Macrophage migration inhibitory factor (MIF): Genetic evidence for participation in early onset and early stage rheumatoid arthritis

Abstract

Macrophage migration inhibitory factor (MIF) is an upstream pro-inflammatory cytokine that is associated with the pathogenesis of autoimmune inflammatory diseases including rheumatoid arthritis (RA).Two polymorphisms in the upstream region exist in the MIF gene and are associated with RA susceptibility or severity in different populations. In this case-control study, we investigated whether MIF polymorphisms are associated with RA susceptibility or activity in a western Mexican population .The relationship of MIF levels with clinical features of disease also was assessed. Genotyping of the -794 CATT5-8(rs5844572) and the -173 G>C (s755622) polymorphisms was performed by PCR and PCR-RFLP respectively on 226 RA patients and 210 healthy subjects. Serum MIF levels were determined by ELISA. We found a significant association between the -794 CATT5-8 6,7 MIF genotype with RA. Moreover, we detected an association between the -794 CATT7 allele with early onset RA. The -794 CATT7 and -173*C alleles, which are in linkage disequilibrium, were associated with high disease activityon RA patients. A positive correlation between circulating MIF levels and C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, anti-citrullinated protein/peptides antibodies and TNFα was detected. MIF levels appear to be associated with disease progression rather than disease activity, which is distinct from the established relationship between disease activity and TNFα levels. In conclusion, the MIF gene and protein are associated with RA in a western Mexican population, with a main contribution onto early onset and early stages of disease.

Macrophage migration inhibitory factor: Association of −794 CATT5–8 and −173 G>C polymorphisms with TNF-α in systemic lupus erythematosus

“…Regarding the genotype and allele frequencies, both polymorphisms were distributed similarly to those reported in our previous study of a Mexican-Mestizo population by Llamas-Covarrubias et al [22] Unlike this previous study, in the case of the −794 CATT 5-8 MIF polymorphism we did not observe the presence of genotypes with the −794 CATT 8 high expression allele which was reported in low frequency (1%) in Mexican Mestizo patients with rheumatoid arthritis (RA). When we compared genotype and allele frequencies of both polymorphisms with frequencies reported in European Caucasians populations in the Netherlands [18], a Spanish population, [27] Caucasian Americans and African Americans populations [28] we observed that the genotype frequencies in our population were distributed similarly to those reported in these previous studies.…”

“…In our previous study by Llamas-Covarrubias et al, the association of the −794 CATT 7 and −173*C high expression alleles with early onset of RA and disease activity was reported in a Mexican-Mestizo population, where both high expression alleles presented a strong linkage disequilibrium (LD = 0.87, p <0.001) which indicates that both alleles are segregated in block from one generation to another and may confer a similar risk [22]. In a Spanish population with SLE, Sánchez et al also reported the association of −794 CATT 7 and −173*C high expression alleles with increased susceptibility to present SLE (OR = 2, p <0.01) [27].…”

“…The second polymorphism is a single nucleotide polymorphism (SNP) -173 G>C MIF (rs755622) at position −173 of the MIF gene in which there is a change from guanine (G) by cytosine (C). The −173*C allele is associated with increased MIF levels in circulation [18,20] in several populations, most likely by linkage disequilibrium with the −794 CATT 7 high expression allele [18,21,22]. Both polymorphisms also occur commonly in different populations, with minor allele frequencies of > 5% [23].…”

MIF and TNFαserum levels in rheumatoid arthritis patients treated with disease-modifying antirheumatic drugs: a cross-sectional study

“…Moreover, considering TNFa serum levels were overexpressed and MIF values were normal as previously reported (2-6 ng/mL) 38 these results could provide further insight into TNFa's association with disease activity and MIF with disease progression 39 .…”

Evaluation of MIF -173 G/C Polymorphism in Turkish Patients with Ankylosing Spondylitis

“…They have not found a significant association between G/G, G/C and C/C genotype distributions whereas they have shown that the risk of RA disease is high in individuals who carry C/C genotype. In another study related to RA patients, it has been stated that C allele is related to the activity of RA disease (16). It was have determined that the MIF -173 C is related to inflammatory sensitivity of polyarthritis whereas it is not in association with the intensity of the disease (17).…”