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

Department of Medicine, University of Minnesota School of Medicine, Minneapolis, MN 55455, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 10/2004; 75(3):504-7. DOI: 10.1086/423790
Source: PubMed


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
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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.
    Clinical Immunology 11/2014; 156(1). DOI:10.1016/j.clim.2014.11.003 · 3.67 Impact Factor
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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.
    Journal of Ophthalmic Inflammation and Infection 07/2014; 4(1):20. DOI:10.1186/s12348-014-0020-1
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    • "Castro-Marrero et al. [18], in Spanish Caucasian patients did not find any association of PTPN22 1858C>T gene polymorphism with primary antiphospholipid syndrome. Kyogoku et al. [19] reported no association between the presence of the T1858 allele of the PTPN22 gene with occurrence antinuclear antibodies (ANA) and aCL in a population of North American white individuals with SLE. "
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    ABSTRACT: To assess the association between PTPN22 1858C>T gene polymorphism and susceptibility to, and clinical presentation of, systemic lupus erythematosus (SLE). Our study included 135 SLE patients (120 women and 15 men; mean age 45.1 years; mean course of disease from 0.5 to 31 years) and 201 healthy subjects. The PTPN22 1858C>T gene polymorphism was genotyped by polymerase chain reaction restriction fragment length polymorphism. A significantly higher incidence of genotype CT in patients with SLE (36.3 %) was found, compared with the control group (24.9 %). The frequencies of C1858 and T1858 alleles were 78.1 and 21.9 % in SLE patients and 86.1 and 13.9 % in controls, respectively. Significantly higher SLE susceptibility was observed in patients carrying at least one T allele (p = 0.009; OR 1.86; 95 % CI 0.14-3.05). Significant association of the PTPN22 T1858 allele (CT + TT vs.CC) and secondary antiphospholipid syndrome was observed (p = 0.049). In SLE patients carrying the T1858 allele, higher levels of antiphospholipid antibodies (anticardiolipin antibodies and/or lupus anticoagulant) were found (p = 0.030; OR 2.17; 95 % CI 1.07-4.44).
    Molecular Biology Reports 07/2014; 41(9). DOI:10.1007/s11033-014-3498-6 · 2.02 Impact Factor
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