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.—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