Article

Genetic Association of the R620W Polymorphism of Protein Tyrosine Phosphatase PTPN22 with Human SLE

Johns Hopkins University, Baltimore, Maryland, United States
The American Journal of Human Genetics (Impact Factor: 10.93). 10/2004; 75(3):504-7. DOI: 10.1086/423790
Source: PubMed

ABSTRACT

We genotyped 525 independent North American white individuals with systemic lupus erythematosus (SLE) for the PTPN22 R620W polymorphism and compared the results with data generated from 1,961 white control individuals. The R620W SNP was associated with SLE (genotypic P=.00009), with estimated minor (T) allele frequencies of 12.67% in SLE cases and 8.64% in controls. A single copy of the T allele (W620) increases risk of SLE (odds ratio [OR]=1.37; 95% confidence interval [CI] 1.07-1.75), and two copies of the allele more than double this risk (OR=4.37; 95% CI 1.98-9.65). Together with recent evidence showing association of this SNP with type 1 diabetes and rheumatoid arthritis, these data provide compelling evidence that PTPN22 plays a fundamental role in regulating the immune system and the development of autoimmunity.

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Available from: Carl Langefeld, Dec 22, 2014
    • "Genome­wide association studies have iden­ tified >40 confirmed genetic loci associated with the development of SLE (Cui et al., 2013). The PTPN22(C1858T) polymorphism, result­ ing in a missense mutation R620W, is associated with increased risk of developing type I diabetes (Bottini et al., 2004), SLE (Kyogoku et al., 2004), rheumatoid arthritis (Begovich et al., 2004), Graves' disease (Velaga et al., 2004), and other autoimmune disorders (Stanford and Bottini, 2014; Rawlings et al., 2015). PTPN22/LYP and its mouse orthologue PEP are members of the PEST­domain containing nonreceptor protein tyrosine phosphatase family and play important roles in TCR, BCR, IFN­ receptor, and Toll­like receptor (TLR) functions (Rhee and Veillette, 2012; Spalinger et al., 2013; Wang et al., 2013; Bottini and Peterson, 2014). "
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    ABSTRACT: The protein tyrosine phosphatase PTPN22(C1858T) allelic polymorphism is associated with increased susceptibility for development of systemic lupus erythematosus (SLE) and other autoimmune diseases. PTPN22 (also known as LYP) and its mouse orthologue PEP play important roles in antigen and Toll-like receptor signaling in immune cell functions. We demonstrate here that PEP also plays an important inhibitory role in interferon-α receptor (IFNAR) signaling in mice. PEP co-immunoprecipitates with components of the IFNAR signaling complex. Pep(-/-) hematopoietic progenitors demonstrate increased IFNAR signaling, increased IFN-inducible gene expression, and enhanced proliferation and activation compared to Pep(+/+) progenitors in response to IFN-α. In addition, Pep(-/-) mice treated with IFN-α display a profound defect in hematopoiesis, resulting in anemia, thrombocytopenia, and neutropenia when compared to IFN-α-treated Pep(+/+) mice. As SLE patients carrying the PTPN22(C1858T) risk variant have higher serum IFN-α activity, these data provide a molecular basis for how type I IFNs and PTPN22 may cooperate to contribute to lupus-associated cytopenias. © 2015 Holmes et al.
    No preview · Article · Jun 2015 · Journal of Experimental Medicine
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    • "The autoimmunity associated allele of PTPN22, R620W (C1858T), has been linked to a number of autoimmune conditions in humans such as type I diabetes (T1D) [1], rheumatoid arthritis (RA) [2] and systemic lupus erythematosus (SLE) [3]. To investigate the role PTPN22 plays in these diseases numerous mouse models of autoimmunity in which PTPN22 has been deleted, overexpressed, knocked down or mutated are beginning to emerge [4] [5] [6] [7] [8]. "
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    ABSTRACT: A single nucleotide polymorphism in PTPN22 is linked to increased disease susceptibility in a range of autoimmune diseases including systemic lupus erythematosus (SLE). PTPN22 encodes the Lyp phosphatase that dampens TCR signaling and is necessary for signaling downstream of toll-like receptors in myeloid cells. To understand these dual functions in disease, we examined the impact of deficiency in PTPN22 on a spontaneous murine model of SLE. Male PTPN22 KO mice carrying BXSB chromosome 1 and the Yaa disease accelerating factor developed disease at a similar rate and severity as PTPN22 WT. In contrast, although female mice showed no differences in survival in the absence of PTPN22, autoantibody production was significantly increased and splenic populations associated with pathogenesis in this model were expanded in the PTPN22 KO group. These findings support the notion that when coupled with other predisposing autoimmunity genes, PTPN22 deficiency contributes to a predisposition to lupus pathogenesis.
    Full-text · Article · Nov 2014 · Clinical Immunology
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    • "PTPN22 is located on chromosome 1p13.3 to 1p13.1 and encodes the lymphoid-specific phosphatase known as Lyp which plays an essential suppressive role in T cell activation [[100]]. Several studies have demonstrated that a SNP in PTPN22, R620W (rs2476601), predisposes individuals to various autoimmune diseases including insulin-dependent diabetes mellitus [[101]], rheumatoid arthritis [[102],[103]], Graves' disease [[104]], and SLE [[105]]. In a study of 67 Japanese patients with VKH disease [[106]], six SNPs in PTPN22 (rs3811021, rs1217413, rs1237682, rs3761935, rs3789608, and rs2243471) were shown to have no significant association with VKH disease. "
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    ABSTRACT: Vogt-Koyanagi-Harada (VKH) disease is a systemic autoimmune disorder against melanocytes. Recent studies have identified multiple genetic factors that might be associated with the pathogenesis of VKH disease. We performed an electronic database search of PubMed, MEDLINE, and EMBASE, and all relevant papers published up to 13 June 2014 were reviewed. A total of 1,031 publications including articles relevant to the genetics of VKH disease and the references of these articles were reviewed. The review identified a number of genetic factors which might be involved in the pathogenesis of VKH disease, some of which may alter the clinical course of VKH disease. Genes which might be involved in the pathogenesis of VKH disease included genes expressing HLA, complement factor H, interleukins, cytotoxic T-lymphocyte antigen 4 (CTLA-4), killer cell immunoglobulin-like receptors (KIR), programmed cell death 1 (PDCD1), protein tyrosine phosphatase non-receptor 22 (PTPN22), osteopontin, tumor necrosis factor alpha-induced protein 3 (TNFAIP3), macrophage migration inhibitory factor (MIF), and other immune response genes. Further studies to explore the correlation among different genotypes and phenotypes of VKH disease will be useful to shed light on the pathogenesis of uveitis in VKH disease and may facilitate the development of new treatment modalities of uveitis in VKH disease.
    Full-text · Article · Jul 2014 · Journal of Ophthalmic Inflammation and Infection
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