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  • Original Article
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A macrophage migration inhibitory factor promoter polymorphism is associated with high-density parasitemia in children with malaria

Abstract

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that regulates innate and adaptive immune responses to bacterial and parasitic infections. Functional promoter variants in the MIF gene influence susceptibility to inflammatory diseases in Caucasians. As the role of genetic variation in the MIF gene in conditioning malaria disease outcomes is largely unexplored, the relationship between a G to C transition at MIF −173 and susceptibility to high-density parasitemia (HDP) and severe malarial anemia (SMA) was examined in Kenyan children (aged 3–36 months; n=477) in a holoendemic Plasmodium falciparum transmission region. In a multivariate model, controlling for age, gender, HIV-1 status, and sickle-cell trait, MIF −173CC was associated with an increased risk of HDP compared to MIF −173GG. No significant associations were found between MIF −173 genotypic variants and susceptibility to SMA. Additional studies demonstrated that homozygous G alleles were associated with lower basal circulating MIF levels relative to the GC group. However, stimulation of cultured peripheral blood mononuclear cells with malarial pigment (hemozoin) increased MIF production in the GG group and decreased MIF production in the GC group. Thus, variability at MIF −173 is associated with functional changes in MIF production and susceptibility to HDP in children with malaria.

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Acknowledgements

We sincerely thank the parents/guardians and children from the Siaya District community, as well as the US blood donors for their participation in the study. We are also grateful to the staff at the Siaya District Hospital, University of Pittsburgh/KEMRI, and University of Pittsburgh Laboratories for their contributions to the study. We also thank Dr Davy Koech, Director of KEMRI, for approving this manuscript for publication.

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Correspondence to D J Perkins.

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The study was approved by the Ethics Committee of the Kenya Medical Research Institute (KEMRI) and the University of Pittsburgh Institutional Review Board. Written informed consent was obtained from the parents/legal guardians of all participating children.

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There is no conflict of interest for any of the authors of the manuscript due to either commercial or other affiliations.

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Awandare, G., Ouma, C., Keller, C. et al. A macrophage migration inhibitory factor promoter polymorphism is associated with high-density parasitemia in children with malaria. Genes Immun 7, 568–575 (2006). https://doi.org/10.1038/sj.gene.6364332

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