1. ¹Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
2. ²University of Pittsburgh/KEMRI Laboratories of Parasitic and Viral Diseases, Center for Vector Biology and Control Research, Kisumu, Kenya
3. ³Laboratories of Human Pathogens, Lake Erie College of Osteopathic Medicine, Erie, PA, USA
4. ⁴Department of Psychology, College of Charleston, Charleston, SC, USA
5. ⁵Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

Correspondence: Dr DJ Perkins, Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, 603 Parran Hall, Pittsburgh, PA 15261, USA. E-mail: djp@pitt.edu

Received 2 June 2006; Revised 12 July 2006; Accepted 17 July 2006; Published online 24 August 2006.

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.