rs2476601

This important SNP, located in the PTPN22 gene and also known as R620W, C1858T, or 1858C>T, may influence risk for multiple autoimmune diseases, such as Rheumatoid Arthritis, Type-1 diabetes, Autoimmune thyroiditis, and Systemic lupus erythematosus. ==Overview== . A 2014 article explained that "PTPN22 exemplifies a shared autoimmunity gene, affecting the pathogenesis of systemic lupus erythematosus, vasculitis and other autoimmune diseases." They explored "the role of PTPN22 in autoimmune connective tissue disease" and theorized "a number of PTPN22-dependent functional models of the pathogenesis of autoimmune diseases." (Abstract). They explained that "the PTPN22 gene is a major risk factor for autoimmunity." As well, "In addition to autoimmune diseases, PTPN22 1858C>T also affects susceptibility to infectious diseases." A 2005 study titled "Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes" stated "We report that a recently described functional single-nucleotide polymorphism (rs2476601, encoding R620W) in the intracellular tyrosine phosphatase (PTPN22) confers risk of four separate autoimmune phenotypes in these families: T1D, RA, SLE, and Hashimoto's thyroiditis. MS did not show association with the PTPN22 risk allele. These findings suggest a common underlying etiologic pathway for some, but not all, autoimmune disorders, and they suggest that MS may have a pathogenesis that is distinct from RA, SLE, and T1D." (Abstract). NOTE Promethease reports for rs2476601 from Trait-o-matic are consistently finding this called as (A;G), while microarray results seem to follow the HapMap predictions. The source of this originates upstream in several different genotype callers: *maq *SoapSNP *AB_SOLiD_SNP_caller *JW *NA18507 *SIQ2 *CV *GSNAP This is probably triggered by the oddness of this dbSNP entry in which it is a C=>T in NM_012411.2 and a T=>C in NM_015967.3 and/or the fact NT_019273.18 was replaced by NT_032977 ==Rheumatoid arthritis== A 2007 study titled "Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls" examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls in the British population. They found that in the case of rs2476601, the risk was consistent with previous estimates for RA, approximately OD 1.8, and that "known associations with HLA-DRB1 and PTPN22 explain around 50% of the familial aggregation of RA." They found a correlated marker for RA, rs6679677. In addition, SNP rs11761231 had no effect on risk in males, but in females had an "additive OR for females 1.32" A 2005 study titled "PTPN22 genetic variation: evidence for multiple variants associated with rheumatoid arthritis" found that R620W rs2476601 polymorphism was the most significant SNP in sample set of 37 SNPs. They also found these significant ORs for RA (estimated for the minor allele of each SNP; Table 1): * rs2476601 1.65 (p=6.6E-04) * rs974404 1.49 (p=2.4E-05) * rs2476600 1.49 (p=2.5E-05) * rs2797416 1.49 (p=2.2E-05) * rs1310182 1.48 (p=3.2E-05) * rs2476604 1.48 (p=2.7E-05) * rs1217420 1.48 (p=2.7E-05) (same) * rs1217406 1.47 (p=4.6E-05) * rs12730735 0.65 (reduced risk) (p=2.0E-05) * rs3789609 0.65 (reduced risk) (p=2.7E-05) * rs12760457 0.65 (reduced risk) (p=2.0E-05) However, they found that "R620W by itself does not account for all the association observed between RA and PTPN22 in both sample sets." Further analysis revealed that two of the SNPs were important in relation to rs2476601, namely their SNP "number 27" (rs1310182) and "number 37" (rs3789604, which had OR 1.39 (p=0.0071). It showed that the R620W polymorphism was moderated by other SNPs, one increasing its OR, the other decreasing it.. * In combination, the minor allele of rs3789604 gave an increased OR of 2.53 to minor allele homozygotes and 1.77 to heterozygotes of rs2476601 * In combination, the minor allele of rs1310182 gave a decreased OR of 1.63 to minor allele homozygotes and 1.34 to heterozygotes of rs2476601 No association of PTPN22 gene polymorphism with rheumatoid arthritis in Turkey. A 2005 study titled "The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose-dependent manner but not with HLA-SE status" stated two copies of the PTPN22 R620W allele more than doubled the risk for RF positive RA A 2005 study titled "Association between the PTPN22 gene and rheumatoid arthritis and juvenile idiopathic arthritis in a UK population: further support that PTPN22 is an autoimmunity gene" found that "There was a significant association between the PTPN22 SNP and RA (P = 1.8 x 10(-8)) and JIA (P = 0.0005). In contrast, no association with psoriasis, PsA, or MS was detected." (Abstract). A 2006 study titled "Effects of PTPN22 C1858T polymorphism on susceptibility and clinical characteristics of British Caucasian rheumatoid arthritis patients" confirms the association of rs2476601 rheumatoid arthritis This SNP rs2476601 was confirmed in a 2007 study to be a risk factor for RA ==Juvenile idiopathic arthritis== A 2005 study titled "Association between the PTPN22 gene and rheumatoid arthritis and juvenile idiopathic arthritis in a UK population: further support that PTPN22 is an autoimmunity gene" found that "There was a significant association between the PTPN22 SNP and RA (P = 1.8 x 10(-8)) and JIA (P = 0.0005). In contrast, no association with psoriasis, PsA, or MS was detected." (Abstract). ==Type 1 Diabetes== A 2006 study was titled "Systematic search for single nucleotide polymorphisms in a lymphoid tyrosine phosphatase gene (PTPN22): association between a promoter polymorphism and type 1 diabetes in Asian populations" . LADA = latent autoimmune diabetes in adults. Similar to Type 1 Diabetes. In a 2007 study of >6,000 controls and 6,000 patients, the heterozygote odds ratio for type-1 diabetes for this SNP was recalculated to be 1.98 (CI 1.82-2.15). ] Confirms association of rs2476601 with type-1 diabetes in a Sardinian population of 490 sporadic patients (794 families). rs2476601(A) has a higher relative risk in type-1 diabetes cases carrying lower risk HLA class II genotypes than in those carrying higher risk ones (p=1.36x10 -4 in a test of interaction). ==Lupus (Systemic Lupus Erythematosus; SLE)== A 2005 study titled "The R620W C/T polymorphism of the gene PTPN22 is associated with SLE independently of the association of PDCD1" in addition to SLE results also "found evidence of a genetic association between PTPN22 and renal disorder" (Abstract) Women with (T;T) and (C;T) genotypes displayed a 2x increased risk of systemic lupus erythematosus (95% CI=1.324 - 3.070, P=0.0014) ==Systemic sclerosis== Meta-analysis across 12 studies, totaling 4,300+ patients, concludes that there is an association between the rs2476601(A) allele and risk for systemic sclerosis, with an odds ratio of 1.169 (CI: 1.05 - 1.3, p = 0.004). associations of rs2476601 in PTPN22 R620W single-nucleotide polymorphism (SNP) with systemic sclerosis (SSc) or with anticentromere antibody (ACA)-positive or anti-topoisomerase I (anti-topo I) antibody-positive SSc, in a case-control study of US white, black, Hispanic, and Choctaw Indian individuals. rs2476601(A) allele is associated with (slightly) increased risk for systemic sclerosis in European Caucasians. ==Vasculitis, arteritis== ==Autoimmune thyroiditis== ] rs2476601 is not associated with Graves' disease in a study of Japanese patients. ==Crohn's disease, Ulcerative colitis, and Inflammatory bowel disease== A 2005 study was titled "The functional genetic variation in the PTPN22 gene has a negligible effect on the susceptibility to develop inflammatory bowel disease." ==Other diseases== studied ~300 UK patients with Behcet's disease and found that the R620W allele (i.e. rs2476601(A)) appeared to provide protection from Behcet's disease. The odds ratio for protection was calculated to be 2.4 (CI: 1.2 - 4.7). PTPN22 1858T allele had an allelic odds ratio (OR) of 2.16 for generalized vitiligo and a genotypic OR of 2.35 as C/T heterozygotes. Similarly, individuals carrying the PTPN22 1858T allele had an allelic OR of 2.05 for the expanded autoimmunity phenotype, and a genotypic OR of 2.19 for C/T heterozygotes. In study of 332 Norwegian patients plus a meta-analysis, the rs2476601(A) allele was linked to autoimmune Addison's disease (p=0.003) ==PTPN22 in genetics research==

A;G

Missense Mutation in the PTPN22 gene resulting in R620W change in the resulting protein LypW (normal is Lyp). Note that the (A;A) genotype is quite rare. LypW carriage is associated with diminished type I interferon (IFN) productin in response to Toll-like receptor (TLR) activation. Dysregulation of interferon, an inflammatory cytokine has been implicated in the pathogenesis of multiple autoimmune disorders including systemic lupus erythematosis (SLE). Associated Autoimmune Disorders One study suggested increased risk of multiple autoimmune disorders to varying degrees: *2.5x risk for type-1 diabetes *1.5x risk for rheumatoid arthritis *1.5x risk for SLE *1.8x risk for Hashimoto thyroiditis Study of a very genetically homogenous population in Crete also showed association of R620W with SLE. Other studies demonstrated an association of R620W with ANCA vasculitis, specifically GPA aka Wegener's and MPA, and association with increased pathology of specific organs (lung involvement, ENT involvement, skin involvement, and peripheral neuropathy were all ~1.5-2x more likely) Another study examined myasthenia gravis (MG) and found increased risk of MG specifically early onset / thymoma associated. Ethnic Variation of Significance Meta-analysis showed that PTPN22 T allele resulting in R620W was significantly associated with RA in European, but not in Asian and African subjects, and failed to show any association with the presence or absence of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies in those affected.