Objective: The protein tyrosine phosphatase N22 (PTPN22) gene exhibits regulatory activities for both T cells and B cells. A missense single‐nucleotide polymorphism (SNP) within this gene (rs2476601) has recently been associated with 4 autoimmune diseases: rheumatoid arthritis (RA), systemic lupus erythematosus, autoimmune thyroid disease, and type 1 diabetes mellitus, all of which are T cell–mediated and associated with the elaboration of autoantibody. The aim of this study was to investigate associations of the missense SNP of PTPN22 in a number of autoimmune diseases in the UK population, including RA, juvenile idiopathic arthritis (JIA), psoriasis, psoriatic arthritis (PsA), and multiple sclerosis (MS), some of which have not been examined previously.Methods: The PTPN22 missense SNP was genotyped in 886 RA, 661 JIA, 279 psoriasis, 455 PsA, and 379 MS patients and in 595 healthy controls. Association with the PTPN22 SNP was analyzed by chi‐square test as implemented in Stata software.Results: There was a significant association between the PTPN22 SNP and RA (P = 1.8 × 10^–8) and JIA (P = 0.0005). In contrast, no association with psoriasis, PsA, or MS was detected.Conclusion: We replicated the findings of a previous association with RA and identified a novel association with JIA. Together with previous data showing associations with other autoimmune diseases, our findings provide further evidence that the PTPN22 gene plays a role in the pathogenesis of a subgroup of autoimmune diseases.

Objective: To determine if polymorphisms of the macrophage migration inhibitory factor (MIF) gene are associated with juvenile idiopathic arthritis (JIA).Methods: Denaturing high‐performance liquid chromatography was used to screen the MIF gene in 32 UK Caucasian controls and 88 UK Caucasian JIA patients. Ninety‐two healthy UK Caucasian controls were then genotyped for each of the polymorphic positions identified. A panel of 526 UK Caucasian JIA patients and 259 UK Caucasian controls were subsequently genotyped for a single‐nucleotide polymorphism (SNP) identified in the 5′‐flanking region of the gene, using SNaPshot ddNTP primer extension and capillary electrophoresis. The functional significance of this polymorphism was also studied using luciferase‐based reporter gene assays in human T lymphoblast and epithelial cell lines.Results: A tetranucleotide repeat CATT_(5–7) beginning at nucleotide position −794 and 3 SNPs at positions −173 (G to C), +254 (T to C), and +656 (C to G) of the MIF gene were identified. No JIA‐specific mutations were found. Allele and genotype frequencies differed significantly between the controls and the JIA patients for the MIF‐173 polymorphism. Individuals possessing a MIF‐173*C allele had an increased risk of JIA (34.8% versus 21.6%) (odds ratio 1.9, 95% confidence interval 1.4–2.7; P = 0.0002). Furthermore, the MIF‐173* G and C variants resulted in altered expression of MIF in a cell type–specific manner. Serum levels of MIF were also significantly higher in individuals who carried a MIF‐173*C allele (P = 0.04).Conclusion: The −173‐MIF*C allele confers increased risk of susceptibility to JIA. Our data suggest a cell type–specific regulation of MIF, which may be central to understanding its role in inflammation.

Objective: To study whether genetic variants of macrophage migration inhibitory factor (MIF), the MIF −173G>C and CATT^5–8 alleles, are associated with disease severity and levels of circulating MIF in patients with rheumatoid arthritis (RA).Methods: Genotyping was performed in patients with early RA and in healthy controls. Demographic data, disease activity, and outcome measurements were compared between patients with and without the MIF variants. MIF −173G>C and CATT^5–8 polymorphisms were genotyped, and a newly developed enzyme‐linked immunosorbent assay for human MIF was used. Allele and genotype distributions of the MIF −173G>C and CATT^5–8 polymorphisms were compared between patients and controls by chi‐square test. Multiple regression analysis was performed to assess the independence of the MIF functional genetic variants as risk factors for radiologic joint damage.Results: Genotyping of the −173G>C and CATT^5–8 polymorphisms of MIF in RA patients and healthy individuals (n = 277 each) revealed similar frequencies of genotypes and haplotypes in both groups. No significant differences in demographic or clinical features were observed between RA patients carrying the MIF −173C allele or the MIF CATT⁷ allele or both and noncarrier RA patients. Radiologic joint damage was significantly higher in patients carrying risk alleles of the MIF −173G>C or the MIF CATT^5–8 functional variants. No synergistic effects between both genetic variants were observed. Multivariate regression analysis revealed that presence of the MIF −173C/C and MIF CATT^7/7 genotypes and having 1 MIF −173C allele were independent prognostic variables. Carriership of the MIF −173C allele (P = 0.002) or MIF CATT⁷ allele (P = 0.004) was associated with significantly higher circulating MIF levels compared with those in subjects having none of the risk‐conferring alleles, and greater circulating MIF levels correlated with more severe radiologic joint damage (r = 0.64, P = 0.001).Conclusion: The MIF polymorphisms are not associated with RA susceptibility but are associated with high levels of radiologic joint damage. High circulating MIF levels were shown to correlate strongly with radiologic joint damage, suggesting that MIF expression is genetically determined and can be used as a novel prognostic tool in RA.

Objective: To address the functional and prognostic relevance of the −173 single‐nucleotide G‐to‐C polymorphism of the macrophage migration inhibitory factor (MIF) gene in patients with systemic‐onset juvenile idiopathic arthritis (systemic‐onset JIA) by evaluating its association with serum and synovial fluid levels of MIF, with glucocorticoid requirement, and with the outcome of the disease.Methods: A total of 136 patients with systemic‐onset JIA were studied, including 98 patients from the British Paediatric Rheumatology Study Group's National Repository for JIA and 38 patients who were followed up at the IRCCS Policlinico San Matteo (Pavia, Italy) and the IRCCS G. Gaslini (Genoa, Italy). The MIF‐173 polymorphism was genotyped using SnaPshot ddNTP primer extension and capillary electrophoresis. MIF levels were measured by enzyme‐linked immunosorbent assay. The evaluation of the association of the MIF‐173 polymorphism with outcome was performed only in Italian patients who were followed up for >5 years, by analyzing retrospectively 1) the number of joints with active arthritis and the number of joints with limited range of motion; 2) the score, at the last visit, on the Italian version of the Childhood Health Assessment Questionnaire (C‐HAQ); and 3) data concerning the treatment regimens during the disease course.Results: Systemic‐onset JIA patients carrying a MIF‐173*C allele had serum and synovial fluid levels of MIF significantly higher than those in patients with the GG genotype. The duration of glucocorticoid treatment on a daily regimen was significantly longer in patients carrying a MIF‐173*C allele than in MIF‐173 GG homozygous patients. Moreover, the duration of clinical response to intraarticular injection of triamcinolone hexacetonide was significantly shorter in patients carrying a MIF‐173*C allele. At the last visit, the numbers of joints with active arthritis, the C‐HAQ scores, and the numbers of joints with limited range of motion were significantly higher in patients carrying the MIF‐173*C allele.Conclusion: Our study shows the functional relevance of the MIF‐173 polymorphism and suggests that the MIF‐173*C allele is a predictor of poor outcome in systemic‐onset JIA.