Toll-like receptor (TLR) polymorphisms in African children: common TLR-4 variants predispose to severe malaria.

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dc.contributor.authorMockenhaupt, F Pen_US
dc.contributor.authorCramer, J Pen_US
dc.contributor.authorHamann, Len_US
dc.contributor.authorStegemann, M Sen_US
dc.contributor.authorEckert, Jen_US
dc.contributor.authorOh, Na-Rien_US
dc.contributor.authorOtchwemah, R Nen_US
dc.contributor.authorDietz, Een_US
dc.contributor.authorEhrhardt, Sen_US
dc.contributor.authorSchröder, N W Jen_US
dc.contributor.authorBienzle, Uen_US
dc.contributor.authorSchumann, R Ren_US
dc.date.accessioned2006-03-22en_US
dc.date.accessioned2009-06-01T18:52:01Z
dc.date.available2006-03-22en_US
dc.date.available2009-06-01T18:52:01Z
dc.date.issued2006-03-22en_US
dc.description.abstractGenetic 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.en_US
dc.description.affiliationInstitute of Tropical Medicine Berlin, Charité-Universitätsmedizin Berlin, Spandauer Damm 130, 14050 Berlin, Germany.en_US
dc.identifier.citationMockenhaupt 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): 230-45en_US
dc.identifier.urihttps://imsear.searo.who.int/handle/123456789/112536
dc.language.isoengen_US
dc.subject.meshChilden_US
dc.subject.meshChild, Preschoolen_US
dc.subject.meshFemaleen_US
dc.subject.meshGenetic Predisposition to Diseaseen_US
dc.subject.meshGhanaen_US
dc.subject.meshHumansen_US
dc.subject.meshImmunity, Innate --geneticsen_US
dc.subject.meshInfanten_US
dc.subject.meshMalaria, Falciparum --geneticsen_US
dc.subject.meshMaleen_US
dc.subject.meshPolymorphism, Single Nucleotide --immunologyen_US
dc.subject.meshToll-Like Receptor 2 --geneticsen_US
dc.subject.meshToll-Like Receptor 4 --geneticsen_US
dc.subject.meshToll-Like Receptor 9 --geneticsen_US
dc.titleToll-like receptor (TLR) polymorphisms in African children: common TLR-4 variants predispose to severe malaria.en_US
dc.typeJournal Articleen_US
dc.typeResearch Support, Non-U.S. Gov'ten_US
dc.typeRetracted Publicationen_US
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