Mockenhaupt, F PCramer, J PHamann, LStegemann, M SEckert, JOh, Na-RiOtchwemah, R NDietz, EEhrhardt, SSchröder, N W JBienzle, USchumann, R R2006-03-222009-06-012006-03-222009-06-012006-03-22Mockenhaupt FP, Cramer JP, Hamann L, Stegemann MS, Eckert J, Oh NR, Otchwemah RN, Dietz E, Ehrhardt S, Schröder NW, Bienzle U, Schumann RR. Toll-like receptor (TLR) polymorphisms in African children: common TLR-4 variants predispose to severe malaria. Journal of Communicable Diseases. 2006 Mar; 38(3): 230-45http://imsear.searo.who.int/handle/123456789/112536Genetic host factors play a substantial role in susceptibility to and severity of malaria, which continues to cause at least one million deaths per year. Recently, members of the toll-like receptor (TLR) family have been shown to be involved in recognition of the etiologic organism Plasmodium falciparum: The glycosylphosphatidylinisitol anchor induces signaling in host cells via TLR-2 and -4, while hemozoin-induced immune activation involves TLR-9. Binding of microbial ligands to the respective TLRs triggers the release of pro-inflammatory cytokines via the TLR/IL-1 receptor (TIR) domain and may contribute to the host response, including pro-inflammatory cytokine induction and malarial fever. In a case-control study among 870 Ghanaian children, we examined the influence of TLR-2, -4, and -9 polymorphisms in susceptibility to severe malaria. TLR-2 variants common in Caucasians and Asians were completely absent. However, we found a new, rare mutation (Leu658Pro), which impairs signaling via TLR-2. We failed to detect any polymorphisms within the TLR-9/interleukin-1 receptor domain. Two frequent TLR-9 promoter polymorphisms did not show a clear association with malaria severity. In contrast, the TLR-4-Asp299Gly variant occurred at a high rate of 17.6% in healthy controls, and was even more frequent in severe malaria patients (24.1%, p<0.05). Likewise, TLR-4-Thr399Ile was seen in 2.4% of healthy children and in 6.2% of patients (p=0.02). TLR-4-Asp299Gly and TLR-4-Thr399Ile conferred an 1.5- and 2.6-fold increased risk of severe malaria, respectively. These findings suggest TLR4-mediated responses to malaria in vivo and TLR-4 polymorphisms to be associated with disease manifestation. However some gray areas also suggest the scope for further improvements.engChildChild, PreschoolFemaleGenetic Predisposition to DiseaseGhanaHumansImmunity, Innate --geneticsInfantMalaria, Falciparum --geneticsMalePolymorphism, Single Nucleotide --immunologyToll-Like Receptor 2 --geneticsToll-Like Receptor 4 --geneticsToll-Like Receptor 9 --geneticsJournal Article