PTPN22 R620W polymorphism in the ANCA-associated vasculitides

Martorana, Davide; Maritati, Federica; Malerba, Giovanni; Bonatti, Francesco; Alberici, Federico; Oliva, Elena; Sebastio, Paola; Manenti, Lucio; Brugnano, Rachele; Catanoso, Mariagrazia; Fraticelli, Paolo; Guida, Giuseppe; Gregorini, Gina; Possenti, Stefano; Moroni, Gabriella; Leoni, Antonio; Pavone, Laura; Pesci, Alberto; Sinico, Renato Alberto; Toma, Lucafrancesco Di; D’Amico, Marco; Tumiati, B; D’Ippolito, Raffaele; Buzio, Carlo; Neri, Tauro Maria; Vaglio, Augusto

doi:10.1093/rheumatology/ker446

Cited by 59 publications

(49 citation statements)

References 46 publications

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“…The extensive Botnia study did not confirm the association of c.1858C>T polymorphism with T1DM, but did support the association of c.1858C>T with the expression of GADA with an OR of 1.6 (95% CI 1.2-2.2) [52]. Similarly, the T allele is associated with the presence of anticitrullinated α-enolase peptide-1 autoantibodies (but not anticitrullinated vimentin peptide 60-75 or the anticyclic citrullinated peptide autoantibodies) in rheumatoid arthritis [53] and ANCA in ANCA disease [17,18]. In contrast to the above findings, Gabbay et al [54] did not find any association of the c.1858C>T polymorphism with GADA or IA-2A levels in T1DM patients.…”

Section: Discussionmentioning

confidence: 99%

“…The single nucleotide polymorphisms (SNPs) of PTPN22 , predominantly p.Arg620Trp (c.1858C>T), are among the major causative agents of human autoimmune disorders. Associations of PTPN22 SNPs with type 1 diabetes (T1DM) [3,4,5], latent autoimmune diabetes in adults (LADA) [6,7], autoimmune thyroid diseases (including Graves' disease and Hashimoto's thyroiditis) [8,9,10], rheumatoid arthritis (including anticitrullinated peptide antibody-negative subjects) [11], juvenile idiopathic arthritis [12], systemic lupus erythematosus [13,14,15], thymoma-associated myasthenia gravis [16], antineutrophil cytoplasmic autoantibodies (ANCA) disease [17,18], vasculitis (including ANCA-associated vasculitis, Wegener's granulomatosis and Behçet's disease) [19], chronic spontaneous autoreactive urticaria [20], and generalized vitiligo [21,22,23] have repeatedly been reported. PTPN22 polymorphisms also affect the responses of chronic-phase chronic myeloid leukemia patients to treatment with the tyrosine kinase inhibitor imatinib [24].…”

Section: Introductionmentioning

confidence: 99%

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Low Frequencies of Autoimmunity-Associated PTPN22 Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies

Heneberg¹,

Malá²,

Yorifuji³

et al. 2015

Int Arch Allergy Immunol

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Background: The protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene encodes lymphoid tyrosine phosphatase (LYP), which is expressed primarily in lymphoid tissues. The functional but geographically highly variable PTPN22 single-nucleotide polymorphisms (SNPs), particularly c.1858C>T, contribute to the onset and progression of autoimmunity-associated diseases and facilitate the expression of disease-associated autoantibodies. In Central Europe, 17-25% of patients with monogenic diabetes (maturity-onset diabetes of the young, MODY) transiently express islet cell autoantibodies. Methods: We addressed the links between the functional and geographically variable PTPN22 SNPs with MODY manifestation and the expression of islet cell autoantibodies in 276 MODY patients who originated from four regions (the Czech Republic, Israel, Japan and Brazil). Results: The frequency of PTPN22 polymorphisms in the MODY patients was similar to those in geographically matched healthy populations, with the exception of c.788G>A, the minor allele frequency of which was significantly elevated in the Czech hepatocyte nuclear factor 1-α (HNF1A) MODY patients [odds ratio (OR) 4.8, 95% confidence interval (CI) 2.2-10.7] and the Brazilian MODY patients (OR 8.4, 95% CI 1.8-39.1). A barely significant increase in the c.788G>A minor allele was also detected in the islet cell autoantibody-positive Czech MODY patients. However, c.788A behaves as a loss-of-function mutant in T cells, and thus protects against autoimmunity. Conclusions: MODY patients (including islet cell autoantibody-positive cases) do not display any increase in autoimmunity-associated PTPN22 alleles. The absence of autoimmunity-associated PTPN22 alleles was also demonstrated in latent autoimmune diabetes in adults, which suggests that the slow kinetics of the onset of autoantibodies is subject to a regulation that is different from that experienced in type 1 diabetes and other autoimmune disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Low Frequencies of Autoimmunity-Associated PTPN22 Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies

Heneberg¹,

Malá²,

Yorifuji³

et al. 2015

Int Arch Allergy Immunol

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“…Deficiency of α 1 -antitrypsin has been shown to correlate with PR3-ANCA positive vasculitis, and the PiZ allele has been found to be associated with a more severe disease and worse prognosis [9]. An association between a polymorphism in PTPN22 have been reported in AAV [10] and in ANCA positive GPA [11,12]. A genomewide association study (GWAS) showed associations between AAV and a number of single-nucleotide polymorphisms following ANCA specificity rather than the clinical syndromes.…”

Section: Introductionmentioning

confidence: 99%

A Candidate Gene Approach to ANCA-Associated Vasculitis Reveals Links to the C3 and CTLA-4 Genes but not to the IL1-Ra And Fcγ-RIIa Genes

Persson¹,

Gullstrand

Pettersson³

et al. 2013

Kidney Blood Press Res

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Background/Aims: The aim of the study is to search for associations between Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) and polymorphisms in the genes of four key molecules possibly involved in different pathogenic pathways; complement C3, CTLA-4, Fcγ-RIIa and IL1-Ra. Patients and Methods: Patients with AAV (n=105) subgrouped as microscopic polyangiitis or granulomatosis with polyangiitis (Wegener's granulomatosis) and myeloperoxidase (MPO) or proteinase 3 (PR3) ANCA positive were compared to a control group of 200 blood donors. Polymorphisms in the genes were analysed with PCR amplification of DNA. Results: The diagnosis of AAV was confirmed in the 105 cases. The gene frequency of C3F was 0.27 in the PR3-ANCA subgroup (p=0.041) compared to 0,19 in the control group. The number of patients homozygous for the shortest 86 bp allele of CTLA-4 was significantly decreased in the whole group of patients (p=0.049). No differences were evident in the Fcγ-RIIa and IL1-Ra polymorphisms when compared to controls, neither in the whole group of patients, nor in any of the sub-groups. Conclusion: The aberrant gene frequency of the C3F allele among PR3-ANCA positive patients and the findings with the CTLA-4 polymorphism indicates that complement may be involved in pathogenesis and that T-cell activation also is of importance in these diseases.

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“…Interestingly, the group of patients with ANCA-negative EGPA was associated with the haplotype IL10.2 of the IL-10 promoter polymorphism, functionally resulting in an increase expression of IL-10 [22]. Other nucleotide polymorphisms have shown little or no effect on EGPA susceptibility [23][24][25].…”

Section: Genetic and Environmental Factorsmentioning

confidence: 99%

Churg-Strauss Syndrome or Eosinophilic Granulomatosis with Polyangiitis

et al. 2015

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Eosinophilic granulomatosis with polyangiitis (Churg-Strauss, EGPA) is a systemic small-to-medium-sized vasculitis associated with asthma and eosinophilia. Histologically EGPA presents tissue eosinophilia, necrotizing vasculitis, and granulomatous inflammation with eosinophil tissue infiltration. EGPA commonly involves the upper airway and lung parenchyma, peripheral neuropathy, cardiac disorders, and skin lesions. The anti-neutrophil cytoplasmic antibodies (ANCA) are positive in 40% of cases, especially in those patients with clinical signs of vasculitis. The pathogenesis of EGPA is multifactorial. The disease can be triggered by exposure to a variety of allergens and drugs, but a genetic background has also been described, particularly an association with HLA-DRB4. Th2 response is of special importance in the upregulation of different interleukins such as IL-4, IL-13, and IL-5. Th1 and Th17 responses are also of significance. Activated eosinophils have a prolonged survival and probably cause tissue damage by releasing eosinophil granule proteins, while their tissue recruitment can be regulated by chemokines such as eotaxin-3 and CCL17. Humoral immunity is also OPEN ACCESSSinusitis 2016, 1 25 abnormally regulated, as demonstrated by excessive responses of IgG4 and IgE. EGPA has a good respond to glucocorticoids, although the combination of glucocorticoids and immunosuppressants (e.g., cyclophosphamide, azathioprine) is needed in most of cases. Newer treatment options include anti-IL-5 antibodies (mepolizumab), whose efficacy has been described in clinical trials, and anti-CD-20, a B cell-depleting agent (rituximab), reported in several case series.

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PTPN22 R620W polymorphism in the ANCA-associated vasculitides

Abstract: The PTPN22 620W allele confers susceptibility to the development of GPA (but not of MPA or CSS), and particularly of its ANCA-positive subset.

Cited by 59 publications

References 46 publications

Low Frequencies of Autoimmunity-Associated <b><i>PTPN22</i></b> Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies

Low Frequencies of Autoimmunity-Associated <b><i>PTPN22</i></b> Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies

A Candidate Gene Approach to ANCA-Associated Vasculitis Reveals Links to the C3 and CTLA-4 Genes but not to the IL1-Ra And Fcγ-RIIa Genes

Churg-Strauss Syndrome or Eosinophilic Granulomatosis with Polyangiitis

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PTPN22 R620W polymorphism in the ANCA-associated vasculitides

Abstract: The PTPN22 620W allele confers susceptibility to the development of GPA (but not of MPA or CSS), and particularly of its ANCA-positive subset.

Cited by 59 publications

References 46 publications

Low Frequencies of Autoimmunity-Associated <b><i>PTPN22</i></b> Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies

Low Frequencies of Autoimmunity-Associated <b><i>PTPN22</i></b> Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies

A Candidate Gene Approach to ANCA-Associated Vasculitis Reveals Links to the C3 and CTLA-4 Genes but not to the IL1-Ra And Fc&#947;-RIIa Genes

Churg-Strauss Syndrome or Eosinophilic Granulomatosis with Polyangiitis

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Resources

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A Candidate Gene Approach to ANCA-Associated Vasculitis Reveals Links to the C3 and CTLA-4 Genes but not to the IL1-Ra And Fcγ-RIIa Genes