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: 10.99). 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
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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 · 3.99 Impact Factor
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    • "1 6 7 . 5 5 PTPN22 [22] [23] [24] [25] 1 11 4.1 6 FCGR2A, FCGR3A [26] [27] 1 159 .7 4 TNFSF4 [22, 28–33] 1 171.42 NMNAT2 [22] [24] [32] 1 181.48 "
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    ABSTRACT: The reasons for the ethnic disparities in the prevalence of systemic lupus erythematosus (SLE) and the relative high frequency of SLE risk alleles in the population are not fully understood. Population genetic factors such as natural selection alter allele frequencies over generations and may help explain the persistence of such common risk variants in the population and the differential risk of SLE. In order to better understand the genetic basis of SLE that might be due to natural selection, a total of 74 genomic regions with compelling evidence for association with SLE were tested for evidence of recent positive selection in the HapMap and HGDP populations, using population differentiation, allele frequency, and haplotype-based tests. Consistent signs of positive selection across different studies and statistical methods were observed at several SLE-associated loci, including PTPN22, TNFSF4, TET3-DGUOK, TNIP1, UHRF1BP1, BLK, and ITGAM genes. This study is the first to evaluate and report that several SLE-associated regions show signs of positive natural selection. These results provide corroborating evidence in support of recent positive selection as one mechanism underlying the elevated population frequency of SLE risk loci and supports future research that integrates signals of natural selection to help identify functional SLE risk alleles.
    01/2014; 2014:203435. DOI:10.1155/2014/203435
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    • "SAR and QSAR in Environmental Research, 2013 autoimmune diseases such as Type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus , leprosy and psoriatic arthritis [10] [11] [12] [13] [14] [15] [16]. Further studies reported that it is actually a gain of function mutation that suppresses TCR signalling much more effectively [17]. "
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    ABSTRACT: Lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene, has a critical negative regulatory role in T-cell antigen receptor (TCR) and emerged as a promising drug target for human autoimmune diseases. A five-point pharmacophore with two hydrogen bond acceptors, one hydrogen bond donor and two aromatic ring features was generated for a series of benzofuran salicylic acid derivatives as LYP inhibitors in order to elucidate their anti-autoimmune activity. The generated pharmacophore yielded a significant 3D-QSAR model with r (2) of 0.9146 for a training set of 27 compounds. The model also showed excellent predictive power with Q (2) of 0.7068 for a test set of eight compounds. The investigation of the 3D-QSAR model has revealed the structural insights which could lead to more potent analogues. The most active and inactive compounds were further subjected to electronic structure analysis using density functional theory (DFT) at B3LYP/3-21(∗)G level to support the 3D-QSAR predictions. The results obtained from this study are expected to be useful in the proficient design and development of benzofuran salicylic acid derivatives as inhibitors of LYP.
    SAR and QSAR in environmental research 08/2013; DOI:10.1080/1062936X.2013.821421 · 1.92 Impact Factor
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