Functional and prognostic relevance of the −173 polymorphism of the macrophage migration inhibitory factor gene in systemic‐onset juvenile idiopathic arthritis

Abstract

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 systemiconset 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. 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.Systemic-onset juvenile idiopathic arthritis (JIA) accounts for ϳ15-20% of JIA in children. It is characterized by the association of chronic arthritis with systemic features, such as spiking fever, macular erythematous rash, serositis, hepatosplenomegaly, and Supported by IRCCS Policlinico San Matteo and by Ministero dell'Università e della Ricerca Scientifica.

Correlation of rheumatoid arthritis severity with the genetic functional variants and circulating levels of macrophage migration inhibitory factor

“…Second, MIF levels were also found to be increased in synovial fluid and synovial tissue from patients with RA and from patients with juvenile idiopathic arthritis; in the latter group, this was independent of disease activity as measured by the C-reactive protein levels (6,15,40). These findings indicate that MIF expression is not specific for RA but may also function as an important regulator of immunity in other autoimmune conditions such as systemic lupus erythematosus, multiple sclerosis, and diabetes.…”

“…In contrast with this finding, Barton and colleagues found that the MIF Ϫ173C allele and the MIF CATT 7 repeat were associated with susceptibility to inflammatory arthritis, but they were unable to find a correlation with disease severity (14). Susceptibility to juvenile idiopathic arthritis was found to be associated with both functional promotor polymorphisms in the MIF gene (6,15). In addition, the circulating MIF level was found to be increased in individuals with juvenile idiopathic arthritis carrying the MIF Ϫ173C functional variant, and the MIF Ϫ173C allele was suggested to be a predictor of poor outcome in this disease (15).…”

“…Susceptibility to juvenile idiopathic arthritis was found to be associated with both functional promotor polymorphisms in the MIF gene (6,15). In addition, the circulating MIF level was found to be increased in individuals with juvenile idiopathic arthritis carrying the MIF Ϫ173C functional variant, and the MIF Ϫ173C allele was suggested to be a predictor of poor outcome in this disease (15). The role of the MIF genetic polymorphisms in RA susceptibility and severity, however, remains controversial, since previous studies were hampered by potential ethnic differences, inclusion biases, and lack of validated followup data.…”

“…Since circulating MIF levels were found to be increased during RA, MIF is abundantly expressed in various synovial cells, and genetic variants are potentially linked to MIF levels, it could be hypothesized that MIF is intimately involved in the pathogenesis of RA (15,16). The fact that a substantial amount of evidence points toward a role for MIF in RA pathogenesis prompted us to investigate the potential association of 2 MIF genetic variants with the susceptibility to and severity of RA, using a large cohort of well-documented, prospectively followed up patients with RA.…”

De novo 19q13.42 duplications involving NLRP gene cluster in a patient with systemic-onset juvenile idiopathic arthritis

“…3 However, such associations are seen mostly in polyarticular JIA, but not in s-JIA. Other genes including MIF, IL6, IL10 and TNF are reported to be associated with s-JIA in different populations and subtypes, [4][5][6][7][8] although these genes account for only a small part of the total genetic contribution to JIA. Therefore, the genetic background underlying the s-JIA remains mostly undetermined.…”