A functional microsatellite of the macrophage migration inhibitory factor gene associated with meningococcal disease

Infectious Diseases Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
The FASEB Journal (Impact Factor: 5.04). 02/2012; 26(2):907-16. DOI: 10.1096/fj.11-195065
Source: PubMed


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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    • "Macrophage migration inhibitory factor: Association of À794 CATT 5–8 and À173 G>C polymorphisms with TNF-a in systemic lupus erythematosus. Hum Immunol (2014), region appear to have functional importance, the first is the short tandem repeat (STR) À794 CATT 5–8 MIF (rs5844572) which is a microsatellite repetition of cytosine–adenine–thymine–thymine (CATT) at position À794 bp, in which the repeat length (5–8 repetitions ) correlates with increased gene expression and with serum MIF circulation levels [18] [19]. The second polymorphism is a single nucleotide polymorphism (SNP) À173 G>C MIF (rs755622) at position À173 of the MIF gene in which there is a change from guanine (G) by cytosine (C). "
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    ABSTRACT: Macrophage migration inhibitory factor (MIF) is an upstream immunoregulatory cytokine associated with the pathogenesis of autoimmune inflammatory diseases. There is evidence that MIF functions in a positive feedback loop with TNF-α that could perpetuate the inflammatory process in systemic lupus erythematosus (SLE). In this case-control study we investigated whether commonly occurring functional MIF polymorphisms are associated with SLE as well as with MIF and TNF- α serum levels in a Mexican-Mestizo population. Genotyping of the -794CATT5-8(rs5844572) and -173G>C(rs755622) MIF polymorphisms was performed by PCR and PCR-RFLP respectively in186 SLE patients and 200 healthy subjects. MIF and TNF- α serum levels were determined by ELISA. A significant increase of MIF and TNF- α levels was found in SLE patients. According to a genetic model, we found a significant association of genotypes carrying the -794CATT7 and -173∗C risk alleles with susceptibility to SLE and with a significant increase of TNF-α. In conclusion, MIF gene polymorphisms are associated with SLE susceptibility and with an increase of TNF-α serum levels in a Mexican-Mestizo population.
    Human immunology 05/2014; 75(5). DOI:10.1016/j.humimm.2014.02.014 · 2.14 Impact Factor
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    • "Thus, despite prior suggestions that sepsis pathology results from an excessive or overreactive systemic inflammatory response, high MIF expression was protective, presumably because of its high upstream role in eliminating invasive microbial infections or because of its ability to counteract the immunoparalytic state. A strong role for MIF also has been reported for clinical outcome from meningococcemia [179], invasive streptococcal infection [180], and severe malaria [181]. "
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    ABSTRACT: Sepsis and septic shock are among the leading causes of death in intensive care units worldwide. Numerous studies on their pathophysiology have revealed an imbalance in the inflammatory network leading to tissue damage, organ failure, and ultimately, death. Cytokines are important pleiotropic regulators of the immune response, which have a crucial role in the complex pathophysiology underlying sepsis. They have both pro- and anti-inflammatory functions and are capable of coordinating effective defense mechanisms against invading pathogens. On the other hand, cytokines may dysregulate the immune response and promote tissue-damaging inflammation. In this review, we address the current knowledge of the actions of pro- and anti-inflammatory cytokines in sepsis pathophysiology as well as how these cytokines and other important immunomodulating agents may be therapeutically targeted to improve the clinical outcome of sepsis.
    Mediators of Inflammation 06/2013; 2013(6):165974. DOI:10.1155/2013/165974 · 3.24 Impact Factor
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    • "Notably, in a recent study of SLE, a dual effect of the -794 CATT polymorphism was noted with the low expression CATT5 found to be associated with disease susceptibility and the CATT7 allele with clinical severity [17]. Numerous studies based on defined reporter assays [15] or plasma MIF levels in different disease [17,30] support the designation of CATT7 as a high expression MIF allele. By contrast, there are fewer functional data for the -173*C allele, and its association with increased MIF expression may reside in its strong linkage disequilibrium with -794 CATT7, although to date, most studies have been confined to Caucasian populations. "
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    ABSTRACT: Introduction Adult-onset still's disease (AOSD) is a rare systemic inflammatory disorder in which abnormalities in inflammatory cytokines production appear to play a pathophysiological role. Our previous work has reported increased expression of macrophage migration inhibitory factor (MIF) and revealed its correlation with disease severity and activity in AOSD. A -173 G/C single nucleotide polymorphism (SNP) (rs755622) and a -794 CATT5-8 repeat (rs5844572) in the MIF promoter have been reported. In this study, we sought to explore the relationship between functional MIF promoter polymorphisms and MIF expression in AOSD. Methods 100 patients and 200 controls were recruited in the study. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was utilized to analyze the -173 G/C SNP (rs755622) and PCR-based size discrimination assay was applied to detect the -794 CATT5-8 repeat (rs5844572) in the MIF promoter. Plasma MIF levels were measured by ELISA. MIF mRNA levels were quantified by real-time reverse transcription (RT)-PCR. Bisulfate genomic sequencing was employed to evaluate DNA methylation status within the MIF promoter. Results We identified that the frequencies of MIF -794 CATT5 (P = 0.001) allele and the expression of MIF (P <0.001) were increased in patients compared to healthy controls. Plasma levels of MIF in patients with CC genotype were higher than those of patients with GC or GG genotypes (P = 0.05). In patients with established AOSD, a higher frequency of -794 CATT7 containing MIF genotypes was observed in those with liver dysfunction (P = 0.009). Haplotype analysis revealed a higher representation of the MIF haplotype defined by -173*C/-794 CATT5 (C5) in AOSD patients (P = 0.001). Conclusion Functional promoter polymorphisms in the MIF gene influence plasma MIF levels in AOSD and may contribute to disease susceptibility or clinical presentation of AOSD.
    Arthritis research & therapy 05/2013; 15(3):R65. DOI:10.1186/ar4239 · 3.75 Impact Factor
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