Protein Tyrosine Phosphatase Non-receptor 22 Polymorphisms 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 between PTPN22 C1858T polymorphism and juvenile idiopathic arthritis: A meta-analysis update with trial sequential analysis.

Our aim was to determine whether protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism (rs2476601) is associated with susceptibility to juvenile idiopathic arthritis (JIA). MEDLINE and EMBASE databases were searched to identify articles in which PTPN22 C1858T polymorphism was reported to be identified in JIA patients and controls. A meta-analysis was conducted to evaluate the association between PTPN22 C1858T polymorphism and RA using allelic contrast. Trial sequential analysis (TSA) was performed. Sixteen separate comparisons involving 5696 JIA patients and 9483 controls (a total of 15,179 subjects) were considered in this meta-analysis. A meta-analysis was performed with all JIA patients as well as JIA patients in each ethnic group. Meta-analysis revealed an association between the T allele of PTPN22 C1858T polymorphism and JIA in all subjects (OR, 1.322; 95% CI, 1.233-1.418; p<.001). Analysis after stratification by ethnicity indicated that the T allele was significantly associated with JIA in the European population (OR, 1.312; 95% CI, 1.2211-1.410; p<.001). However, analysis performed in the non-European population showed no significant association between the T allele and JIA. TSA indicated that the observed association between the PTPN22 polymorphism and JIA in all subjects and the European population is consistent with the existing evidence. This meta-analysis confirms that PTPN22 C1858T polymorphism is associated with susceptibility to JIA in Europeans, and that no additional studies are needed to verify these results. However, current evidence in the non-European population is insufficient, and further studies are warranted.

Meta-Analysis of the Genetic Association between PTPN22 and CTLA-4 Variants and Risk of Uveitis

Background: Though the risk of protein tyrosine phosphatase nonreceptor 22 (PTPN22) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) genetic variants with uveitis have been developed, the combined results still remain uncertain and controversial. Objectives: The aim of this study was to perform a meta-analysis to estimate the precise association of PTPN22 (rs2488457 and rs2476601) and CTLA-4 (rs231775, rs5742909, rs4553808, and rs3087243) polymorphisms with uveitis susceptibility. Method: Five electronic databases (PubMed, Embase, Web of Science, China Biomedical Database, and China National Knowledge Infrastructure) were systematically searched for relevant literature up to July 20, 2021. All statistical analyses were evaluated by Stata 12.0 software and R programming language. Results: Our meta-results indicated that PTPN22 rs2488457 conferred positive susceptibility to uveitis (odds ratio [OR] = 1.18, 95% confidence interval [CI] = 1.02–1.38, p = 0.029). In stratified analysis by ethnicity, the rs2488457 C allele had a growing tendency toward uveitis in the Asian region (OR = 1.21, 95% CI = 1.00–1.45, p = 0.046). For CTLA-4 rs231775, subgroup analysis based on ethnicity manifested a negative association among uveitis individuals in the Africa region (OR = 0.25, 95% CI = 0.19–0.33, p < 0.001). For CTLA-4 rs4553808, subgroup analysis by the disease type revealed that the GG genotype was associated with an elevated risk of Behcet’s disease (BD) (OR = 3.22, 95% CI = 1.05–9.90, p = 0.042). Conclusions: Our research revealed that PTPN22 rs2488457 conferred strong susceptibility to uveitis in general, especially in the Asian region. CTLA-4 rs231775 conveyed protection against uveitis in African populations, and CTLA-4 rs4553808 displayed an increased risk of BD.

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.

Role of C1858T Polymorphism of Lymphoid Tyrosine Phosphatase in Egyptian Children and Adolescents with Type 1 Diabetes.

Type 1 Diabetes Mellitus (T1DM) is a multifactorial autoimmune disease. The Protein Tyrosine Phosphatase Non-receptor 22 (PTPN22) gene is an important negative regulator of signal transduction through the T-cell Receptors (TCR). A PTPN22 polymorphism, C1858T, has been found to be a risk determinant for several autoimmune diseases, including T1DM, in different populations. The present study was aimed to analyze a possible association between the C1858T polymorphism in Egyptian children with T1DM. This case-control study included 240 children divided evenly between T1DM patients and controls. The PTPN22 C1858T polymorphism was genotyped using polymerase chain reaction with Restriction Fragment Length Polymorphism (RFLP). Both the 1858CΤ and 1858ΤΤ genotypes and the 1858T allele were found more frequently in patients (32.5% and 18.7%, respectively) than in controls (10% and 5.0%, respectively), P=0.013 and P=0.007, respectively. Among females, the 1858T allele was more common in patients (18%) than in controls (2.6%), P=0.014. These findings suggest that the PTPN22 1858T allele could be a T1DM susceptibility factor in the Egyptian population and that it might play a different role in susceptibility to T1DM according to gender in T1DM patients.

Dual Role of PTPN22 but Not NLRP3 Inflammasome Polymorphisms in Type 1 Diabetes and Celiac Disease in Children.

Genetic polymorphisms in genes coding for inflammasome components nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain-containing protein 3 (NLRP3) and caspase recruitment domain-containing protein 8 (CARD8) have been associated with autoinflammatory and autoimmune diseases. On the other hand several studies suggested that NLRP3 inflammasome contributes to maintenance of gastrointestinal immune homeostasis and that activation of NLRP3 is regulated by protein tyrosine phosphatase non-receptor 22 (PTPN22). PTPN22 polymorphism was implicated in the risk for various autoimmune diseases including type 1 diabetes (T1D) but not for celiac disease (CD). The aim of our study was to evaluate the role of inflammasome related polymorphisms in subjects with either T1D or CD as well as in subjects affected by both diseases. We examined PTPN22 rs2476601 (p.Arg620Trp), NLRP3 rs35829419 (p.Gln705Lys), and CARD8 rs2043211 (p.Cys10Ter) in 66 subjects with coexisting T1D and CD, 65 subjects with T1D who did not develop CD, 67 subjects diagnosed only with CD and 127 healthy unrelated Slovenian individuals. All results were adjusted for clinical characteristic and human leukocyte antigen (HLA) risk. PTPN22 rs2476601 allele was significantly more frequent among subjects with T1D (Padj = 0.001) and less frequent in subjects with CD (Padj = 0.039) when compared to controls. In patients with coexisting T1D and CD this variant was significantly less frequent compared to T1D group (Padj = 0.010). Protective effect on CD development in individuals with T1D was observed only within the low risk HLA group. On the other hand, we found no association of NLRP3 rs35829419 and CARD8 rs2043211 with the development of T1D, CD or both diseases together. In conclusion PTPN22 rs2476601polymorphism was significantly associated with the risk of developing T1D in Slovenian population, while no associations of proinflammatory NLRP3 and CARD8 polymorphisms with T1D and CD were observed. Interestingly, the same PTPN22 variant protected from CD. We hypothesize that this effect may be mediated through the NLRP3 inflammasome activation.

Protein tyrosine phosphatase non-receptor 22 and C-Src tyrosine kinase genes are down-regulated in patients with rheumatoid arthritis

Several protein tyrosine phosphatase non-receptor 22 (PTPN22) single-nucleotide polymorphisms (SNPs) have been significantly related with rheumatoid arthritis (RA) susceptibility. Nevertheless, its potential influence on PTPN22 expression in RA has not been completely elucidated. Furthermore, PTPN22 binds to C-Src tyrosine kinase (CSK) forming a key complex in autoimmunity. However, the information of CSK gene in RA is scarce. In this study, we analyzed the relative PTPN22 and CSK expression in peripheral blood from 89 RA patients and 43 controls to determine if the most relevant PTPN22 (rs2488457, rs2476601 and rs33996649) and CSK (rs34933034 and rs1378942) polymorphisms may influence on PTPN22 and CSK expression in RA. The association between PTPN22 and CSK expression in RA patients and their clinical characteristics was also evaluated. Our study shows for the first time a marked down-regulation of PTPN22 expression in RA patients carrying the risk alleles of PTPN22 rs2488457 and rs2476601 compared to controls (p = 0.004 and p = 0.007, respectively). Furthermore, CSK expression was significantly lower in RA patients than in controls (p < 0.0001). Interestingly, a reduced PTPN22 expression was disclosed in RA patients with ischemic heart disease (p = 0.009). The transcriptional suppression of this PTPN22/CSK complex may have a noteworthy clinical relevance in RA patients.

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.

STAT4 rs7574865 G/T and PTPN22 rs2488457 G/C polymorphisms influence the risk of developing juvenile idiopathic arthritis in Han Chinese patients.

Juvenile idiopathic arthritis (JIA) is a common autoimmune disease characterized by environmental influences along with several predisposing genes in the pathogenesis. The protein tyrosine phosphatase nonreceptor 22 (PTPN22) and signal transducer and activator of transcription factor 4 (STAT4) have been recognized as susceptibility genes for numerous autoimmune diseases. Associations of STAT4 rs7574865 G/T and PTPN22 (rs2488457 G/C and rs2476601 C/T) polymorphisms with JIA have repeatedly been replicated in several Caucasian populations. The aim of this study was to investigate the influence of three polymorphisms mentioned above on the risk of developing JIA in Han Chinese patients. Genotyping was performed on a total of 137 Chinese patients with JIA (JIA group) and 150 sex and age frequency-matched healthy volunteers (Control group). The single-nucleotide polymorphisms (SNP) were determined by using direct sequencing of PCR-amplified products. There were significant differences of PTPN22 rs2488457 G/C and STAT4 rs7574865 G/T polymorphisms between both groups. However, no significant difference was observed in distribution frequencies of PTPN22 rs2476601 polymorphism. The association with the PTPN22 rs2488457 G/C polymorphism remained significant in the stratifications by age at onset, ANA status, splenomegaly, lymphadenectasis and involvement joints. As with the STAT4 rs7574865 G/T polymorphisms, the enthesitis-related arthritis and presence of hepatomegaly had strong effect on the association. Our data strengthen STAT4 rs7574865 G/T and PTPN22 rs2488457 G/C polymorphisms as susceptibility factors for JIA.

Influence of protein tyrosine phosphatase gene (PTPN22) polymorphisms on rheumatic heart disease susceptibility in North Indian population

This study was aimed to assess the association of Protein tyrosine phosphatase non-receptor22 (PTPN22) gene single nucleotide polymorphisms (SNPs) with rheumatic heart disease (RHD) susceptibility in 400 RHD patients and 300 controls. The PTPN22 polymorphisms (rs2476601, rs1217406 and rs3789609) were genotyped using Taqman probes (Applied Biosystems, Foster City, CA). Statistical analysis was performed by spss and haplotype analysis by snpstat. The frequencies of variant alleles were not different between controls and cases (rs2476601: 2.00% & 1.05%; rs1217406: 36.33% & 34.75%; and rs3789609: 38.17% & 40.00%, respectively]. However, G rs2476601 A rs1217406 T rs3789609 haplotype turned out to be a low risk factor for RHD (P = 0.0042) predisposition in females and adult patients. This study suggests PTPN22 haplotype may modulate the risk to RHD in North Indians.

Zinc transporter 8 autoantibodies in patients with type 1 diabetes from a multiethnic population and their first degree relatives.

Zinc transporter 8 autoantibodies (ZnT8A) have been poorly studied in non-Caucasian individuals. We aimed to investigate the prevalence of ZnT8 autoantibodies in patients with T1D and their first degree relatives (FDR) from a multiethnic population, as well as its relation with the insulin (INS) or the protein tyrosine phosphatase non-receptor 22 (PTPN22) gene polymorphisms. ZnT8A were analyzed in sera from T1D patients (n = 72, mean age of 30.3 ± 11.4 years) of variable duration (15.7 ± 11.8 years) and their FDR (n = 78, mean age of 18.3 ± 9.1 years) by a triple mix Radioligand Binding Assay (RBA) for the ZnT8 autoantibody (ZnT8-RWQ) variants. SNP (single nucleotide polymorphism) for INS and PTPN22 were genotyped. The prevalence of ZnT8A was higher in T1D patients than FDR, for ZnT8TripleA (24% vs. 4%,p = 0.001), ZnT8RA (24% vs. 4%, p < 0.001) and ZnT8QA (15% vs. 3%, p = 0.004). All FDR with ZnT8A (n = 3) had at least another positive antibody. Heterozygosis for PTPN22 was associated with a higher frequency of ZnT8TripleA (p = 0.039) and ZnT8RA (p = 0.038). ZnT8A is observed in non-Caucasian patients with T1D, even years after the disease onset, as well as in their FDR. In those, there was an overlap between ZnT8A and other T1D antibodies. ZnT8A was associated with PTPN22 polymorphisms. Further longitudinal studies are necessary to elucidate the importance of these findings in the natural history of T1D patients with multiethnic background.

Associations of the PTPN22 and CTLA-4 genetic polymorphisms with Taiwanese ankylosing spondylitis

Ankylosing spondylitis (AS) is an autoimmune disease, and the imbalance of peripheral tolerance is involved in its pathogenesis. Importantly, the negative signal of activated T cells plays a crucial role in the balance of peripheral tolerance. It has been postulated that human protein tyrosine phosphatase nonreceptor 22 (PTPN22) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) genes encode proteins that are actively involved in regulating T-cell activation. Therefore, we evaluated the effects of PTPN22 and CTLA-4 genotypes on the occurrence of AS. Genetic polymorphisms of PTPN22 -1123G/C and CTLA-4 +49A/G were identified by polymerase chain reaction for 391 AS patients and 391 healthy controls. Subjects with PTPN22 CC and GC genotypes had a greater risk of AS occurrence than those with PTPN22 GG genotype [relative risk=1.39, 95% confidence interval (95% CI) 1.03-1.88]. Further, subjects with PTPN22 CC/CTLA-4 AA or PTPN22 GC/CTLA-4 AA genotypes had 1.90-fold (95% CI 1.02-3.49) greater risk of AS development than those with other combinations of PTPN22 and CTLA-4 genotypes. Our findings indicated that PTPN22 -1123G/C and CTLA-4 +49A/G genetic polymorphisms have a combined effect on the development of AS.

THU0109 The PTPN22 C1858T Polymorphism and Rheumatoid Arthritis: A Meta-Analysis

BackgroundThe protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene encodes a lymphoid-specific phosphatase (Lyp). Lyp is an intracellular PTP, and physically binds through its proline-rich motif to the SH3 domain of...

The PTPN22 1858T allele but not variants in the proximal promoter region ofIL-21gene is associated with the susceptibility to type 1 diabetes and the presence of autoantibodies in a Brazilian cohort

Interleukin (IL)-21 and protein tyrosine phosphatase non-receptor 22 (PTPN22) regulate lymphocyte function and have been implicated in the pathogenesis of autoimmune diabetes. We sequenced the proximal promoter of the IL-21 gene for the first time and analysed the PTPN22 1858T polymorphism in type 1A diabetes (T1AD) patients and healthy controls (HC). We correlated the frequencies of islet and extra-pancreatic autoantibodies with genotypes from both loci. The case series comprised 612 T1AD patients and 792 HC. Genotyping of PTPN22 C1858T was performed on 434 T1AD patients and 689 HC. The -448 to +83 base pairs (bp) region of the IL-21 gene was sequenced in 309 Brazilian T1AD and 189 HC subjects. We also evaluated human leucocyte antigen (HLA) DR3/DR4 alleles. The frequencies of glutamic acid decarboxylase (GAD65), tyrosine phosphatase-like protein (IA)-2, anti-nuclear antibody (ANA), thyroid peroxidase (TPO), thyroglobulin (TG), thyrotrophin receptor autoantibody (TRAb), anti-smooth muscle (ASM) and 21-hydroxylase (21-OH) autoantibodies were higher in T1AD patients than in HC. The PTPN22 1858T allele was associated with an increased risk for developing T1AD [odds ratio (OR) = 1·94; P < 0·001], particularly in patients of European ancestry, and with a higher frequency of GAD65 and TG autoantibodies. HLA-DR3/DR4 alleles predominated in T1AD patients. A heterozygous allelic IL-21 gene variant (g.-241 T > A) was found in only one patient. In conclusion, only PTPN22 C1858T polymorphism and HLA-DR3 and/or DR4 alleles, but not allelic variants in the 5'-proximal region of the IL-21 gene were associated with T1AD risk. Patients with T1AD had increased frequencies of anti-islet-cell, anti-thyroid, anti-nuclear, anti-smooth muscle and anti-21-OH autoantibodies. The C1858T PTPN22 polymorphism was also associated with a higher frequency of GAD65 and TG autoantibodies.

The PTPN22 C1858T polymorphism and rheumatoid arthritis: a meta-analysis

The aim of this study was to determine whether the protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism confers susceptibility to rheumatoid arthritis (RA) in populations with different ethnicities. MEDLINE database and manual search were utilized to identify articles in which the PTPN22 polymorphism was determined in RA patients and controls. A meta-analysis was conducted on the associations between the PTPN22 C1858T polymorphism and RA using (1) allelic contrast and (2) dominant model. A total of 30 separate comparisons involving 17,961 RA patients and 18,611 controls were considered in this meta-analysis. Meta-analysis showed an association between the T allele and RA in all subjects (OR = 1.490, 95% CI = 1.332-1.668, P < 1.0 × 10(-9)). After stratification by ethnicity, analysis indicated that the T allele was significantly associated with RA in Europeans and in Non-Europeans (OR = 1.423, 95% CI = 1.260-1.605, P = 1.0 × 10(-8); OR = 1.902, 95% CI = 1.488-2.430, P = 2.8 × 10(-8)). Meta-analysis of the CT + TT genotype showed the same result patterns as that shown by the PTPN22 C1858T polymorphism T allele. Furthermore, a direct comparison between rheumatoid factor (RF)-positive and RF-negative subjects revealed a significant association with the T allele in RA patients with RF, but not in subjects without RF (OR = 1.561, 95% CI = 1.373-1.775, P < 1.0 × 10(-9)). This meta-analysis confirms that the PTPN22 C1858T polymorphism is associated with RA susceptibility in different ethnic groups, especially in Europeans, and the PTPN22 C1858T polymorphism T allele is significantly more prevalent in RF-positive patents than in RF-negative patients.

The CTLA-4 +49 A/G, CT60 A/G and PTPN22 1858 C/T polymorphisms and susceptibility to vitiligo: a meta-analysis

The aim of this study was to explore whether cytotoxic T lymphocyte antigen-4 (CTLA-4) +49 A/G, CT60 A/G, and protein tyrosine phosphatase nonreceptor 22 (PTPN22) 1858 C/T polymorphisms confer susceptibility to vitiligo. A meta-analysis was conducted of the associations between the CTLA-4 +49 A/G, CT60 and PTPN22 1858 C/T polymorphisms and vitiligo using; (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) the additive model. A total of 14 separate comparisons were considered in our meta-analysis consisting of 3,404 patients with vitiligo and 5,069 controls (nine studies with 1,252 cases and 2,152 controls for the CTLA-4 polymorphisms and five studies with 1,800 cases and 3,269 controls for the PTPN22 polymorphism). Meta-analysis showed no association between vitiligo and the CTLA-4 +49 A/G polymorphism in all study subjects (OR of the G allele = 1.186, 95 % CI = 0.893-1.575, p = 0.240) and in European (OR = 1.016, 95 % CI = 0.873-1.182, p = 0.838). However, meta-analysis of the CTLA-4 CT60 A/G polymorphism showed an association between vitiligo and the CTLA-4 CT60 G allele in all study subjects (OR = 1.267, 95 % CI = 1.110-1.447, p = 4.5 × 10(-5)) and in the European group (OR = 1.345, 95 % CI = 1.163-1.556, p = 6.3 × 10(-6)). Analysis using the recessive model and homozygote contrast showed the same pattern for the CTLA-4 CT60 G allele. Meta-analysis of the PTPN22 1858 C/T polymorphism showed an association between the PTPN22 T allele and vitiligo in all subjects (OR = 1.507, 95 % CI = 1.320-1.720, p < 1.0 × 10(-8)) and in European group (OR = 1.530, 95 % CI = 1.339-1.748, p < 1.0 × 10(-8)), but not in Asians (OR = 0.482, 95 % CI = 0.152-1.530, p = 0.216). Analysis using the recessive, dominant model, and homozygote contrast showed the same pattern for the PTPN22 T allele. This meta-analysis demonstrates that the CTLA-4 CT60 A/G polymorphism confers susceptibility to vitiligo in Europeans, but no association was found between the CTLA-4 +49 A/G polymorphism and vitiligo susceptibility. The PTPN22 C1858T polymorphism is associated with vitiligo susceptibility in European population.

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.

Combined influence of genetic and environmental factors in age of rheumatoid arthritis onset

To study the combined effect of both genetic and environmental factors in the age of rheumatoid arthritis onset. Patients (n = 507). Shared epitope characterization was performed using Lifecodes HLA-SSO. Genotyping of protein tyrosine phosphatase non-receptor 22 (PTPN22) rs2476601 and signal transducers and activators of transcription 4 (STAT4) rs7574865 polymorphism was performed using fast real-time PCR System. Shared epitope, antibodies directed against cyclic citrulinated peptide (anti-CCP) antibodies and a higher level of education were associated with a younger age at disease onset (P = 0.033, P = 0.004 and P < 0.0001, respectively). Neither carriers of the minor allele of PTPN22 rs2476601 nor STAT4 rs7574 polymorphisms showed a significant association with a younger age at disease onset (P = 0.355, P = 0.065, respectively). We found an additive effect of the three genetic markers in the age at onset: subjects with three markers were associated with a disease onset 9.56, 8.61, and 6.41 years before than those with none, one, or two genetic markers (P = 0.004, P = 0.006 and P = 0.043, respectively). We also described the additive effect of shared epitope, anti-CCP antibodies, educational level, PTPN22, and STAT4 polymorphisms in age at onset. Patients with two, three, four, or five variables were associated with a significant younger age of disease onset (4.72 [0.05-9.38] years (P = 0.048), 9.56 [4.72-14.40] years (P < 0.0001), 12.74 [6.84-18.64] years (P < 0.0001), and 20.87 [10.40-37.17] years (P < 0.0001)). Risk factors for the development of rheumatoid arthritis are also associated, with an additive effect, with a younger age at disease onset.