Unraveling the functional implications of GWAS: How T cell protein tyrosine phosphatase drives autoimmune disease

Division of Rheumatology, Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, UCSF, San Francisco, California, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 11/2011; 121(12):4618-21. DOI: 10.1172/JCI60001
Source: PubMed


Genome-wide association studies (GWAS) have identified a large number of SNPs that are linked to human autoimmune diseases. However, the functional consequences of most of these genetic variations remain undefined. T cell protein tyrosine phosphatase (TCPTP, which is encoded by PTPN2) is a JAK/STAT and growth factor receptor phosphatase that has been linked to the pathogenesis of type 1 diabetes, rheumatoid arthritis, and Crohn's disease by GWAS. In this issue of the JCI, Wiede and colleagues have generated a T cell-specific deletion of TCPTP and identified a novel role for this phosphatase as a negative regulator of TCR signaling. These data provide new insight as to how noncoding PTPN2 SNPs identified in GWAS could drive human autoimmune diseases.

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Available from: Arthur Weiss, Jun 30, 2014
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    • "PTPN2 encodes for the ubiquitously expressed T cell protein tyrosine phosphatase (TCPTP), a JAK/STAT and growth factor receptor phosphatase that has been linked with the pathogenesis of type 1 diabetes mellitus, rheumatoid arthritis and Crohn’s disease by GWAS findings of non-coding SNP associations. Mouse and human studies have shown that reduced expression of TCPTP may drive autoimmune pathologies by enhancing signalling downstream of the T cell receptor (TCR), cytokines, or growth factors to produce a pro-inflammatory cytokine milieu [65]. "
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    Arthritis Research & Therapy 05/2014; 16(3):R109. DOI:10.1186/ar4559 · 3.75 Impact Factor
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    ABSTRACT: Genome-wide association studies have identified single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase nonreceptor type 2 (PTPN2) as a risk factor for the development of chronic inflammatory diseases, such as inflammatory bowel disease (IBD), type 1 diabetes, and rheumatoid arthritis. IBD is characterized by a breakdown of the intestinal epithelial barrier function leading to an overwhelming and uncontrolled immune response to bacterial antigens. Recent studies demonstrated that PTPN2 regulates cytokine-induced signaling pathways, epithelial barrier function, and cytokine secretion in human intestinal cells. Dysfunction of PTPN2 is also associated with impaired autophagosome formation and defective bacterial handling in intestinal cells. All of these cellular functions have been demonstrated to play a crucial role in the pathogenesis of IBD. The genetic variations within the PTPN2 gene may result in altered protein function, thereby essentially contributing to the onset and perpetuation of chronic inflammatory conditions in the intestine.
    Annals of the New York Academy of Sciences 06/2012; 1257(1):93-102. DOI:10.1111/j.1749-6632.2012.06578.x · 4.38 Impact Factor
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