Protein Tyrosine Phosphatase Non-receptor Type 22 C1858T Research Articles

The association between PTPN22 C1858T gene polymorphism and type 1 diabetes mellitus: an Indonesian study

Background Type 1 diabetes mellitus (T1DM) is disease caused by the destruction of β pancreatic cells. The activation of T-lymphocyte and proliferation inhibitor are induced by protein tyrosine phosphatase non-receptor type 22 (PTPN22). However, the link between PTPN22 C1858T gene polymorphism and T1DM is still controversy. This study aimed to analyse the C1858T gene polymorphism in Indonesian children with T1DM. Materials and methods This case-control study was conducted from March 2021 to May 2022 in the Endocrinology Outpatient Clinic at Dr. Soetomo Hospital and Tropical Disease Center Universitas Airlangga. Patients with controlled T1DM during the study period were included. The PTPN22 analysis used polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. Results Sixty-two children voluntarily participated in this study, and were equally divided into the T1DM and control groups. Most of the patients (94%, 58/62) are Javanese. This study revealed a more frequent CC genotype (9.4%) and allele-C (54.6%) polymorphism in the T1DM group, while more frequent CT genotype (100%) and allele-T (50%) polymorphism were in the control group. The C- and T-allele frequency was 54.6% and 45.4% in the T1DM group, respectively. The T1DM and control groups did not significantly differ (p= .2381). Conclusions PTPN22 homozygous genotype-CC and allele-C polymorphisms are more frequent in patients with T1DM. However, the PTPN22 C1858T gene polymorphism did not significantly correlate to T1DM children in this study. Key Messages: The PTPN22 C1858T gene polymorphism does not significantly affect the susceptibility of T1DM in Indonesian children. PTPN22 homozygous genotype-CC polymorphism was more observed in the T1DM group; thus, this genotype may play as a risk factor for T1DM children in the Indonesian population.

The Potential Role of PTPN-22 C1858T Gene Polymorphism in the Pathogenesis of Type 1 Diabetes in Saudi Population

ABSTRACTBackground: Recent investigations have reported an association between protein tyrosine phosphatase non-receptor type-22 (PTPN-22) gene polymorphism and susceptibility to the development of type 1 diabetes (T1D) in some populations and not in others. In this study, we aimed to investigate the association of PTPN-22 C1858T polymorphism with T1D in Saudi children.Methods: A cohort of 372 type 1 diabetic children and 372 diabetes-free subjects was enrolled in the current investigation. The PTPN-22 C1858T polymorphism was identified using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.Results: Our data showed that the frequency of CT and TT genotypes of PTPN-22 C1858T was higher in T1D children (17.7% and 4.3%, respectively) compared to healthy controls (4.8% and 1.6%, respectively), and both genotypes were statistically associated with T1D patients (OR = 4.4, 95% CI: 2.55–7.58, p < 0.001; and OR = 3.2, 95% CI: 1.23–8.28, p = 0.017, respectively). Moreover, the 1858T allele was significantly associated with T1D patients compared to the C allele (OR = 3.2, 95% CI: 1.59–6.88, p < 0.001). In addition, the T allele was significantly associated with elevated levels of HbA1c, anti-GAD, and anti-insulin antibodies (p < 0.001) and a lower concentration of C-peptide (p < 0.001) in T1D children.Conclusion: The data presented here suggests that the T allele of PTPN-22 C1858T polymorphism might be a risk factor for T1D development in Saudi children.

Prognostic importance of human leukocyte antigen DRβ1 gene and protein tyrosine phosphatase nonreceptor Type 22 gene polymorphism in rheumatoid arthritis

Background: Major histocompatibility complex (MHC) or human leukocyte antigen (HLA) gene and some of the non-MHC genes are associated with genetic predisposition in rheumatoid arthritis (RA). The aim of the present study was to find the prevalence of HLA DRβ1 alleles and protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene single-nucleotide polymorphism (SNP) in RA patients and also assessed their correlation with laboratory and clinical parameters. Materials and Methods: One hundred and fifty cases of RA and 100 healthy controls were studied. relation to RA patients. HLA DRβ1 typing was done by low-resolution sequence-specific primer polymerase chain reaction and auto-antibodies (Abs) (rheumatoid factor [RF], anti-cyclic citrullinated peptide 2 (CCP2) Ab, anti-nuclear Ab, double-stranded deoxyribose nucleic acid, anticardiolipin Ab) were done by enzyme-linked immunosorbent assay. Results: In patients with RA, the most common HLA DRβ1 allele was DRβ1*04 (23.3%), followed by DRβ1*10 (20.7%), DRβ1*03 (9.3%), and DRβ1*01 (8.7%). Contrary to this, some alleles of DRβ1 were significantly less expressed in RA such as DRβ1*07 (P = 0.000) and DRβ1*14 (P = 0.010). DRβ1*04 positive patients had significantly more RF positivity while DRβ1*10 positive patients had increased RF and anti-CCP2 Ab. DRβ1*04 positive cases had positive correlation with disease activity score. DRβ1*10 positive patients had negative correlation with the age of the RA patients. These patients have shown early onset of disease. PTPN22 C1858T SNP was found in only 4% cases of RA. No correlation was established with PTPN22 SNP positivity and clinical parameters. Conclusion: In our study, RA patients have less DRβ1*04 positivity as compared to the Western literature. In our area, DRβ1*10 is more common than DRβ1*01. HLA DRβ1*07 and *14 are found to be protective for RA. PTPN22 SNP has not shown any diagnostic or prognostic significance while a follow-up study may be useful for prognostic importance of HLA DRβ1 typing in RA.

Lack of the Association of the PTPN22 C1858T Gene Polymorphism With Susceptibility to Familial Mediterranean Fever.

This study aims to investigate whether the protein tyrosine phosphatase non-receptor type 22 (PTPN22) C1858T gene polymorphism plays a role in the pathogenesis of familial Mediterranean fever (FMF) through T-lymphocyte activation. We conducted a case-control study with 180 FMF patients (68 males, 112 females; mean age 38.2±1.6 years; range 16 to 81 years) and 184 healthy controls (86 males, 98 females; mean age 32.9±9.2 years; range 18 to 58 years). The PTPN22 C1858T polymorphism (rs2476601) was genotyped by polymerase chain reaction restriction fragment length polymorphism. In patients with FMF, clinical features, disease severity score, the frequencies of amyloidosis, positive family history, and Mediterranean fever gene mutations were determined. The frequencies of heterozygous genotype (CT) were 4.5% in FMF patients and 2.8% in healthy controls, respectively. The frequencies of polymorphic homozygous genotypes (TT) were 0.5% in both FMF patients and healthy controls. There were no statistically significant differences in the frequencies of CT and TT genotypes between FMF patients and healthy controls (odds ratio: 1.65, 95% confidence interval: 0.53-5.14, p>0.05 for CT genotype). The frequencies of clinical features, sex, amyloidosis, positive family history, Mediterranean fever gene mutations, and disease severity score were not significantly different between the patients. The distribution of PTPN22 C1858T polymorphism did not reveal any association with FMF in a Turkish population.

Role of the C1858T polymorphism of protein tyrosine phosphatase non-receptor type 22 (PTPN22) in children and adolescents with type 1 diabetes.

In recent years, increasing interest has been devoted to the susceptibility gene polymorphisms in type 1 diabetes (T1D) as well as in other autoimmune diseases. Among these, a nucleotide polymorphism of the gene encoding for the protein tyrosine phosphatase non-receptor type 22 (PTPN22) has been associated with T1D in several studies. The aim of this study is to define the frequency of the C1858T polymorphism in the PTPN22 gene in a cohort of 113 Caucasian patients (58 males and 55 females) with T1D, and to assess a possible correlation with a group of clinically relevant variables: age at onset, gender, diabetes-related autoantibodies, residual β-cell function and daily insulin requirement (IR) 6 months after diagnosis. Using a PCR-RFLP approach, we evidenced a 17.7% frequency of the PTPN22 C1858T polymorphism in diabetic patients, higher than the frequency showed in the general population. A statistically significant correlation between this polymorphism and higher levels of C-peptide at diagnosis and lower IR at 6 months from diagnosis was observed (P=0.001 and P=0.04). Moreover, 1858T variant carriers were more frequently positive for glutamic acid decarboxylase (GAD) autoantibodies at diagnosis than wild-type subjects (P=0.19). On the other hand, no significant difference regarding age at onset, gender distribution, insulinoma-associated 2 molecule (IA2) and islet cell antibodies (ICA) positivity was found. These findings, if adequately confirmed in the future and extended to larger samples, may characterize a subset of T1D patients with a defined genetic pattern, who may be eligible for trials aimed to preserve residual β-cell function in the coming years.

Association between PTPN22 C1858T polymorphism and alopecia areata risk

Alopecia areata (AA) is a skin condition in which hair is lost from certain or all areas of the body. This condition has been described as an immune-mediated complex genetic disease, characterized by the presence of lymphocytes that are directed to the hair follicles in the anagen phase. The gene encoding the protein tyrosine phosphatase, non-receptor type 22 (PTPN22), which is exclusively expressed in immune cells, has been considered as a risk factor associated with a number of autoimmune diseases. In AA, the single nucleotide polymorphism, rs2476601, has been identified as a risk factor in several populations. The aim of the present study was to investigate the effect of PTPN22 C1858T inherited genetic polymorphism on the predisposition to severe forms of AA, in a case-control study on individuals. The study included 64 unrelated patients diagnosed with several types of AA, as well as 225 healthy unrelated subjects. The DNA samples were genotyped for PTPN22 C1858T polymorphism using the polymerase chain reaction-restriction fragment length polymorphism technique. Causal associations were determined by χ2 test and their respective odds ratio (OR) was assessed in a 2×2 contingency table. The results demonstrated a significant association of the T allele [P=0.040; OR=3.196; 95% confidence interval (CI), 0.094-10.279] and the CT genotype (P=0.038; OR=3.313; 95% CI, 1.008-10.892) with patchy AA. In conclusion, the results of the present study suggested the possible involvement of the T allele of the PTPN22 C1858T SNP as a genetic risk factor for this type of AA in the population studied.

The rheumatoid arthritis susceptibility polymorphism PTPN22 C1858T is not associated with leflunomide response or toxicity.

A common polymorphism (C1858T) in the gene that encodes the protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with altered T-cell responses and increased susceptibility to rheumatoid arthritis (RA) and other autoimmune diseases. Teriflunomide, the active metabolite of leflunomide, reduces T-cell responses through inhibition of tyrosine kinase p56LCK. We examined a potential association between PTPN22 genotype and response or toxicity to leflunomide in Caucasian RA patients taking leflunomide in combination with other disease-modifying antirheumatic drugs (DMARDs). Patients enrolled in the Royal Adelaide Hospital RA inception cohort and taking leflunomide were eligible for inclusion. Participants were followed for 12months after leflunomide initiation or until either another DMARD was added or leflunomide was ceased. Clinical response according to change in 28-joint Disease Activity Score (DAS28) and cessation due to toxicity were assessed. A total of 94 participants were included in the study, 75 of whom carried the CC genotype, 18 the CT, whereas one individual carried the TT genotype. Over the first 12months of leflunomide treatment, there was no statistically significant relationship between carrying the T allele and change in DAS28 (-0·84 vs. -1·15, P=0·446) nor with cessation of leflunomide treatment due to side effects (P=0·433). These results indicate that PTPN22 C1858T genotype has no effect on response or toxicity outcomes in leflunomide-treated RA patients. This is the first study to evaluate the biologically plausible hypothesis that PTPN22 genotype might be a predictor of response/toxicity to leflunomide therapy. Despite this, PTPN22 genotype was not associated with leflunomide response or toxicity in patients with RA.

Protein Tyrosine Phosphatase Non-receptor 22 Gene C1858T Polymorphism in Patients with Coexistent Type 2 Diabetes and Hashimoto's Thyroiditis.

A protein tyrosine phosphatase non-receptor type 22 (PTPN22) C1858T gene polymorphism has been reported to be associated with both Type 2 diabetes mellitus (T2DM) and Hashimoto's thyroiditis (HT) separately. However, no study has been conducted to explore the C1858T polymorphism in T2DM and HT coexistent cases up to now. The study aimed to determine whether a relationship exists or not between the PTPN22 C1858T polymorphism and this coexistent patient group. Case-control study. Peripheral blood samples from 135 T2DM patients, 102 patients with coexistent T2DM+HT, 71 HT patients and 135 healthy controls were collected into ethylenediaminetetraacetic acid (EDTA) anticoagulant tubes and genomic DNA was extracted. The PTPN22 C1858T polymorphism was analyzed using polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) methods. Statistically significant differences were not observed between the patient and control groups. This study demonstrated a statistically significant association between both the CT genotype and the T allele in the female patient group with coexistent T2DM+HT (CT genotype: p=0.04; T allele: p=0.045) with a statistically significant association between the CT genotype and the mean values of body mass index (BMI) and free T3 levels (FT3) (BMI: p=0.044 and FT3: p=0.021) that was detected in the patient group with coexistent T2DM+HT. The minor genotype TT was observed in none of the groups in this study. The CT genotype frequency was [number (frequency): 5 (3.8%), 7 (6.86%), 5 (7.04%), 3 (2.22%), while the T allele frequency was 5 (1.86%), 7 (3.44%), 5 (3.53%) and 3 (1.12%)] in the T2DM, T2DM+HT, HT and control groups, respectively. Our data suggest that the PTPN22 1858T allele and the CT genotype are associated with increased risk in female patients for coexistent T2DM+HT. The CT genotype was associated with high mean BMI and free T3 values in the patient group with coexistent T2DM+HT. These results demonstrate that T allele carriers were more often in the T2DM+HT group than in the T2DM group. Therefore, the combination of T2DM and HT with female gender may have higher T allele carriage in comparison to the T2DM only and male groups.

Association of Protein Tyrosine Phosphatase Non-receptor, Type 22 (PTPN22) C1858T Polymorphism with Type 1 Diabetes in North India: A Replication Study

Objective: Type 1 diabetes (T1D) is a multifactorial autoimmune disorder where several genes have been associated with the disease. While the major histocompatibility complex has been shown to be the major locus, contributions of other loci in different combinations seem to have synergistic effects. PTPN22 (Protein tyrosine phosphatase non-receptor, type 22) gene encoding lymphoid tyrosine phosphatase (LYP) is a negative regulator of T cell signaling. A gain of function mutant at nucleotide position 1858 C>T has been associated with diabetes, however, it is reported to be absent in Asians. We have studied PTPN22 C1858T polymorphism in T1D patients from North India since there are no reports from this region. Methods: PTPN22 C1858T polymorphism was studied in 250 T1D patients and 480 healthy controls using polymerase chain reaction followed by restriction digestion (PCR-RFLP). Alleles of HLA-DRB1 locus were studied using PCR followed by hybridization with sequence specific oligonucleotide probes using a bead based assay on Luminex platform. Results: In spite of reports of absence of 1858T allele in Asians, we observed this allele to be present in North Indians, albeit with low frequency (1.98%). However, T1D patients from the same ethnic background showed significantly higher frequency of the allele and heterozygous genotype 1858CT as compared to controls. Patients with both 1858CT and 1858CC genotypes had predisposing MHC alleles. Conclusion: The association of PTPN22 1858CT genotype with Type 1 diabetes was independent of the predisposing Human leukocyte antigen (HLA) alleles DRB1*03:01, DRB1*04:01, DRB1*04:05 in North Indian patients, suggesting their integrated roles in manifestation of T1D. Based on the reported role of PTPN22 1858CT genotype in defective innate immune responses against viral infections, and defects in early T cell signaling, it is tempting to speculate that it may be detrimental for the destruction of pancreatic beta cells in the present scenario.

Association between PTPN22 C1858T Gene Polymorphism and Graves’ Disease in Egyptians, Correlation with Tc-99m Pertechnetate Thyroid Uptake

Background: The protein tyrosine phosphatase non receptor 22 gene (PTPN22) is an important negative regulator of signal transduction through the T-cellreceptors (TCR). A single-nucleotide polymorphism (SNP) C1858T within this gene was shown to be a risk factor for several autoimmune diseases such asGraves’disease (GD). Objective: The aim of this study was to analyze the possible association between C1858T SNP of protein tyrosine phosphatase non receptor type 22 (PTPN22) and GD in Egyptian patients and to correlate this gene expression with Tc-99m Pertechnetate uptake value and thyroid hormonal profile.Patients and Methods: The current study evaluated the PTPN22 C1858T polymorphism in 40 GD patients and 20 healthy age and sex matched control subjects with no family history of GD or any other autoimmune disease. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (RFLP).Tc-99m Pertechnetate thyroid scan and uptake was performed for GD patients. Thyroid hormonal profile including serum FT3, FT4 and TSHwas also performed for patients and control subjects.Results: No statistical significant difference in the distribution of genotypes and allelefrequency for the PTPN22 C1858T SNP between GD patients and controls (P >0.05). Genotype analysis revealed that all control group and 36/40 GD patients had the CC genotype while only 4 GD patients hadthe TT genotype. Patients with TT genotype had a significantly higher uptake % when compared with that of patients with CC genotype (26.2 ±11.5 % versus 9.2±3.1 %, respectively) (P<0.001).Conclusion: No association was found between the PTPN22 C1858Tpolymorphism and Graves’ disease in Egyptian patients. However, preliminary data suggest that the expression of TT genotype together with high Tc-99m uptake percent might be a predictor for refractory disease that would necessitate more aggressive treatment.

Protein tyrosine phosphatase non-receptor type 22 gene polymorphism C1858T is not associated with leprosy in Azerbaijan, Northwest Iran

BACKGROUND:Leprosy (Hansen's disease) is a human chronic granulomatous infectious disease caused by Mycobacterium leprae. Several types of study support a role for host genetics in susceptibility to leprosy. The protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene encodes an intracellular lymphoid protein tyrosine phosphatase that has been shown to play a negative regulatory role in T-cell activation.AIMS:The aim of the present study was to find out associating the PTPN22 C1858T (R620W) polymorphism and leprosy in the Azeri population from Northwest Iran.MATERIALS AND METHODS:A total of 153 treated leprosy patients and 197 healthy and ethnic matched controls entered this study. We used restriction fragment length polymorphism method to type PTPN22 C1858T polymorphism.RESULTS:There was no significant difference in distribution of genotype and allele frequencies of PTPN22 C1858T polymorphism between leprosy patients and controls (P = 0.641 and 0.645; respectively). Moreover, there was no significant association between different clinical findings (karnofsky performance status score, clinical forms and manifestations of leprosy) and PTPN22 C1858T polymorphism. Data showed a low frequency of the minor (T) allele by 2.3% in leprosy and 1.5% in healthy individuals.CONCLUSIONS:The PTPN22 C1858T (R620W) is not relevant in susceptibility to leprosy in the Azeri population of Northwest Iran.

The Role of PTPN22 C1858T Gene Polymorphism in Diabetes Mellitus Type 1: First Evaluation in Greek Children and Adolescents

Type 1 diabetes mellitus (T1DM) is an autoimmune multifactorial disease. Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene encodes lymphoid-specific tyrosine phosphatase (Lyp), an inhibitor of T cell activation. PTPN22 C1858T polymorphism was associated with T1DM in populations of Caucasian origin. The aim of this study was the investigation for the first time of the association of PTPN22 C1858T polymorphism with T1DM in Greek population. We studied 130 children and adolescents with T1DM and 135 healthy individuals of Greek origin. The polymorphism was genotyped using polymerase chain reaction with restriction fragment length polymorphism. C1858T and T1858T genotypes as well as 1858T allele were found more frequently in patients (10.8% and 5.8%, resp.) than in healthy individuals (5.9% and 3.0%, resp.) but at non statistically significant level. There was no statistically significant association found with gender, age at diagnosis, severity of onset, history of Hashimoto thyroiditis or family history of T1DM. Increased frequency of 1858T allele in patients than in controls, implying a probable association, agrees with results of similar studies on other populations. The inability to find a statistically significant difference is probably due to the decreased frequency of minor allele in Greek population, indicating the need for a larger sample.

Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a strong susceptibility gene shared by many autoimmune diseases. The aim of this study was to explore the mechanisms underlying this relationship. We performed a comprehensive analysis of the association between PTPN22 polymorphism C1858T and autoimmune diseases. The results showed a remarkable pattern; PTPN22 C1858T was strongly associated with type I diabetes, rheumatoid arthritis, immune thrombocytopenia, generalized vitiligo with concomitant autoimmune diseases, idiopathic inflammatory myopathies, Graves' disease, juvenile idiopathic arthritis, myasthenia gravis, systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody-associated vasculitis and Addison's disease. By contrast, PTPN22 C1858T showed a negligible association with systemic sclerosis, celiac disease, multiple sclerosis, psoriasis, ankylosing spondylitis, pemphigus vulgaris, ulcerative colitis, primary sclerosing cholangitis, primary biliary cirrhosis, Crohn's disease and acute anterior uveitis. Further analysis revealed a clear distinction between the two groups of diseases with regard to their targeted tissues: most autoimmune diseases showing an insignificant association with PTPN22 C1858T manifest in skin, the gastrointestinal tract or in immune privileged sites. These results showed that the association of PTPN22 polymorphism with autoimmune diseases depends on the localization of the affected tissue, suggesting a role of targeted organ variation in the disease manifestations.

Evidence of cis-acting regulatory variation in PTPN22 in patients with rheumatoid arthritis

Objectives: To assess whether there are cis-regulatory polymorphisms that regulate protein tyrosine phosphatase, non-receptor type 22 (PTPN22) expression in rheumatoid arthritis (RA).Methods: RNA was extracted from positively selected CD56+, CD8+, and CD4+ mononuclear cells and the ‘residual’ cells from 12 RA patients heterozygous for the PTPN22 C1858T single nucleotide polymorphism (SNP) (rs2476601). Relative allelic expression was measured by single base extension (SBE) assay.Results: There was relative differential allelic expression (DAE ≥ 20%) in eight patients (p < 10−5); seven patients demonstrated DAE in more than one cell type; four patients had statistically significant differences between these cell populations (pcorrected < 0.05).Conclusions: We have demonstrated significant differences in expression of PTPN22 alleles in RA patients, indicating the probable existence of cis-acting regulatory elements.

TNF-α-308 promoter G/A and PTPN22 (1858 C/T) genes polymorphisms in Egyptian patients with systemic lupus erythematosus

Tumor necrosis factor alpha (TNF-α) promoter gene polymorphism at position 308 and that of the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) at position 1858 C/T have been inconsistently implicated as genetic risk factors for systemic lupus erythematosus (SLE) in some populations. We investigated the possible association of these polymorphisms with SLE susceptibility, and whether serum TNF-α level is related to different genotypes and disease activity in Egyptian SLE patients. TNF-α-308 G/A and PTPN22 C1858T polymorphisms were determined by PCR-restriction fragment length polymorphism analysis in 40 SLE patients and 40 unrelated healthy controls. Serum TNF-α level was measured by ELISA method. The median serum TNF-α was significantly higher in SLE patients than in controls (P < 0.001). A significant positive correlation was detected between serum TNF-α and SLE activity index (r = 0.723, P < 0.001). There was no significant difference in TNF-α-308 G/A genotypes or allele frequency between SLE cases and controls (P = 0.108 and P = 0.133, respectively). Diabetes was the only clinical feature in SLE patients that showed significant higher frequency with GA genotype than with GG genotype (P = 0.001). Risk estimation for the TNF-α-308 genotypes was of no significant (odds ratio = 2.429; 95 % CI = 0.8–7.2; P = 0.108). Concerning PTPN22 1858 C/T, there was no significant difference in PTPN22 C/T genotypes or allele frequency between SLE cases and controls (P = 0.152 and P = 0.155, respectively). TNF-α-308 G/A and PTPN22 (1858 C/T) polymorphisms do not exhibit a significant influence on the susceptibility of SLE in Egyptian patients. However, serum TNF-α level could be a sensitive marker of SLE disease activity.

R620W functional polymorphism of protein tyrosine phosphatase non-receptor type 22 is not associated with pulmonary tuberculosis in Zahedan, southeast Iran

The protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, which encodes an intracellular lymphoid-specific phosphatase, is considered an important regulator of T-cell activation. We investigated a possible association between the PTPN22 C1858T (R620W) polymorphism and pulmonary tuberculosis in an Iranian population. Single nucleotide polymorphisms of PTPN22 C1858T (rs2476601) were genotyped in 172 pulmonary tuberculosis cases and 204 normal subjects from Zaheden, Iran. Frequencies of genotypes CC, CT and TT of the PTPN22 C1858T polymorphism were 98.3, 1.7 and 0% in the pulmonary tuberculosis patients, and 96.1, 3.9 and 0% in the control group, respectively (P = 0.239). The frequency of the minor (T) allele was 0.8% in pulmonary tuberculosis patients and 2.0% in controls. Significant differences were not observed in genotype or allele frequencies of PTPN22 C1858T in the comparison between pulmonary tuberculosis patients and healthy subjects in our Iranian population sample.

Association of the PTPN22 R620W polymorphism with increased risk for SLE in the genetically homogeneous population of Crete.

Autoimmune diseases affect approximately 5% of the population, but much work remains to define the genetic risk factors and pathogenic mechanisms underlying these conditions. There is accumulating evidence that common genetic factors might predispose to multiple autoimmune disorders. Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are complex autoimmune disorders with multiple susceptibility genes. The functional R620W (C1858T) polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, a member of the PTPs that negatively regulate T-cell activation, has been recently associated with susceptibility to various autoimmune diseases. The aim of this study was to assess whether the C1858T polymorphism of PTPN22 also confers increased risk for SLE and RA in the genetically homogeneous population of Crete. It was found that the minor T allele of the PTPN22 C1858T SNP was more common in SLE patients than in control individuals (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.11 to 3.9, p = 0.017). No significant difference was observed in the frequency of this allele when RA patients were compared with controls (OR = 1.14, 95% CI = 0.65 to 1.9, p = 0.64). Although the PTPN22 1858 T allele is found at decreased frequency in Southern Europe, including Crete, an association was found between this allele and SLE in the population studied.

The Protein Tyrosine Phosphatase Non-Receptor Type 22 C1858T Polymorphism Is a Joint Susceptibility Locus for Immunthyroiditis and Autoimmune Diabetes

The lymphoid tyrosine phosphatase (LYP) encoded by the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene is a strong inhibitor of T cells. The single nucleotide polymorphism (SNP) C1858T within the PTPN22 gene was recently associated with autoimmune thyroid disease (AITD) and type I diabetes (T1D). The purpose of this study was to examine the joint association of this polymorphism with the co-occurrence of AITD and T1D. In this association study, 310 white subjects were genotyped for the C1858T polymorphism. The study population included 70 patients with both AITD and T1D (AITD+T1D), 70 patients with AITD only, 70 patients with T1D only, and 100 healthy controls. Patients with both AITD and T1D, and controls were also typed for HLA-DRB1. PTPN22 C1858T genotyping was performed by minisequencing. For HLA-DRB1 typing, polymerase chain reaction (PCR) sequence-specific oligonucleotide probes were used. The PTPN22 1858 minor T-allele frequency was strongly increased in patients with AITD+T1D (23.6%) compared with controls (8.0%, pc<0.001), with patients with AITD only (8.6%, pc=0.006), or with T1D only (10.7%, pc=0.028). T-allele carriers were also more frequently present in the group with AITD+T1D versus controls (41.4% vs. 14.0%, OR=4.35, 95% CI=2.08-9.09), AITD (17.1%, OR=3.42, 95% CI=1.56-7.48), and T1D (21.4%, OR=2.59, 95% CI=1.23-5.45). Especially in subjects with Hashimoto's thyroiditis (HT)+T1D, T-allele carriers were mostly frequent (50% vs. 14%, OR=6.14, 95% CI=2.62-14.38, pc<0.001). Considering all included patients with AITD, T-allele carriers were 29.3% vs. 14.0% in controls (p=0.008, OR=2.54, 95% CI=1.30-4.98). Patients carrying the PTPN22 1858 T allele had a twofold increased frequency of the HLA-DRB1*03 allele (64.7% vs. 37.3%, pc=0.034). The PTPN22 gene is a joint susceptibility locus for AITD (especially HT) and T1D.

Protein tyrosine phosphatase non‐receptor type 22 gene variants at position 1858 are associated with type 1 and type 2 diabetes in Estonian population

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is considered an important regulator of T-cell activation. Polymorphisms within the PTPN22 gene have been suggested to confer susceptibility to autoimmune endocrine disorders. To evaluate the impact of a functional variation in the PTPN22 gene in type 1 (T1D) and type 2 diabetes (T2D), the PTPN22 C1858T single nucleotide polymorphism (SNP) was studied in the population of Estonian origin, including 170 T1D patients, 244 T2D patients and 230 controls. Using two methods for PTPN22 C1858T detection in parallel, we found that not only T1D but also T2D is associated with the PTPN22 1858T allele. The role of PTPN22 gene in the pathogenesis of T2D is yet unclear and needs further investigation.

The Protein Tyrosine Phosphatase Nonreceptor 22 (PTPN22) Is Associated With High GAD Antibody Titer in Latent Autoimmune Diabetes in Adults

OBJECTIVE—We previously demonstrated the presence of two different populations among individuals with adult-onset autoimmune diabetes: those having either a high titer or a low titer of antibodies to GAD (GADAs). Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) has been identified as a new susceptibility gene for type 1 diabetes and other autoimmune diseases. The aim of the present study was to evaluate whether the phenotypic heterogeneity of adult-onset autoimmune diabetes based on the GADA titer is associated with the PTPN22 C1858T polymorphism. RESEARCH DESIGN AND METHODS—Analysis for the C1858T polymorphism using the TaqMan assay was performed in 250 subjects with adult-onset autoimmune diabetes, divided into two subgroups with low (≤32 arbitrary units) or high (&amp;gt;32 arbitrary units) GADA titers and 450 subjects with classic type 2 diabetes (from the Non Insulin Requiring Autoimmune Diabetes [NIRAD] Study cohort of 5,330 subjects with adult-onset diabetes) and in 558 subjects with juvenile-onset type 1 diabetes and 545 normoglycemic subjects. RESULTS—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. An increase in TT and CT genotypes was observed in individuals with a high GADA titer compared with a low GADA titer, those with type 2 diabetes, and control subjects (P &amp;lt; 0.002 for all comparisons). The PTPN22 1858T allele and phenotype frequencies were increased in high GADA titer compared with a low GADA titer, type 2 diabetic, and control subjects (P &amp;lt; 0.001 for all comparisons, odds ratio 2.6). CONCLUSIONS—In adult-onset autoimmune diabetes, the PTPN22 1858T variant is associated only with a high GADA titer, providing evidence of a genetic background to clinical heterogeneity identified by GADA titer.