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

• Published in: The FASEB journal 2012-02, Vol.26 (2), p.907-916
• Main Authors: Renner, Pascal, Roger, Thierry, Bochud, Pierre‐Yves, Sprong, Tom, Sweep, Fred C. G. J., Bochud, Murielle, Faust, Saul N., Haralambous, Elene, Betts, Helen, Chanson, Anne‐Laure, Reymond, Marlies Knaup, Mermel, Elliot, Erard, Veronique, Deuren, Marcel, Read, Robert C., Levin, Michael, Calandra, Thierry
• Format: Article
• Language: English
• Subjects: Adolescent; Alleles; Base Sequence; Cell Line; Child; Child, Preschool; cytokine; DNA Primers - genetics; Female; gene polymorphism; Homozygote; Humans; Infant; Intramolecular Oxidoreductases - genetics; Macrophage Migration-Inhibitory Factors - genetics; Male; Meningitis, Meningococcal - genetics; Meningitis, Meningococcal - mortality; Meningococcal Infections - genetics; Meningococcal Infections - mortality; Microsatellite Repeats; Neisseria meningitidis; Netherlands - epidemiology; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Risk Factors; sepsis; Sepsis - genetics; Sepsis - mortality; United Kingdom - epidemiology
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.11-195065

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 CATT5–8 microsatellite and –173 G/C SNP) were associated with the occurrence and outcome of meningococcal disease in children. The CATT5 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 CATT5 copy number (P=0.04). The CATT5 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 CATT5 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, CATT5 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.—Renner, P., Roger, T., Bochud, P.‐Y., Sprong, T., Sweep, F. C. G. J., Bochud, M., Faust, S. N., Haralambous, E., Betts, H., Chanson, A.‐L., Reymond, M. K., Mermel, E., Erard, V., van Deuren, M., Read, R. C., Levin, M., Calandra, T. A functional microsatellite of the macrophage migration inhibitory factor gene associated with meningococcal disease. FASEB J. 26, 907–916 (2012). www.fasebj.org