A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes

Bottini, Nunzio; Musumeci, Lucia; Alonso, Andrés; Rahmouni, Souad; Nika, Konstantina; Rostamkhani, Masoud; MacMurray, James P.; Meloni, T; Lucarelli, P.; Pellecchia, Maurizio; Eisenbarth, George S.; Comings, David E.; Mustelin, Tomas

doi:10.1038/ng1323

Cited by 1,219 publications

(1,150 citation statements)

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“…Recently, the 1858T allele encoding Trp at amino-acid residue 620 of the PTPN22 gene has been shown to dramatically reduce the binding of LYP to CSK in vitro. 18 This has been suggested to disrupt the downregulation of T-cell activation so that T cells lacking a LYP-CSK complex are likely to be hyper-reactive and more readily able to mount an autoimmune response.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have associated the 1858T allele with autoimmune diseases [18][19][20][21][22][23][24][25] and generalised vitiligo is thought to have an autoimmune aetiology, 1 although this remains undefined. The frequent association of vitiligo with autoimmune disorders and the demonstration of autoantibodies to melanosomal proteins in the serum of patients with the disease support this theory.…”

Section: Discussionmentioning

confidence: 99%

“…[10][11][12][13][14][15][16][17] Recently, the missense R620W polymorphism in the PTPN22 gene at nucleotide 1858 (1858C-T) in codon 620 (620Arg-Trp) has been associated with autoimmune diseases including type I diabetes mellitus, Graves' disease, systemic lupus erythematosus and rheumatoid arthritis. [18][19][20][21][22][23][24][25] The gene, located on chromosome 1p13, 19 encodes lymphoid protein tyrosine phosphatase (LYP), which is important in the negative control of T lymphocyte activation. 26 Lymphoid protein tyrosine phosphatase is expressed in T lymphocytes and associates with C-terminal Src kinase (CSK) to form a complex that suppresses the T-cell receptor signalling kinases LCK and FYN.…”

Section: Introductionmentioning

confidence: 99%

“…[27][28] Experimental evidence suggests that the disease-associated LYP variant Trp620 prevents the interaction of LYP with CSK. 18 Consequently, the T-cell receptor-associated kinases might be able to induce T-cell activation in an uncontrolled manner and this may increase the overall reactivity of the immune system and predispose an individual to autoimmune disease. Since generalised (nonsegmental) vitiligo may have an autoimmune aetiology, the frequencies of the PTPN22 1858C/T genotypes in 165 English patients with generalised vitiligo and 304 ethnically matched controls were examined in a case-control study using a restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) genotyping method.…”

Section: Introductionmentioning

confidence: 99%

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A single-nucleotide polymorphism in the gene encoding lymphoid protein tyrosine phosphatase (PTPN22) confers susceptibility to generalised vitiligo

et al. 2005

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Vitiligo is an acquired hypomelanotic skin disorder resulting from the loss of functional melanocytes from the cutaneous epidermis and autoimmunity has been suggested to play a part in its pathogenesis. Recently, the missense R620W polymorphism in the PTPN22 gene, which encodes lymphoid protein tyrosine phosphatase (LYP), has been associated with susceptibility to autoimmune disorders. The objective of this study was to ascertain if the disease-associated 1858T allele was also associated with generalised (nonsegmental) vitiligo and so the frequencies of the PTPN22 1858C/T alleles were investigated in 165 English patients with generalised vitiligo and 304 ethnically matched control subjects. The results indicated that the 1858T allele was significantly over-represented in the vitiligo patient group compared with the control cohort. Of 330 vitiligo alleles, 48 (14.5%) encoded the Trp620 variant compared to 52 of 608 (8.6%) control alleles (P ¼ 0.006; odds ratio ¼ 1.82, 95% confidence interval ¼ 1.17-2.82). The results indicate that the LYP missense R620W polymorphism may have an influence on the development of generalised vitiligo and provide further evidence for autoimmunity as an aetiological factor with respect to this disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A single-nucleotide polymorphism in the gene encoding lymphoid protein tyrosine phosphatase (PTPN22) confers susceptibility to generalised vitiligo

et al. 2005

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“…They showed that B‐cells from carriers of this PTPN22 risk allele contained high frequencies of autoreactive clones compared with those from non‐carriers showing how a single polymorphism at one genetic locus can affect the B‐cell repertoire 61. This PTPN22 polymorphism is a gain‐of‐function variant leading to reduced B‐ and T‐cell receptor signalling,62, 63 and has been associated with a range of autoimmune diseases, including RA,64, 65 type 1 diabetes66 and SLE 67. Similar studies on variation in other genes are likely to provide further useful information on how specific biological pathways regulate the B‐cell repertoire.…”

Section: Slementioning

confidence: 99%

Antibody repertoire analysis in polygenic autoimmune diseases

2018

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SummaryHigh‐throughput sequencing of the DNA/RNA encoding antibody heavy‐ and light‐chains is rapidly transforming the field of adaptive immunity. It can address key questions, including: (i) how the B‐cell repertoire differs in health and disease; and (ii) if it does differ, the point(s) in B‐cell development at which this occurs. The advent of technologies, such as whole‐genome sequencing, offers the chance to link abnormalities in the B‐cell antibody repertoire to specific genomic variants and polymorphisms. Here, we discuss the current research using B‐cell antibody repertoire sequencing in three polygenic autoimmune diseases where there is good evidence for a pathological role for B‐cells, namely systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. These autoimmune diseases exhibit significantly skewed B‐cell receptor repertoires compared with healthy controls. Interestingly, some common repertoire defects are shared between diseases, such as elevated IGHV4‐34 gene usage. B‐cell clones have effectively been characterized and tracked between different tissues and blood in autoimmune disease. It has been hypothesized that these differences may signify differences in B‐cell tolerance; however, the mechanisms and implications of these defects are not clear.

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Genome‐wide Association Studies

Pawitan

2009

Encyclopedia of Life Sciences

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The power of genome-wide SNP association studies is limited, among others, by the large number of false positive test results. To provide a remedy, we combined SNP association analysis with the pathway-driven gene set enrichment analysis (GSEA), recently developed to facilitate handling of genome-wide gene expression data. The resulting GSEA-SNP method rests on the assumption that SNPs underlying a disease phenotype are enriched in genes constituting a signaling pathway or those with a common regulation. Besides improving power for association mapping, GSEA-SNP may facilitate the identification of disease-associated SNPs and pathways, as well as the understanding of the underlying biological mechanisms. GSEA-SNP may also help to identify markers with weak effects, undetectable in association studies without pathway consideration. The program is freely available and can be downloaded from our website.

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A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes

Cited by 1,219 publications

References 14 publications

A single-nucleotide polymorphism in the gene encoding lymphoid protein tyrosine phosphatase (PTPN22) confers susceptibility to generalised vitiligo

A single-nucleotide polymorphism in the gene encoding lymphoid protein tyrosine phosphatase (PTPN22) confers susceptibility to generalised vitiligo

Antibody repertoire analysis in polygenic autoimmune diseases

Genome‐wide Association Studies

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