A functional microsatellite of the macrophage migration inhibitory factor gene associated with meningococcal disease.
ABSTRACT Macrophage migration inhibitory factor (MIF) is an abundantly expressed proinflammatory cytokine playing a critical role in innate immunity and sepsis and other inflammatory diseases. We examined whether functional MIF gene polymorphisms (-794 CATT(5-8) microsatellite and -173 G/C SNP) were associated with the occurrence and outcome of meningococcal disease in children. The CATT(5) allele was associated with the probability of death predicted by the Pediatric Index of Mortality 2 (P=0.001), which increased in correlation with the CATT(5) copy number (P=0.04). The CATT(5) allele, but not the -173 G/C alleles, was also associated with the actual mortality from meningoccal sepsis [OR 2.72 (1.2-6.4), P=0.02]. A family-based association test (i.e., transmission disequilibrium test) performed in 240 trios with 1 afflicted offspring indicated that CATT(5) was a protective allele (P=0.02) for the occurrence of meningococcal disease. At baseline and after stimulation with Neisseria meningitidis in THP-1 monocytic cells or in a whole-blood assay, CATT(5) was found to be a low-expression MIF allele (P=0.005 and P=0.04 for transcriptional activity; P=0.09 and P=0.09 for MIF production). Taken together, these data suggest that polymorphisms of the MIF gene affecting MIF expression are associated with the occurrence, severity, and outcome of meningococcal disease in children.
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ABSTRACT: Graves disease (GD) is an autoimmune disease. Macrophage migration inhibitory factor (MIF) is a potent cytokine that plays an important role in the regulation of immune responses. Two polymorphisms in the promoter region of MIF, rs5844572 and rs755622, are known to affect MIF expression. The purpose of this study was to investigate the relationship between polymorphisms in the MIF gene promoter and the severity of GD. A total of 677 individuals, including 481 GD patients and 196 ethnically matched healthy controls, were genotyped to identify differences in the distribution of the MIF polymorphisms rs5844572 and rs755622. Although there were no significant differences in the allele or genotype distributions among patients with different grades of goiter in GD and healthy controls, the distribution of the C allele, especially C/C genotype, of the rs755622 single nucleotide polymorphism (SNP) in MIF, may be as a risk factor for goiter initiation whereas a protector against development of severe goiter in patients with untreated GD (p<0.05). A goiter-developmental model incorporating genetic (MIF SNP rs755622) and environmental risk factors (gender, radioiodine treatment, thyroid gland surgery and vitiligo) significantly increased the prediction accuracy. Further studies are required to address the role of MIF polymorphisms, as well as their association with other candidate genes, in GD.PLoS ONE 03/2014; 9(3):e92849. · 3.53 Impact Factor
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ABSTRACT: Human genetic polymorphisms associated with decreased expression of macrophage migration inhibitory factor (MIF) have been linked to the risk of community-acquired pneumonia. Because Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and nasal carriage is a precursor to invasive disease, we explored the role of MIF in the clearance of pneumococcal colonization in a mouse model. MIF-deficient mice (Mif(-/-)) showed prolonged colonization with both avirulent (23F) and virulent (6A) pneumococcal serotypes compared with wild-type animals. Pneumococcal carriage led to both local upregulation of MIF expression and systemic increase of the cytokine. Delayed clearance in the Mif(-/-) mice was correlated with reduced numbers of macrophages in upper respiratory tract lavages as well as impaired upregulation of MCP-1/CCL2. We found that primary human monocyte-derived macrophages as well as THP-1 macrophages produced MIF upon pneumococcal infection in a pneumolysin-dependent manner. Pneumolysin-induced MIF production required its pore-forming activity and phosphorylation of p38-MAPK in macrophages, with sustained p38-MAPK phosphorylation abrogated in the setting of MIF deficiency. Challenge with pneumolysin-deficient bacteria demonstrated reduced MIF upregulation, decreased numbers of macrophages in the nasopharynx, and less effective clearance. Mif(-/-) mice also showed reduced Ab response to pneumococcal colonization and impaired ability to clear secondary carriage. Finally, local administration of MIF was able to restore bacterial clearance and macrophage accumulation in Mif(-/-) mice. Our work suggests that MIF is important for innate and adaptive immunity to pneumococcal colonization and could be a contributing factor in genetic differences in pneumococcal disease susceptibility.The Journal of Immunology 06/2014; · 5.36 Impact Factor
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ABSTRACT: Psoriatic arthritis (PsA) is an autoimmune disease with a complex interaction of gene and with a dysregulation of pro-inflammatory cytokine such as Macrophage migration Inhibitory Factor (MIF) and Tumor Necrosis Factor-alpha (TNFα). Two polymorphisms identified in the promoter region of the MIF gene have been described: the STR-794 CATT5-8 (rs5844572) and the SNP-173 G>C (rs755622), which are associated with increased MIF levels in circulation and with autoimmune diseases in several populations. In this case-control study we investigated whether commonly occurring functional MIF polymorphisms are associated with PsA susceptibility and clinical variables as well as with MIF and TNFα serum levels in a Mexican-Mestizo population. Genotyping of the -794 CATT5-8 and -173 G>C MIF polymorphisms was performed by PCR and PCR-RFLP respectively in 50 PsA patients and 100 healthy subjects (HS). MIF and TNFα serum levels were determined by ELISA. A significant increase of MIF (PsA: 7.8 vs. HS: 5.25 ng/mL; p < 0.001) and TNFα (PsA: 24.6 vs. HS: 9.9 pg/mL; p < 0.001) levels was found in PsA patients, a significant correlation was observed between MIF and TNFα (r = 0.41; p < 0.01). The 5,6 repeats genotype of the -794 CATT5-8 MIF was associated with protection to PsA (OR = 0.29; CI 0.77-0.98; p = 0.03), and the G/C genotype (OR = 7.5; CI 2.92-21.64; p < 0.001) and the -173*C allele (OR = 2.45; CI 1.43-4.20; p < 0.001) of the -173 G>C MIF were associated with susceptibility to PsA. In conclusion the -173*C allele is associated with susceptibility to PsA in Mexican-Mestizo population, whereas the correlation between MIF and TNFα soluble levels provided evidence that both cytokines are closely related in the pathophysiology of the PsA.International Journal of Clinical and Experimental Medicine 01/2014; 7(9):2605-14. · 1.42 Impact Factor