A Missense Single-Nucleotide Polymorphism in a Gene Encoding a Protein Tyrosine Phosphatase (PTPN22) Is Associated with Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is the most common systemic autoimmune disease, affecting approximately 1% of the adult population worldwide, with an estimated heritability of 60%. To identify genes involved in RA susceptibility, we investigated the association between putative functional single-nucleotide polymorphisms (SNPs) and RA among white individuals by use of a case-control study design; a second sample was tested for replication. Here we report the association of RA susceptibility with the minor allele of a missense SNP in PTPN22 (discovery-study allelic P=6.6 x 10(-4); replication-study allelic P=5.6 x 10(-8)), which encodes a hematopoietic-specific protein tyrosine phosphatase also known as "Lyp." We show that the risk allele, which is present in approximately 17% of white individuals from the general population and in approximately 28% of white individuals with RA, disrupts the P1 proline-rich motif that is important for interaction with Csk, potentially altering these proteins' normal function as negative regulators of T-cell activation. The minor allele of this SNP recently was implicated in type 1 diabetes, suggesting that the variant phosphatase may increase overall reactivity of the immune system and may heighten an individual carrier's risk for autoimmune disease.

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

“…29 Furthermore, RNAi experiments have demonstrated that reduced LYP expression in Jurkat's cells occurs concomitantly with an increase in the expression of T-cell receptordependent activation. 25 The downregulatory activity of LYP is mediated as a complex with CSK, which suppresses the T-cell receptor signalling kinases LCK and FYN. 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.…”

“…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.…”

“…[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.…”

Antibody repertoire analysis in polygenic autoimmune diseases

“…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.…”

Gene expression profiling of arthritis using a QTL chip reveals a complex gene regulation of the Cia5 region in mice

“…Ptpn22 encodes the protein LYP, which is an inhibitor of T-cell activation. 24,25 Different allelic variants of Ptpn22 have recently been associated with several autoimmune disorders in humans including RA and Type I diabetes [26][27][28] The upregulation of Tspan-2 and the downregulation of Ptpn22 could indicate a higher activation state of T cells in the congenic strain. This activation might be required for self-reactive T cells to undergo apoptosis or to become T regulatory cells; however, further experiments are needed in order to answer this question.…”