of 1858T allele (P < 0.001, OR = 0.44, 95% CI = 0.291 to 0.663)showed association and frequency of 1123C allele (P = 0.307, OR = 0.811, 95% CI = 0.543 to 1.212)showed no association with SLE in patients compared with the control group in the studied population. Conclusions: Statistical analysis showed no relationship among gender, genotype, and SLE risk. However, there was a significant relationship between age and the SLE risk (P = 0.006).

Role of PTPN22 and CSK gene polymorphisms as predictors of susceptibility and clinical heterogeneity in patients with Henoch-Schönlein purpura (IgA vasculitis).

IntroductionTo determine whether the PTPN22 (protein tyrosine phosphatase nonreceptor 22)/CSK (c-src tyrosine kinase) pathway is implicated in the susceptibility and clinical heterogeneity of Henoch-Schönlein purpura (HSP) in the largest series of Caucasian HSP patients ever assessed for genetic studies.MethodsA set of 329 Spanish patients diagnosed with HSP fulfilling the American College of Rheumatology and the Michel et al. classification criteria and 515 sex and ethnically matched controls were recruited in this study. Two well-known CSK (CSK rs34933034 and CSK rs1378942) and two functional PTPN22 (PTPN22 rs2476601 (R620W) and PTPN22 rs33996649 (R263Q)) polymorphisms, previously associated with autoimmunity, were genotyped with TaqMan single nucleotide polymorphism (SNP) genotyping assays.ResultsNo significant differences in the genotype and allele frequencies between HSP patients and controls were observed when the CSK rs34933034, CSK rs1378942, PTPN22 rs2476601 (R620W) and PTPN22 rs33996649 (R263Q) polymorphisms were analyzed independently. In keeping with this observation, no significant differences were found when we assessed these polymorphisms combined conforming haplotypes. In addition, there were no differences in the allele or genotype frequencies when HSP patients were stratified according the age at disease onset, sex, presence of arthralgia/arthritis, nephritis or gastrointestinal manifestations.ConclusionsOur results do not support association between PTPN22/CSK and HSP.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0796-x) contains supplementary material, which is available to authorized users.

Association of PTPN22 gene polymorphisms with chronic hepatitis B virus infection in Chinese Han population

Lymphoid protein tyrosine phosphatase encoded by protein tyrosine phosphatase non-receptor 22 (PTPN22) gene plays an important regulatory role in T- and B-cell activation. This study investigated PTPN22 −1123G/C and intron 16 T/C polymorphisms in 372 patients with chronic hepatitis B virus (HBV) infection, 72 HBV infection resolvers and 273 healthy controls. Genotypic association tests between groups assuming codominant, dominant or log-additive genetic models were performed. In recessive model, PTPN22 −1123G/C genotype GG in healthy controls was more frequent than infection resolvers (P=0.037, OR=3.606, 95%CI=1.079–12.053) and this genotype in HBV patients was more frequent than resolvers although the difference was not significant (P=0.059). The PTPN22 intron 16 T/C genotype TC in cirrhosis patients was significantly higher than asymptomatic carriers (ASC) in codominant (P=0.028, OR=9.792, 95%CI=1.281–74.832) and overdominant (P=0.025, OR=10.142, 95%CI=1.332–77.214) models. This genotype in hepatocellular carcinoma (HCC) patients was significantly higher than ASC in codominant (P=0.034, OR=9.200, 95%CI=1.176–71.990) and overdominant (P=0.030, OR=9.677, 95%CI=1.241–75.442) models. These findings suggest that PTPN22 polymorphisms may predispose the chronicity or the development of cirrhosis and HCC in HBV infection.

Generation of NOD mice carrying R619W mutation in PTPN22 gene by CRISPR/Cas9-mediated genome engineering (BA4P.134)

Abstract An allelic variant of protein tyrosine phosphatase nonreceptor 22 (PTPN22), PTPN22R620W, is strongly associated with type 1 diabetes (T1D) and several other autoimmune diseases in human, and increases the risk of developing T1D by 2-4 fold. Non-obese diabetic (NOD) mouse is an ideal spontaneous T1D model that shares with human many genetic pathways contributing to T1D; however, it has not previously been possible to introduce targeted mutations into NOD mice due to a lack of germline competent NOD embryonic stem cells. To overcome this technological hindrance, we used CRISPR/Cas9 technology to precisely mutate PTPN22 gene in its endogenous locus in NOD zygotes, and successfully produced 2 independent lines of NOD mice expressing PTPN22R619W variant, a murine ortholog of the human autoimmune-associated allele. We have also obtained a line carrying PTPN22 null allele. We have demonstrated the mutated PTPN22 genes in all lines have successfully germline transmitted. We have found a significant increase of T1D incidence in the heterozygous NOD PTPN22R619W mice, suggesting its strong effect in heterozygosity, which is very relevant to human T1D since PTPN22R620W is most commonly carried in heterozygosity. This is the first time the autoimmune-associated PTPN22 allele has been introduced into a spontaneous model of T1D and, to the best of our knowledge, the first time CRISPR/Cas9 technology has been used to genetically modify NOD mice.

AB0250 IL-6, IL-10 and PTPN22 gene polymorphism in children with juvenile idiopathic arthritis

BackgroundJuvenile idiopathic arthritis (JIA) is heterogenous group of diseases and it is most common rheumatic disease in children. Inflammatory cytokines and their regulatory gene polymorphisms are important in the pathogenesis...

PTPN22 and CTLA-4 gene polymorphisms in resected thymomas and thymus for myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease of striated muscle tissue mediated by autoantibodies. MG is often treated with thymectomy. Protein tyrosine phosphatase non-receptor 22 (PTPN22) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) have recently been found to be the genes that predispose to autoimmune diseases. The mechanisms of PTPN22 and CTLA-4 single nucleotide polymorphisms in resected thymomas and thymuses in MG remain unclear. In the present study, 90 patients with thymomas, including 44 patients with MG, 46 patients without MG, and 35 MG patients without thymoma were studied, with 50 healthy people as the controls. The +1858C>T polymorphism of the PTPN22 gene and the 49A>G polymorphism of the CTLA-4 gene were investigated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The PTPN22 -1123G>C polymorphism at the promoter site was genotyped using single allele-specific primer polymerase chain reaction (SASP-PCR). The PTPN22 +1858C>T polymorphism was not significantly different between the patients and the controls. Statistically significant differences in the allelic and genotypic frequencies of PTPN 22 -1123G>C and CTLA-4 49A>G were observed between the MG(+)-thymoma group and the controls (P = 0.000, 0.003), but not between the MG(-)-thymoma and MG-thymoma(-) groups and the controls (P = 0.192/P = 0.214 and P = 0.067/P = 0.254). Statistically significant differences in allelic and genotypic frequencies of the 49A>G for CTLA-4 were observed between the MG(+)-thymoma group and the controls (P = 0.000, P = 0.003), but not between the MG(-)-thymoma and MG-thymoma(-) groups and the controls (P = 0.077/P = 0.261 and P = 0.058/P = 0.058). Individuals with the PTPN22 CC genotype and the CTLA-4 G alleles had an increased risk of developing paraneoplastic MG (odds ration [OR]= 4.722, 95% confidence interval [CI]: 1.460-15.277) compared with those with the PTPN22 G allele and the CTLA-4 AA genotype. The results show an association between the PTPN22 1123G>C genotype and thymoma-associated MG, with significant synergy with the CTLA-4 G alleles.

No Association of PTPN22 Polymorphisms with Susceptibility to Ocular Behcet's Disease in Two Chinese Han Populations

BackgroundBehcet's disease is known as a recurrent, multisystem inflammation and immune-related disease. Protein tyrosine phosphatase non-receptor 22 (PTPN22) is a key negative regulator of T lymphocytes and polymorphisms of the PTPN22 gene have been shown to be associated with various immune-related diseases. The present study was performed to assess the association between PTPN22 polymorphisms and Behcet's disease in two Chinese Han populations.Methodology/Principal FindingsA total of 516 patients with ocular Behcet's disease and 690 healthy controls from two Chinese Han populations were genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method for three single nucleotide polymorphisms (SNPs). Hardy-Weinberg equilibrium was tested using the χ2 test. Genotype frequencies were estimated through direct counting. Allele and genotype frequencies were compared between patients and controls using logistic regression analysis. The results revealed that there was no association between the tested three PTPN22 SNPs (rs2488457, rs1310182 and rs3789604) and ocular Behcet's disease (p>0.05). Categorization analysis according to the clinical features did not show any association of these three polymorphisms with these parameters (p>0.05).Conclusions/SignificanceThe investigated PTPN22 gene polymorphisms (rs2488457, rs1310182 and rs3789604) were not associated with ocular Behcet's disease in two Chinese Han populations, and showed that it may be different from other classical autoimmune diseases. More studies are needed to confirm these findings for Behcet's disease in other ethnic backgrounds.

The association of lymphoid protein tyrosine phosphatase non-receptor 22 (PTPN22) gene polymorphism with Egyptian immune thrombocytopenic purpura

Immune thrombocytopenic purpura (ITP) is an autoimmune syndrome involving platelets destruction and suppression of platelet production that may predispose to bleeding. Protein tyrosine phosphatase non-receptor 22 gene (PTPN22) is an important negative regulator of signal transduction through the T-cell receptors (TCR). A single nucleotide polymorphism (SNP) 1858C > T within this gene was reported to be associated with increased risk of autoimmune diseases. The aim of the work was to study the frequency of the 1858C > T single nucleotide polymorphism in the PTPN22 gene in Egyptian ITP patients. After full clinical and laboratory examination of our subjects, the expression of the PTPN22 (1858C > T) gene polymorphism was analyzed in 60 ITP patients—40 childhood ITP (26 acute and 14 chronic) and 20 adulthood ITP (eight acute and 12 chronic)—and 100 healthy controls using a polymerase chain reaction-restriction fragment length polymorphism assay [PCR-RFLP]. The PTPN22 1858C > T SNP was significantly overrepresented in ITP patients than controls. It was detected in 11 childhood ITP (27.5%) and five adulthood ITP (25.0%) compared to 8.0% in controls (p = 0.002, p = 0.02) when comparing childhood ITP and adulthood ITP to controls, respectively. The T allele was significantly higher in ITP patients than controls. It was 20% for childhood ITP, 15% in adulthood ITP and 4% in controls (p = 0.002, p = 0.05) when comparing childhood ITP and adulthood ITP to controls, respectively. From this study we concluded that the PTPN22 1858C > T polymorphism is more prevalent in ITP patients; thus, it may be considered as a genetic risk factor in development of ITP in Egyptian patients.

The balance of expression of PTPN22 splice forms is significantly different in rheumatoid arthritis patients compared with controls

BackgroundThe R620W variant in protein tyrosine phosphatase non-receptor 22 (PTPN22) is associated with rheumatoid arthritis (RA). The PTPN22 gene has alternatively spliced transcripts and at least two of the splice forms have been confirmed to encode different PTPN22 (LYP) proteins, but detailed information regarding expression of these is lacking, especially with regard to autoimmune diseases.MethodsWe have investigated the mRNA expression of known PTPN22 splice forms with TaqMan real-time PCR in relation to ZNF592 as an endogenous reference in peripheral blood cells from three independent cohorts with RA patients (n = 139) and controls (n = 111) of Caucasian origin. Polymorphisms in the PTPN22 locus (25 SNPs) and phenotypic data (gender, disease activity, ACPA and RF status) were used for analysis. Additionally, we addressed possible effects of methotrexate treatment on PTPN22 expression.ResultsWe found consistent differences in the expression of the PTPN22 splice forms in unstimulated peripheral blood mononuclear cells between RA patients and normal controls. This difference was more pronounced when comparing the ratio of splice forms and was not affected by methotrexate treatment.ConclusionsOur data show that RA patients and healthy controls have a shift in balance of expression of splice forms derived from the PTPN22 gene. This balance seems not to be caused by treatment and may be of importance during immune response due to great structural differences in the encoded PTPN22 proteins.

A Sequence Variation in the Promoter Region of PTPN22 Gene Predicts Relapse After HLA-Fully-Matched Unrelated Bone Marrow Transplantation for Hematologic Malignancies

Abstract 3088The protein tyrosine phosphatase non-receptor 22 (PTPN22), also known as LYP, is an intracellular phosphatase ubiquitously expressed with particularly high expression in hematopoietic tissues that is a critical negative regulator of signaling through the T cell receptor and has emerged as the strongest common genetic risk factor for human autoimmunity outside the major histocompatibility complex. In this study we analyzed the impact of the polymorphism rs2488457 (1123G>C) in the promoter region of PTPN22 gene on transplant outcomes in patients undergoing unrelated HLA-matched bone marrow transplantation (BMT) through the Japan Donor Marrow Program. The PTPN22 rs2488457 genotypes were retrospectively analyzed in a cohort of 663 patients with hematologic malignancies and their unrelated donors. The presence of the C/C or C/G genotype in the donor side was associated with a significantly lower incidence of relapse compared to the donor G/G genotype (28% vs. 34% 5-years, P =0.05) (Fig.1). No difference was noted in transplant-related mortality, or graft-versus-host disease in relation to the rs2488457 polymorphism. The donor C/C or C/G genotype remained statistically significant for relapse in the multivariate analyses (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.43 to 0.85; P =0.004). These differences in relapse did not significantly affect on overall survival (OS) (48% vs. 49% 5-years, P =0.85). The recipient PTPN22 genotypes did not significantly influence the transplant outcomes. These results suggest an association of the donor C/C or C/G genotype with lower disease relapse. These could therefore be useful in selecting the donor and creating therapeutic strategies for improving the final outcome of allogeneic BMT. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

The −1123G&gt;C Variant of PTPN22 Gene Promoter is Associated with Latent Autoimmune Diabetes in Adult Chinese Hans

The protein tyrosine phosphatase non-receptor 22 (PTPN22) gene encodes for lymphoid protein tyrosine phosphatase. Recent studies demonstrated the association between the +1858T, -1123G>C variants of PTPN22 gene and type 1 diabetes mellitus in Caucasian and Japanese populations. This study examined the relationship between the polymorphism of PTPN22 gene and latent autoimmune 1 diabetes in adults (LADA) in Chinese Hans. We studied 229 adult Chinese patients with LADA (LADA group) and 210 healthy volunteers (control group). The -1123G>C and +1858C>T polymorphisms of PTPN22 gene were determined by PCR-restriction fragment length polymorphism method. Further, genotypic/allelic frequencies and clinical characteristics were compared between two groups. There was a significant difference of frequencies of the -1123G>C polymorphism between LADA and control groups (OR = 1.99, 95% CI = 1.24-3.2; P = 0.001). However, no significant differences in the +1858C>T genotypic (CC, CT) and allelic (C, T) frequencies were found. Furthermore, the frequencies of the -1123 GC, CC genotype in male patients with LADA were significantly higher compared with male healthy volunteers (OR = 1.65, 95% CI = 1.21-2.26; P = 0.005). The analysis of covariance demonstrated no difference between glycosylated hemoglobin, body mass index, duration of diabetes, C-peptide, and GAD-Ab titer between the group carrying GC/CC and the group without allele C. In conclusion, the -1123G>C promoter polymorphism of PTPN22 gene, but not the +1858C>T variant, is associated with LADA in adult Chinese Hans.

Association of the Protein Tyrosine Phosphatase Nonreceptor 22 Haplotypes with Autoimmune Thyroid Disease in the Japanese Population

A missence single-nucleotide polymorphism (SNP) in the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene known as R620W (rs2476601) was recently reported to be associated with several autoimmune diseases including Graves' disease (GD). The association was repeatedly confirmed in the populations of North European ancestry. However, this amino acid was reported to be nonpolymorphic in the Asian populations. Since the gene confers an impact on autoimmune diseases, we attempt to explore an association between the PTPN22 gene and autoimmune thyroid disease (AITD) in a Japanese population without restricting to rs2476601. Previous investigations have also demonstrated that two intronic SNPs (rs706778 and rs3118470) in the interleukin-2 receptor-alpha (IL2RA) gene were associated with type 1 diabetes in the Japanese population. We genotyped the five SNPs (rs12760457, rs2797415, rs1310182, rs2476599, and rs3789604) of the PTPN22 and the two SNPs (rs706778 and rs3118470 in the IL2RA gene) in 456 Japanese patients with AITD (286 with GD, 170 with Hashimoto's thyroiditis) and 221 matched Japanese control subjects. Seven SNPs were analyzed by either the SNAPshot method or the high-resolution melting and unlabeled probe methods. Case-control association studies were performed using the chi(2) and Fisher's exact tests with Yates correction. Haplotype was conducted using the expectation-maximization algorithm. No association was found between any of the individual SNPs of the PTPN22 gene and AITD. Permutation analysis revealed that the distribution of one haplotype is significantly different between patients with AITD and controls (p = 0.0036). A novel protective effect of a haplotype containing five SNPs was observed (p < 0.0001 for AITD, p < 0.0001 for GD, and p < 0.0001 for Hashimoto's thyroiditis, respectively). The GG allele of rs3118470 in the IL2RA gene was significantly associated with GD (p = 0.03), although the association was weak. Significant difference in the distribution of the haplotype suggests that the PTPN22 gene rather than rs2476601 is involved in the development of AITD in the Japanese population.

Associations of Protein Tyrosine Phosphatase Nonreceptor 22 (PTPN22) Gene Polymorphisms with Susceptibility to Graves' Disease in a Japanese Population

The polymorphism of the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene, which encodes an important negative regulator of T cell activation, has been reported to be associated with susceptibility to Graves' disease (GD) in Caucasians. The objective of this study was to investigate whether PTPN22 gene polymorphisms confer susceptibility to GD and Graves' ophthalmopathy (GO) in a Japanese population. We performed a case-control study of PTPN22 gene polymorphisms in Japanese GD patients (n = 414) and healthy control subjects with no antithyroid autoantibodies or family history of autoimmune disorders (n = 231). The G-1123C polymorphism (rs2488457) in the promoter region, Arg620Trp (C1858T) polymorphism (rs2476601) in exon 14, IMS-JST146695 polymorphism (rs3789607) in intron 19, and SNP37 (rs3789604) downstream of the PTPN22 gene were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism using restriction enzymes and direct PCR sequencing methods. None of the GD patients or control subjects had the 1858T allele of the PTPN22 gene polymorphism. The AA-genotype and A-allele frequencies of SNP37 were significantly higher in GD patients than in control subjects (A-allele frequency: p = 0.0085, odds ratio = 1.45). The genotype frequencies and allele frequencies of the G-1123C and IMS-JST146695 polymorphisms did not differ between GD patients and control subjects. The -1123G/1858C/JST146695T/SNP37C haplotype frequency was significantly lower in GD patients than in control subjects. There were no associations between PTPN22 gene polymorphisms and GO. The results suggest that SNP37 of the PTPN22 gene is associated with susceptibility to GD in a Japanese population. Further studies including functional analyses are required.

The functional R620W variant of the PTPN22 gene is associated with celiac disease

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. In an association study of this single nucleotide polymorphism with celiac disease (CD), comparison of 262 young diagnosis patients and 214 adult controls from Spain showed a higher frequency of the minor allele in the CD group (9.7% vs 5.6% in controls; P = 0.018), suggestive of an increased genetic risk to the disease (odds ratio = 1.82; 95% confidence interval 1.1-3.0). These results support the role of PTPN22 as a general autoimmunity locus involved in tolerance induction in the thymus.

Association between PTPN22 and endometriosis

PTPN22 is currently one of the few known shared-autoimmunity genes and is therefore a candidate marker for endometriosis. Our data show that female carriers of the PTPN22( *)T variant are significantly more susceptible to endometriosis than controls.