Linkage proof for PTPN22 , a rheumatoid arthritis susceptibility gene and a human autoimmunity gene

Abstract

The tyrosine phosphatase PTPN22 allele 1858T has been associated with rheumatoid arthritis (RA) and other autoimmune diseases. RA is the most frequent of those multifactorial diseases. The RA association was usually restricted to serum rheumatoid factor positive disease (RF ؉ ). No interaction was shown with HLA-DRB1, the first RA gene. Many case-control studies replicated the RA association, showing an allele frequency increase of Ϸ5% on average and large variations of population allele frequencies (2.1-15.5%). In multifactorial diseases, the final proof for a new susceptibility allele is provided by departure from Mendel's law (50% transmission from heterozygous parents). For PTPN22-1858T allele, convincing linkage proof was available only for type 1 diabetes. We aimed at providing this proof for RA. We analyzed 1,395 West European Caucasian individuals from 465 ''trio'' families. We replicated evidence for linkage, demonstrating departure from Mendel's law in this subset of early RA onset patients. We estimated the overtransmission of the 1858T allele in RF ؉ families: T ‫؍‬ 63%, P < 0.0007. The 1858T allele frequency increased from 11.0% in controls to 17.4% in RF ؉ RA for the French Caucasian population and the susceptibility genotype (1858T/T or T/C) from 20.2% to 31.6% [odds ratio (OR) ‫؍‬ 1.8 (1.2-2.8)]. In conclusion, we provided the linkage proof for the PTPN22-1858T allele and RF ؉ RA. With diabetes and RA, PTPN22 is therefore a ''linkage-proven'' autoimmunity gene. PTPN22 accounting for Ϸ1% of the RA familial aggregation, many new genes could be expected that are as many leads to definitive therapy for autoimmune diseases.linkage analysis ͉ R620W polymorphism ͉ rheumatoid factor ͉ transmission disequilibrium ͉ LYP protein

The PTPN22gain-of-function+1858T(+) genotypes correlate with low IL-2 expression in thymomas and predispose to myasthenia gravis

“…[5][6][7][9][10][11] These now include EOMG, 12,16 as confirmed here. PTPN22 is mainly expressed in lymphocytes, in which it physically associates with Csk kinase, an important suppressor of Src family kinases, which mediate TCR signaling.…”

“…Their presumed low-expression or low-activity genotypes predispose to multiple autoimmune diseases, including type 1 diabetes, [5][6][7][8][9] Graves' disease, 7,8 hypothyroidism, 6,8 systemic lupus erythematosus, 6,10 rheumatoid arthritis, 6,11 and non-thymoma myasthenia gravis (MG). 12 However, the function of PTPN22 in this tolerance failure 13 has become debatable because of the paradoxically stronger inhibition of T-cell activation 14 by the autoimmunity-prone PTPN22 þ 1858T/T ( 620 W) or C/T genotype rather than the protective þ 1858C/C ( 620 R).…”

Association of PTPN22 single nucleotide polymorphism with rheumatoid arthritis but not with allergic asthma

“…Finally, we found much stronger association of 1858T with RF-negative than with RF-positive RA, in contrast to some other studies. 8,17 However, many laboratories 6,7,18 did not observe substantial differences between 1858T frequencies in RF-positive and RF-negative RA patients, and Dieudé et al 5 found 1858T-RF association in transmission disequilibrium test, but not in affected sib-pair test. Therefore, the restriction of the association of 1858T with RF-positive RA is still controversial and requires further study.…”

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.…”