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A functional PTPN22 polymorphism associated with several autoimmune diseases is not associated with IgA deficiency in the Spanish population
Concepción Nú?ez, Raquel López-Mejías, Alfonso Martínez, M Cruz García-Rodríguez, Miguel Fernández-Arquero, Emilio G de la Concha, Elena Urcelay
BMC Medical Genetics , 2006, DOI: 10.1186/1471-2350-7-25
Abstract: A total of 259 IgAD patients and 455 unrelated matched controls, and 128 families were used for each approach. Comparisons were performed using Chi-Square tests or Fisher's exact test when necessary.No association between the PTPN22 1858C/T SNP and IgA deficiency was found in any case (allelic frequencies 8% vs. 6% in patients and controls, respectively, OR= 1.14 (0.72–1.79), p= 0.56; TDT p = 0.08).The result obtained seems to reinforce the consideration of IgA deficiency as a primary immunodeficiency rather than an autoimmune disease.Selective IgA deficiency (IgAD) is the most prevalent primary immunodeficiency in white populations, with values around one out of 600 [1]. This disease is characterized by a severe deficiency or total absence of IgA class immunoglobulins in the serum and secretions. Their clinical symptoms are very variable, and thus some IgAD patients are relatively healthy while others show significant illness, mainly a higher susceptibility to infections, autoimmune diseases and allergies. IgAD shows a multifactorial origin, with genetic and environmental factors involved. Class II and class III HLA genes have been implicated in the origin of this disease (see [2] and references therein). However, these HLA genetic components can not explain the totality of the genetic influence in this disease.The molecular bases underlying the origin of IgAD are not completely understood. Although it has been recently shown that a mutation in TACI is involved in the origin of the disease in some patients [3], other genetic and environmental factors remain to be discovered. Despite IgAD has been traditionally considered as an immunodeficiency, some authors [4] have pointed out that it could be an autoimmune disease.Recently, a single-nucleotide polymorphism (SNP) of the PTPN22 (protein tyrosine phosphatase, non-receptor type 22) gene, 1858C/T, has been found associated with many autoimmune diseases [5,6]. This gene, located on chromosome 1p13, encodes a lymphoid p
PTPN22.6, a Dominant Negative Isoform of PTPN22 and Potential Biomarker of Rheumatoid Arthritis  [PDF]
Hui-Hsin Chang, Tzong-Shyuan Tai, Bing Lu, Christine Iannaccone, Manuela Cernadas, Michael Weinblatt, Nancy Shadick, Shi-Chuen Miaw, I-Cheng Ho
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0033067
Abstract: PTPN22 is a tyrosine phosphatase and functions as a damper of TCR signals. A C-to-T single nucleotide polymorphism (SNP) located at position 1858 of human PTPN22 cDNA and converting an arginine (R620) to tryptophan (W620) confers the highest risk of rheumatoid arthritis among non-HLA genetic variations that are known to be associated with this disease. The effect of the R-to-W conversion on the phosphatase activity of PTPN22 protein and the impact of the minor T allele of the C1858T SNP on the activation of T cells has remained controversial. In addition, how the overall activity of PTPN22 is regulated and how the R-to-W conversion contributes to rheumatoid arthritis is still poorly understood. Here we report the identification of an alternative splice form of human PTPN22, namely PTPN22.6. It lacks the nearly entire phosphatase domain and can function as a dominant negative isoform of the full length PTPN22. Although conversion of R620 to W620 in the context of PTPN22.1 attenuated T cell activation, expression of the tryptophan variant of PTPN22.6 reciprocally led to hyperactivation of human T cells. More importantly, the level of PTPN22.6 in peripheral blood correlates with disease activity of rheumatoid arthritis. Our data depict a model that can reconcile the conflicting observations on the functional impact of the C1858T SNP and also suggest that PTPN22.6 is a novel biomarker of rheumatoid arthritis.
The PTPN22 C1858T gene variant is associated with proinsulin in new-onset type 1 diabetes
Lotte B Nielsen, Sven P?rksen, Marie Louise M Andersen, Siri Fredheim, Jannet Svensson, Philip Hougaard, Maurizio Vanelli, Jan ?man, Henrik B Mortensen, Lars Hansen, the Hvidoere Study Group on Childhood Diabetes
BMC Medical Genetics , 2011, DOI: 10.1186/1471-2350-12-41
Abstract: The C1858T variant was genotyped in an international cohort of children (n = 257 patients) with newly diagnosed type 1 diabetes during 12 months after onset. We investigated the association of this variant with liquid-meal stimulated beta-cell function (proinsulin and C-peptide) and antibody status 1, 6 and 12 months after onset. In addition HbA1c and daily insulin requirements were determined 1, 3, 6, 9 and 12 months after diagnosis. DKA was defined at disease onset.A repeated measurement model of all time points showed the stimulated proinsulin level is significantly higher (22%, p = 0.03) for the T allele carriers the first year after onset. We also found a significant positive association between proinsulin and IA levels (est.: 1.12, p = 0.002), which did not influence the association between PTPN22 and proinsulin (est.: 1.28, p = 0.03).The T allele of the C1858T variant is positively associated with proinsulin levels during the first 12 months in newly diagnosed type 1 diabetes children.Type 1 diabetes is a T-cell mediated autoimmune disease leading to beta-cell destruction and loss of insulin secretion resulting in severe hyperglycemia. Type 1 diabetes results from a complex interaction between environmental and genetic factors. Several genes have been identified as causative in the development of type 1 diabetes [1,2] and some of these genes as well as other genes are shown to exert an impact on the disease progression from onset in newly diagnosed type 1 diabetes children [3-6]. In a number of studies, the non-synonymous variant, C1858T, of the PTPN22 gene has been associated with development of type 1 diabetes as well as other autoimmune diseases [7-11]. Recently, this PTPN22 susceptibility variant was found to be significantly associated to lower fasting C-peptide levels, poorer glycemic control in recent onset type 1 diabetes subjects [6] and to higher GADA in type 1 diabetes patients with long disease duration [12]. The objective of the current longitudi
Temporal Trends of HLA, CTLA-4 and PTPN22 Genotype Frequencies among Type 1 Diabetes in Continental Italy  [PDF]
Marialuisa Spoletini, Simona Zampetti, Giuseppe Campagna, Lidia Marandola, Marco Capizzi, Raffaella Buzzetti, for the IMDIAB Study Group
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061331
Abstract: The incidence of type 1 diabetes has, progressively, increased worldwide over the last decades and also in Continental Italian population. Previous studies performed in northern European countries, showed, alongside a general increase in the disease incidence, a decreasing frequency of the highest risk HLA genotype in type 1 diabetes populations, thus emphasizing the role of environmental factors. The aim of the study was to evaluate whether a decreasing trend of high risk HLA, CTLA-4 and PTPN22 genotypes would be present in type 1 diabetes subjects of Continental Italy, a country considered at low incidence of the disease compared to northern European populations. N = 765 type 1 diabetes patients diagnosed from 1980 to 2012 in Lazio region were included. For HLA, CTLA4 and PTPN22 temporal trend evaluation, subjects were subdivided into groups of years according to age at diagnosis. All subjects were typed for HLA-DRB1 and DQB1 by a reverse line blot. The CT60 polymorphism of the CTLA4 and C1858T of the PTPN22 gene were genotyped using ABI PRISM 7900HT (n = 419 and n = 364 respectively). HLA genotypes were divided in high, moderate and low risk categories. The proportion of the HLA risk categories was not statistically different over the three decades in subjects with age of onset <15 years and ≥15 years. The genotype distribution of CT60 polymorphism of CTLA4 gene did not show any change in the frequencies during time. The analysis of the PTPN22 C1858T variant revealed, instead, that the frequency of CT+TT susceptibility genotypes decreased during time (23.9% vs 13.6%, p = 0.017). We can hypothesize that the pressure of the diabetogenic environment could be milder and therefore not sufficient to reduce the need of a strong genetic background (HLA) “to precipitate” diabetes; the increased pressure of the environment could have, instead, some effects on minor susceptibility genes in our population.
Assessment of Type 1 Diabetes Risk Conferred by HLA-DRB1, INS-VNTR and PTPN22 Genes Using the Bayesian Network Approach  [PDF]
Rosalba Portuesi, Paolo Pozzilli, Bernhard Boehm, Raffaella Buzzetti, Simonetta Filippi
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079506
Abstract: Background Determining genetic risk is a fundamental prerequisite for the implementation of primary prevention trials for type 1 diabetes (T1D). The aim of this study was to assess the risk conferred by HLA-DRB1, INS-VNTR and PTPN22 single genes on the onset of T1D and the joint risk conferred by all these three susceptibility loci using the Bayesian Network (BN) approach in both population-based case-control and family clustering data sets. Methodology/Principal Findings A case-control French cohort, consisting of 868 T1D patients and 73 French control subjects, a French family data set consisting of 1694 T1D patients and 2340 controls were analysed. We studied both samples separately applying the BN probabilistic approach, that is a graphical model that encodes probabilistic relationships among variables of interest. As expected HLA-DRB1 is the most relevant susceptibility gene. We proved that INS and PTPN22 genes marginally influence T1D risk in all risk HLA-DRB1 genotype categories. The absolute risk conferred by carrying simultaneously high, moderate or low risk HLA-DRB1 genotypes together with at risk INS and PTPN22 genotypes, was 11.5%, 1.7% and 0.1% in the case-control sample and 19.8%, 6.6% and 2.2% in the family cohort, respectively. Conclusions/Significance This work represents, to the best of our knowledge, the first study based on both case-control and family data sets, showing the joint effect of HLA, INS and PTPN22 in a T1D Caucasian population with a wide range of age at T1D onset, adding new insights to previous findings regarding data sets consisting of patients and controls <15 years at onset.
PTPN22 1858C>T Polymorphism Distribution in Europe and Association with Rheumatoid Arthritis: Case-Control Study and Meta-Analysis  [PDF]
Michele Ciro Totaro, Barbara Tolusso, Valerio Napolioni, Francesca Faustini, Silvia Canestri, Alice Mannocci, Elisa Gremese, Silvia Laura Bosello, Stefano Alivernini, Gianfranco Ferraccioli
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024292
Abstract: Objective The PTPN22 rs2476601 polymorphism is associated with rheumatoid arthritis (RA); nonetheless, the association is weaker or absent in some southern European populations. The aim of the study was to evaluate the association between the PTPN22 rs2476601 polymorphism and RA in Italian subjects and to compare our results with those of other European countries, carrying out a meta-analysis of European data. Methods A total of 396 RA cases and 477 controls, all of Italic ancestry, were genotyped for PTPN22 rs2476601 polymorphism. Patients were tested for autoantibodies positivity. The meta-analysis was performed on 23 selected studies. Results The PTPN22 T1858 allele was significantly more frequent in RA patients compared to controls (5.7% vs. 3.7%, p = 0.045). No clear relationship arose with the autoantibodies tested. The 1858T allele frequency in Italian RA patients was lower than the one described in northern European populations and similar to the frequency found in Spain, Turkey, Greece, Tunisia. A clear-cut North-South gradient arose from the analysis. Conclusions The PTPN22 T1858 allele is associated with RA in the Italian population. A North-South gradient of the allele frequency seems to exist in Europe, with a lower prevalence of the mutation in the Mediterranean area.
The PTPN22 1858C/T polymorphism is associated with anti-cyclic citrullinated peptide antibody-positive early rheumatoid arthritis in northern Sweden
Heidi Kokkonen, Martin Johansson, Lena Innala, Erik Jidell, Solbritt Rantap??-Dahlqvist
Arthritis Research & Therapy , 2007, DOI: 10.1186/ar2214
Abstract: Recent studies have shown that a missense single nucleotide polymorphism resulting in a substitution of T for C at position 1858 in the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene is associated with several autoimmune diseases including rheumatoid arthritis (RA) [1-3]. Several of the autoimmune diseases associated with the PTPN22 1858T variant are characterized by the presence of autoantibodies. These autoantibodies can be present several years before onset of the disease [4-6]. We have previously shown that a combination of the T variant of PTPN22 and anti-cyclic citrullinated peptide (anti-CCP) antibodies in combination strongly predicts the future onset of RA with a specificity of 100% for the disease [7].The association between the PTPN22 polymorphism and RA has been replicated by several groups studying different RA populations [1,8-11]. The first study on PTPN22 limited its association to rheumatoid factor-positive disease [1]. This polymorphism has subsequently been associated with both seropositive [8,12] and seronegative disease [13,14].In addition to genetic factors, environmental factors have been proposed to be of importance in the aetiology of RA. Several studies have suggested smoking to be the major environmental risk factor for RA [15,16]. HLA-shared epitope (SE) alleles and smoking have also recently been shown to act synergistically as risk factors, but only in anti-CCP antibody-positive patients with RA [17].Considering our findings of a stronger predictive value of the combination of PTPN22 1858T variant with anti-CCP antibodies compared with HLA-SE and anti-CCP antibodies for development of RA in individuals before disease onset [7], the aim of the present study was to investigate the 1858 C/T polymorphism in relation to the presence of autoantibodies and HLA-SE alleles in an inception cohort of RA patients from northern Sweden for disease susceptibility, onset and inflammatory activity during the first 2 years. The individual
PTPN22 polymorphism and anti-cyclic citrullinated peptide antibodies in combination strongly predicts future onset of rheumatoid arthritis and has a specificity of 100% for the disease
Martin Johansson, Lisbeth ?rlestig, G?ran Hallmans, Solbritt Rantap??-Dahlqvist
Arthritis Research & Therapy , 2005, DOI: 10.1186/ar1868
Abstract: A single nucleotide polymorphism in the PTPN22 gene encoding the lymphoid protein tyrosine phosphatase (Lyp) has recently been found to be associated with several autoimmune disorders. The PTPN22 1858C/T polymorphism was originally associated with type I diabetes [1] and later with other autoimmune diseases, for example, systemic lupus erythematosus [2], Graves' disease [3] and Hashimoto thyroiditis [4]. Several studies report an association of it with rheumatoid arthritis (RA) [4-10]; the association was primarily with sero-positive disease [5,8] but two recent studies show association with both sero-positive and sero-negative RA [9,10]. This association with RA appears to be the most robust and reproducible genetic association outside the human leukocyte antigen (HLA) region. In several of the autoimmune diseases associated with the PTPN22 polymorphism, the appearance of autoantibodies precedes the development of overt clinical disease by months or years [11-13]We previously reported that antibodies against cyclic citrullinated peptide (CCP) and IgA-rheumatoid factor (RF) predict development of RA by a median of 2.5 years [14]. The presence of anti-CCP antibodies together with HLA shared epitope (HLA-SE) genes (HLA-DRB1*0404/0401) increased the relative risk for development of RA [15].In this study, we analysed the PTPN22 1858C/T polymorphism in relation to anti-CCP antibodies, RFs (IgM, IgG and IgA) and HLA-SE gene carriage in individuals who had donated blood before development of RA. The predictive effects of the genes and antibodies were then evaluated.A nested case-control study was performed within the Medical Biobank of Northern Sweden of the Northern Sweden Health and Disease Study (NSHDS). All adults in V?sterbotten county were invited to participate; consequently, the cohort is population-based and no individual was excluded. The Medical Biobank, conditions for recruitment into the cohorts, and the collection and storage of blood samples have previously
Association between the PTPN22 +1858 C/T polymorphism and psoriatic arthritis
Kristina Juneblad, Martin Johansson, Solbritt Rantap??-Dahlqvist, Gerd-Marie Alenius
Arthritis Research & Therapy , 2011, DOI: 10.1186/ar3284
Abstract: A total of 291 patients (145 male/146 female, mean age (± S.D.) 52.2 (± 13.1) years) with PsA were examined clinically, by standard laboratory tests and their DNA was genotyped for the SNP rs2476601 (PTPN22 +1858 C/T). Allelic frequencies were determined and compared with 725 controls.Carriage of the risk allele, PTPN22+1858T, showed a significant association with patients with PsA compared with controls (χ2 = 6.56, P = 0.010, odds ratio (OR) 1.49; 95% confidence interval (CI) 1.10 to 2.02). A significantly higher proportion of carriers of the risk allele (T) had significantly more deformed joints (n ± SEM) (5.9 ± 1.2 vs 2.8 ± 0.5; P = 0.005).In this study the +1858T allele of the PTPN22 gene, known to be associated with several autoimmune diseases, was associated with PsA. The finding of significantly more joints with deformities among carriers of the T variant could indicate a more aggressive phenotype of disease.Psoriatic arthritis (PsA) is a heterogeneous inflammatory arthritis associated with psoriasis. The disease severity not only varies between patients but also within an individual patient over time. The disease expression can vary from a mild mono-oligoarthritis to severe erosive polyarthritis comparable with rheumatoid arthritis (RA) [1]. In contrast to RA, manifestations such as dactylitis and enthesitis are common in patients with PsA, as is the case in patients suffering other diseases within the sero-negative spondylarthropathy group [2,3]. Also, in contrast with RA, most individuals with PsA are sero-negative for rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) [4,5].As with many other autoimmune diseases a number of genes have been suggested to be associated with PsA [6,7]. Epidemiological data implicate a strong genetic basis for PsA [6,8]. Familial aggregation with an estimated recurrence risk ratio in first degree relatives (λ1) of 55 in different studies compared with 5 to 10 for patients with cutaneous psoriasis,
Association of PTPN22 1858 single-nucleotide polymorphism with rheumatoid arthritis in a German cohort: higher frequency of the risk allele in male compared to female patients
Matthias Pierer, Sylke Kaltenh?user, Sybille Arnold, Matthias Wahle, Christoph Baerwald, Holm H?ntzschel, Ulf Wagner
Arthritis Research & Therapy , 2006, DOI: 10.1186/ar1945
Abstract: Rheumatoid arthritis (RA) is a complex autoimmune disease with a strong genetic contribution to its pathogenesis. Studies on twins have shown concordance rates between 12% and 15% in monozygotic twins compared to 4% in dizygotic twins [1]. Calculations based on these data have estimated an overall heritability of about 60% [2,3], indicating that genetic factors account for the majority of population susceptibility to RA.The HLA-DRBI locus accounts for approximately one-third of the genetically determined susceptibility to the disease [4]. The identification of further RA susceptibility loci, both in candidate gene approaches and genome-wide linkage studies, was hindered in the past by difficulties to replicate such results in other study populations. Recently, however, an association between the minor allele (T) of a missense single-nucleotide polymorphism (SNP; R620W (rs2476601, 1858C/T)) in the protein tyrosine phosphatase non-receptor type 22 gene (PTPN22) and susceptibility to RA has been described [5]; this has been confirmed in several large cohorts of patients and controls [6-18]. Besides its association with RA, the PTPN22 1858T allele has been found to be associated also with type I diabetes, systemic lupus erythematosus and autoimmune thyroiditis, suggesting a genetic predisposition towards generalized T cell autoimmunity. The missense SNP lies within the first proline-rich domain of PTPN22 and results in the substitution of tryptophan for arginine at codon 620 (R620W) of PTPN22. The PTPN22 1858T variant has recently been described to result in a gain-of-function form of the enzyme [23], leading to stronger suppression of the early T cell activation process. Possible pathogenetic mechanisms implied by this finding include failure to delete autoreactive T cells during thymic selection or decreased activity of regulatory T cells.The aim of this study was to analyze the association of the 1858C/T SNP with RA in a sample set comprising 390 German white RA case
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