Toll-like receptor polymorphisms and cerebral malaria: TLR2 Δ22 polymorphism is associated with protection from cerebral malaria in a case control study

These polymorphisms were examined in a Ugandan case control study on children with either cerebral malaria or uncomplicated malaria. Serum cytokine levels were analysed by ELISA, according to genotype and disease status. In vitro TLR2 expression was measured according to genotype.Both Δ22 and GTn polymorphisms were highly frequent, but only Δ22 heterozygosity was associated with protection from cerebral malaria (OR 0.34, 95% confidence intervals 0.16, 0.73). In vitro, heterozygosity for Δ22 was associated with reduced pam3cys inducible TLR2 expression in human monocyte derived macrophages. In uncomplicated malaria patients, Δ22 homozygosity was associated with elevated serum IL-6 (p = 0.04), and long GT repeat alleles were associated with elevated TNF (p = 0.007).Reduced inducible TLR2 expression may lead to attenuated pro-inflammatory responses, a potential mechanism of protection from cerebral malaria present in individuals heterozygous for the TLR2 Δ22 polymorphism.In some holoendemic countries, individuals are bitten by malaria-infected mosquitoes 60-300 times a year [1,2]. The most common form of malaria in endemic countries is uncomplicated malaria, characterized by fever, chills, sweats, headaches and nausea. Cerebral malaria is a severe neurologic complication of Plasmodium falciparum infection that occurs much less commonly than uncomplicated malaria. Genetic factors influence infection outcome, and polymorphisms in genes encoding proteins involved in disease pathogenesis are strong candidates for disease association studies. As a receptor for parasite derived GPI, TLR2 is likely involved in disease pathogenesis [3], however, a previous study examining single nucleotide polymorphisms (SNPs) within TLR2 could not detect an association with severe disease because these SNPs were absent in the populations studied [4]. Reportedly, TLR2 SNPs are absent in some African countries as well, but insertion deletion polymorphisms within the 5' un-translated region of T