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TLR9 Polymorphisms Are Associated with Altered IFN-γ Levels in Children with Cerebral Malaria

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  • 1 University of Minnesota, Minneapolis, Minnesota; Case Western Reserve University, Cleveland, Ohio; Makerere University, Kampala, Uganda; Michigan State University, East Lansing, Michigan

Toll-like receptor (TLR) polymorphisms have been associated with disease severity in malaria infection, but mechanisms for this association have not been characterized. The TLR2, 4, and 9 single nucleotide polymorphism (SNP) frequencies and serum interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) levels were assessed in Ugandan children with cerebral malaria (CM, N = 65) and uncomplicated malaria (UM, N = 52). The TLR9 C allele at −1237 and G allele at 1174 were strongly linked, and among children with CM, those with the C allele at −1237 or the G allele at 1174 had higher levels of IFN-γ than those without these alleles (P = 0.03 and 0.008, respectively). The TLR9 SNPs were not associated with altered IFN-γ levels in children with UM or altered TNF-α levels in either group. We present the first human data that TLR SNPs are associated with altered cytokine production in parasitic infection.

Author Notes

*Address correspondence to Chandy C. John, Center for Global Pediatrics, 717 Delaware Street SE, Mail Code 1932, Minneapolis, MN 55414. E-mail: ccj@umn.edu†Nadia Sam-Agudu and Jennifer Greene contributed equally to this paper.

Authors' addresses: Nadia A. Sam-Agudu, Melissa A. Riedesel, and Chandy C. John, Center for Global Pediatrics, Minneapolis, MN. Jennifer A. Greene, James W. Kazura, and Peter A. Zimmerman, Center for Global Health and Diseases, Wolstein Research Building, Cleveland, OH. Robert O. Opoka, Mulago Hospital, Department of Paediatrics and Child Health, Kampala, Uganda. Tracy L. Bergemann, Division of Biostatistics, School of Public Health, Minneapolis, MN. Lisa A. Schimmenti, Pediatric Genetics, Minneapolis, MN.

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