Evaluation of polymorphisms and expression of PTPN22, NLRP1 and TYR genes in vitiligo patients.

Introduction: Vitiligo is a pigmentary disorder associated with a selective loss of melanocytes in the skin, its appendages and mucous membranes. Aim: The aim of the study was to evaluate the association between the rs2476601 polymorphism of the PTPN22 gene, the rs2670660 and rs6502867 polymorphisms of the NLRP1 gene and the rs1847134 and rs1393350 polymorphisms of the TYR gene and vitiligo. Another aim was to compare the gene expression in lesional and symmetrically non-lesional skin of vitiligo patients and healthy controls. Material and methods: The experimental group consisted of 42 patients and the control group consisted of 38 healthy volunteers. The polymorphisms of the genes were assessed with PCR-RFLP technique and gene expression with qRT-PCR technique. Results: We found that the CT genotype of the PTPN22 rs2476601 polymorphism is more frequent in vitiligo patients, in the case of the NLRP1 rs2670660 polymorphism it was the AG genotype, in the NLRP1 rs6502867 polymorphism they were the CT and CC genotypes and in the TYR rs1393350 polymorphism it was the AG genotype. There was no association between vitiligo and the TYR rs1847134 polymorphism. We found statistically significant differences in gene expression in the lesional and symmetrical non-lesional skin of vitiligo patients compared to the control group. Conclusions: Our analysis showed genotypes predisposing to vitiligo. We found that the gene expression is different not only in lesional but also in non-lesional skin of vitiligo patients, what may change the approach to treatment of the disease.

PTPN22 gene functional polymorphism (rs2476601) in older adults with frailty syndrome.

The frailty syndrome is a common clinical marker of vulnerability in older adults conducive to an overall decline in inflammatory stress responsiveness; yet little is known about the genetic risk factors for frailty in elderly. Our aim was to investigate the association between the rs2476601 polymorphism in PTPN22 gene and susceptibility to frailty in Mexican older adults. Data included 630 subjects 70 and older from The Coyoacán cohort, classified as frail, pre-frail, and non-frail following Fried's criteria. Sociodemographic and clinical characteristics were compared between groups at baseline and after a multivariate analysis. The rs2476601 polymorphism was genotyped by TaqMan genotyping assay using real-time PCR and genotype frequencies were determined for each frailty phenotype in all participants and subsets by age range. Genetic association was examined using stratified and interaction analyses adjusting for age, sex and variables selected in the multivariate analysis. Disability for day-life activities, depression and cognitive impairment were associated with the risk of pre-frailty and frailty at baseline and after adjustment. Carrying the T allele increased significantly the risk of frailty in patients 76 and older (OR 5.64, 95% CI 4.112-7.165) and decreased the risk of pre-frailty under no clinical signs of depression (OR 0.53; 95% CI 0.17-1.71). The PTPN22 polymorphism, rs2476601, could be a genetic risk factor for frailty as subject to quality of life. This is the first study analyzing such relationship in Mexican older adults. Confirming these findings requires additional association studies on wider age ranges in populations of older adults with frailty syndrome.

Quantitative evaluation of PTPN22 copy number variation by digital droplet PCR and association with type 2 diabetes risk.

Type 2 diabetes (T2D) is a chronic endocrine disorder with rapidly increasing prevalence worldwide. Genetic instability leading to metabolic dysfunction plays an important role in T2D susceptibility and progression. Structural alteration in genome, that is, copy number variation (CNV) is emerging as the inherent marker for disease identification. Previous genomic CNV array revealed that protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene was overlapped with a CNV region, however, whether this CNV affected T2D risk remains to be further elucidated. In this study, we first identified divergent distributions of the PTPN22 copy number (CN) between T2D patients and healthy controls in Chinese population (p < 0.01). Risk assessment analysis revealed that the CN gain (OR = 3.28, p < 0.001) was the promising risk factor for T2D. Also, significantly positive correlations of the PTPN22 CNV with fasting plasma glucose and glycated hemoglobin were demonstrated in T2D patients. Statistical association analysis investigated that the T2D individuals carrying CN gain showed higher plasma glucose and lower insulin levels than those carrying CN normal and loss at 60 min/120 min/180 min during an OGTT test. In addition, the PTPN22 CNV had an effect on total cholesterol, and the CN gain presented higher values than the other two CN types. These results suggested that the CN gain types of the PTPN22 gene accompany with the glycometabolism dysregulation, and finally predispose their carriers to T2D; therefore, the PTPN22 CNV may be a promising biomarker for predicting T2D risk, or a clinical target for T2D diagnosis and therapy.

[Association of polymorphic markers rs7947461 of the TRIM21 gene and rs33996649 of the PTPN22 gene with the risk of developing exogenous dry eye syndrome]. / Assotsiatsiya polimorfnykh markerov rs7947461 gena TRIM21 i rs33996649 gena PTPN22 s riskom razvitiya sindroma sukhogo glaza ekzogennoi etiologii.

In this age of technological advancement, an increasing number of people is being exposed to external risk factors of damaging their ocular surface (wearing contact lenses, electromagnetic radiation from computers, mobile devices, etc.). However, the presence of external factors does not lead to a 100% risk of developing the dry eye disease (DED). The trigger mechanism in the development of autoimmune lesions of the ocular environment in some systemic diseases is known to be associated with molecular genetic factors. The search for molecular genetic disorders is based on the analysis of polymorphic markers of a number of genes responsible for the state of the eye surface. PURPOSE: To study the relationship of polymorphic markers rs7947461 of the TRIM21 gene and rs33996649 of the PTPN22 gene with the risk of developing dry eye syndrome of exogenous etiology. MATERIAL AND METHODS: The study included 57 people with exogenous risk factors for DED development. The control group included volunteers without a history of ophthalmic pathologies (n=75). Genotyping was done by real-time polymerase chain reaction followed by melting curve analysis. Statistical processing of data was done using the Statistica 6.1 RUS software for statistical analysis. RESULTS: In the course of the study, 31 patients of the main group were diagnosed with DED and separated into the 1st subgroup; DED diagnosis was not confirmed in 26 patients, who were put into the 2nd subgroup. The 1st subgroup showed a significant increase in the frequency of predisposing genotypes of the TRIM21 and PTPN22 genes. The relative risk of developing DED turned out to be 2.5 and 4.86 times higher, respectively. In the 2nd subgroup, no statistically significant data was found on the presence of predisposing genotypes of polymorphic markers of the TRIM21 and PTPN22 genes (p=0.3). CONCLUSION: The revealed association of polymorphic markers rs7947461 of the TRIM21 gene and rs33996649 of the PTPN22 gene with the risk of developing DED of exogenous etiology puts these loci as possible markers for diagnosing this pathology.

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

BACKGROUND: 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.

Association of PTPN22 Gene Polymorphisms with Susceptibility to Juvenile Idiopathic Arthritis in Iranian Population.

Juvenile idiopathic arthritis (JIA), the most common cause of chronic arthritis in children, is a complex immune-mediated disease with considerable long-term morbidity and mortality. According to previous studies, PTPN22 gene has been associated with JIA in several populations. In the present study, we attempted to determine the association of PTPN22 single nucleotide polymorphisms (SNPs) with susceptibility to JIA in Iranian population. Using the Real-time PCR allelic discrimination method, samples consisting of 55 unrelated patients and 93 healthy controls were genotyped. Using Fisher exact test or Chi-square test, genotypic and allelic frequencies were estimated. The results of our study indicated a significantly decreased association of rs1310182 (OR = 0.59, 95% CI = 0.36 -0.97, p = 0.037) with JIA. This association may indicate a protective role for rs1310182 SNP against JIA. More research would be needed to elucidate the mechanistic role of this association.

Association of PTPN22 1858C→T polymorphism, HLA-DRB1 shared epitope and autoantibodies with rheumatoid arthritis.

To assess impact of PTPN22 1858C→T polymorphism, HLA shared epitope and autoantibodies on susceptibility and severity of rheumatoid arthritis (RA). A total of 150 RA patients and 150 controls were included in the study. Anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor isotypes (IgG, IgM and IgA) were assayed by ELISA. PTPN22 1858C→T polymorphism was performed by RFLP analysis and HLA-DRB1 genotyping by PCR-SSP analysis. Single-view, anteroposterior radiographs of the hands and feet were obtained on all RA patients. The results showed association of PTPN22 1858 T allele with RA (OR = 2.3, 95 % CI 1.5-3.5) and bone erosion (OR = 2.9, 95 % CI 1.1-7.6). The associations increased with the combination of positive autoantibodies, HLA-DRB1 SE with PTPN22 1858 T allele carriage. The highest association was with the combination with anti-CCP antibodies (OR = 47.3, 95 % CI 10.9-204.4 for RA and OR = 69.4, 95 % CI 15.8-305.5 for erosion p < 0.001). Combination of PTPN22 1858 T allele carriage with negative RF isotypes or with absence HLA-DRB1 SE showed no significant association with RA. The presence of PTPN22 1858C→T polymorphism with HLA SE and autoantibodies increases risk of RA development and erosive disease.

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.

Association of distance to swine concentrated animal feeding operations with immune-mediated diseases: An exploratory gene-environment study.

BACKGROUND: Concentrated animal feeding operations (CAFOs) are a source of environmental pollution and have been associated with a variety of health outcomes. Immune-mediated diseases (IMD) are characterized by dysregulation of the normal immune response and, while they may be affected by gene and environmental factors, their association with living in proximity to a CAFO is unknown. OBJECTIVES: We explored gene, environment, and gene-environment (GxE) relationships between IMD, CAFOs, and single nucleotide polymorphisms (SNPs) of prototypical xenobiotic response genes AHR, ARNT, and AHRR and prototypical immune response gene PTPN22. METHODS: The exposure analysis cohort consisted of 6,464 participants who completed the Personalized Environment and Genes Study Health and Exposure Survey and a subset of 1,541 participants who were genotyped. We assessed the association between participants' residential proximity to a CAFO in gene, environment, and GxE models. We recombined individual associations in a transethnic model using METAL meta-analysis. RESULTS: In White participants, ARNT SNP rs11204735 was associated with autoimmune diseases and rheumatoid arthritis (RA), and ARNT SNP rs1889740 was associated with RA. In a transethnic genetic analysis, ARNT SNPs rs11204735 and rs1889740 and PTPN22 SNP rs2476601 were associated with autoimmune diseases and RA. In participants living closer than one mile to a CAFO, the log-distance to a CAFO was associated with autoimmune diseases and RA. In a GxE interaction model, White participants with ARNT SNPs rs11204735 and rs1889740 living closer than eight miles to a CAFO had increased odds of RA and autoimmune diseases, respectively. The transethnic model revealed similar GxE interactions. CONCLUSIONS: Our results suggest increased risk of autoimmune diseases and RA in those living in proximity to a CAFO and a potential role of the AHR-ARNT pathway in conferring risk. We also report the first association of ARNT SNPs rs11204735 and rs1889740 with RA. Our findings, if confirmed, could allow for novel genetically-targeted or other preventive approaches for certain IMD.

Recurrence of Graves' Disease: What Genetics of HLA and PTPN22 Can Tell Us.

Background: Approximately half of patients diagnosed with Graves' disease (GD) relapse within two years of thyreostatic drug withdrawal. It is then necessary to decide whether to reintroduce conservative treatment that can have serious side effects, or to choose a radical approach. Familial forms of GD indicate a significant genetic component. Our aim was to evaluate the practical benefits of HLA and PTPN22 genetic testing for the assessment of disease recurrence risk in the Czech population. Methods: In 206 patients with GD, exon 2 in the HLA genes DRB1, DQA1, DQB1 and rs2476601 in the gene PTPN22 were sequenced. Results: The risk HLA haplotype DRB1*03-DQA1*05-DQB1*02 was more frequent in our GD patients than in the general European population. During long-term retrospective follow-up (many-year to lifelong perspective), 87 patients relapsed and 26 achieved remission lasting over 2 years indicating a 23% success rate for conservative treatment of the disease. In 93 people, the success of conservative treatment could not be evaluated (thyroidectomy immediately after the first attack or ongoing antithyroid therapy). Of the examined genes, the HLA-DQA1*05 variant reached statistical significance in terms of the ability to predict relapse (p=0.03). Combinations with either both other HLA risk genes forming the risk haplotype DRB1*03-DQA1*05-DQB1*02 or with the PTPN22 SNP did not improve the predictive value. Conclusion: the DQA1*05 variant may be a useful prognostic marker in patients with an unclear choice of treatment strategy.

Association of PTPN22 polymorphism and its correlation with Graves' disease susceptibility in Polish adult population-A preliminary study.

BACKGROUND: Susceptibility to Graves' disease (GD) is determined by various genetic factors; the gene encoding protein tyrosine phosphatase (PTPN22) may be one of those associated with higher risk of GD. The aim was to estimate the association of the PTPN22 gene polymorphism rs2476601:c.C>T (c.1858C>T) with the predisposition to GD within the adult north-eastern Polish population. METHODS: PTPN22 gene polymorphism was analyzed in individuals with clinical GD history (n = 166) and healthy subjects (n = 154). The presence of different variants of the investigated gene polymorphism was estimated using the DNA Sanger sequencing method. RESULTS: Patients with GD had a more frequent occurrence of the T gene allele of PTPN22 gene compared to the control group, however, it was not significant (p = 0.257). Analysis of genotype distribution showed significantly more frequent occurrence of TT homozygote in GD patients compared to control individuals (p = 0.016, OR = 9.28). Patients with ophthalmopathy had a less frequent occurrence of the T gene allele of PTPN22 gene compared to patients without ophthalmopathy, however, it was not significant (p = 0.12). Occurrence of the T gene allele of PTPN22 gene in GD manifestation in those under 40-year old was more frequent compared to individuals over 40, but the obtained difference was also not significant (p = 0.75). CONCLUSIONS: Our preliminary study suggest that PTPN22:c.1858C>T gene polymorphism may be associated with a predisposition to GD within the adult north-eastern Polish population. The studied polymorphism of the PTPN22 gene did not significantly affect the risk of ophthalmopathy developing and disease manifestation before the age of 40.

PTPN22 1858 C/T polymorphism is associated with alteration of cytokine profiles as a potential pathogenic mechanism in rheumatoid arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) is one of the most common prevalent autoimmune diseases. The 1858 C/T (rs2476601) single nucleotide polymorphism (SNP) within the PTPN22 gene has been associated with susceptibility to inflammatory based diseases in several populations. It is implicated that altered cytokine production has a potential pathogenic role in the development of RA. The aim of this work was to analyze the association of 1858 C/T PTPN22 polymorphism in RA patients with cytokine profiles. MATERIALS AND METHODS: This study was performed on 120 RA patients who were referred to the Rheumatology Research Centre, Shariati Hospital (Tehran, Iran), and 120 healthy controls. Genomic DNA was extracted and genotyped for 1858 C/T PTPN22 gene SNP using the PCR-RFLP technique. Serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ as well as Anti-CCP and RF was measured by ELISA method. RESULTS: Results showed that 1858 C/T PTPN22 SNP significantly (P =  0.007, OR = 2.321, 95% CI = 1.063-5.067) associated with RA. The 1858 T allele frequency was also significantly increased in RA patients in comparison to the controls (P =  0.008, OR = 3.583, 95% CI = 1.3-9.878). Our data demonstrated a significant reduction of IL-4 and IL-10 in PTPN22 1858C/T compared to 1858C/C RA patients. In addition, upregulation of IL-6, IFN-γ, and TNF-α was observed in PTPN22 1858C/T vs. 1858C/C RA patients. DISCUSSION: Our findings implicate altered cytokine profiles as a possible pathogenic mechanism by which the 1858 T allele may contribute to the progress of RA.

Distribution of PTPN22 polymorphisms in SLE from western Mexico: correlation with mRNA expression and disease activity.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune inflammatory disease characterized by loss of self-tolerance with hyperactivation of autoreactive T and B cells. Protein tyrosine phosphatase non-receptor type 22 (PTPN22) encodes for lymphoid-specific phosphatase (Lyp), which is a key negative regulator of T lymphocyte activation. The aim of this study was to evaluate the genetic contribution of PTPN22 -1123G>C and +1858C>T polymorphisms and their haplotypes in SLE patients, as well as mRNA expression according to -1123G>C promoter polymorphism and disease activity. One hundred and fifty SLE patients and 150 unrelated healthy controls (HC), both Mexican mestizos, were genotyped by PCR-RFLP technique for the PTPN22 -1123G>C and +1858C>T polymorphisms. PTPN22 mRNA expression levels were determined by real-time PCR from PBMCs of thirty patients with SLE and fifteen HC carrying different genotypes. Distributions of genotype and allelic frequencies were similar between SLE and HC. The most frequent alleles were -1123 G and +1858 C in both groups (69 vs. 66 % and 97 vs. 98 %, in SLE and HC, respectively). However, the recessive model of inheritance analysis showed a lower frequency of -1123 CC genotype in SLE patients (7 vs. 15 %), suggesting a protection effect to develop SLE (OR 0.41, CI 1.10-5.28, p = 0.02). Haplotype analysis showed strong linkage disequilibrium D' = 0.98 for PTPN22 -1123G>C and +1858C>T polymorphisms, but haplotypes were not associated with SLE. The PTPN22 mRNA expression did not show differences among -1123G>C genotypes; nevertheless, a significant negative correlation with disease activity was found (r = -0.64, p < 0.01). SLE inactive patients showed similar PTPN22 mRNA expression levels to healthy controls, whereas in patients with severe flare, the expression was nearly depleted. In conclusion, we found a lack of association of PTPN22 -1123G>C and +1858C>T polymorphisms with the risk of developing SLE in a Mexican population. Moreover, decreased or absent PTPN22 mRNA expression in SLE patients with severe flare suggests that Lyp plays an important regulatory role, and its absence contributes to the inflammatory response and disease activity in SLE. However, further analysis in a prospective study could help us determine its usefulness as a genetic marker of disease activity in SLE.

Association of juvenile idiopathic arthritis with PTPN22 rs2476601 is specific to females in a Greek population.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is an autoimmune disease characterized by persistent chronic arthritis. Disease risk is believed to be influenced by both genetic and environmental factors. It is well established that the PTPN22 single nucleotide polymorphism (SNP) rs2476601 is associated with JIA susceptibility. It was recently reported in an Australian study that this association is restricted to females and is not observed in males. A significant source of inconsistency amongst the literature on autoimmune disease susceptibility genes stems from an inability to replicate genetic findings across different racial or ethnic groups. We therefore attempted to generate further evidence of the female-specific association of rs2476601 in a homogeneous Greek population. FINDINGS: We genotyped rs2476601 in 128 Caucasian JIA patients (70.3 % female) and 221 healthy controls (28.1 % female) from Northern Greece. Overall, PTPN22 was associated with increased risk of JIA in this Greek sample (OR = 2.3, 95 % CI 1.1 - 5.1, p = 0.038). Sex-stratified analyses showed that, once again, the risk association was restricted to females (Female: OR = 19.9, 95 % CI 1.2 - 342, p = 0.0016; Male: OR = 1.1, 95 % CI 0.3 - 3.1, p = 0.94) supporting the prior findings. CONCLUSIONS: Our data demonstrates that this sex-specific pattern of association is broadly applicable to different populations, and provides further impetus to undertake mechanistic studies to understand the impact of sex on PTPN22 in JIA.

Lack of Association between PTPN22 Gene +1858 C>T Polymorphism and Susceptibility to Generalized Vitiligo in a Turkish Population.

BACKGROUND: Vitiligo is an autoimmune polygenic disorder characterized by loss of pigmentation due to melanocyte destruction. The PTPN22 gene +1858 C>T single nucleotide polymorphism (rs2476601) has been shown to be associated with various autoimmune disorders. OBJECTIVE: The aim of this study was to investigate whether the PTPN22 gene +1858 C>T single nucleotide polymorphism is associated with susceptibility to generalized vitiligo in a Turkish population. METHODS: One hundred and seven patients with generalized vitiligo, and one hundred and twelve gender-, age-, and ethnic-matched controls were enrolled in the study. Genotyping was done by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The PTPN22 +1858 C>T genotype and allele frequencies of the generalized vitiligo patients did not differ significantly from those of healthy controls. CONCLUSION: We found no association between the PTPN22 +1858 C>T gene polymorphism and vitiligo susceptibility in Turkish generalized-vitiligo patients.

Meta-analysis of the correlation between PTPN22 gene polymorphisms and susceptibility to systemic lupus erythematosus.

In this meta-analysis of the association between PTPN22 gene polymorphisms and susceptibility to systemic lupus erythematosus, 4 case-control studies, including one from China, were included. The studies included 1864 participants: 772 cases and 1092 controls. The meta-analysis showed that the 1858C/T polymorphism of the PTPN22 gene is correlated with systemic lupus erythematosus susceptibility, when assessed by distribution characteristics such as nationality, race, and region. A large sample size from the Chinese population is required for a further prospective study before causality can be established.