title: Toll-like receptor (TLR) polymorphisms in African children: Common TLR-4 variants predispose to severe malaria.
abstract: Genetic 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 glycosylphosphatidylinositol anchor induces signaling in host cells via TLR-2 and -4, whereas hemozoin-induced immune activation involves TLR-9. Binding of microbial ligands to the respective TLRs triggers the release of proinflammatory cytokines via the TLR/IL-1 receptor (TIR) domain and may contribute to the host response in malaria, including cytokine induction and 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 rare previously undescribed mutation (Leu658Pro), which impairs signaling via TLR-2. We failed to detect any polymorphisms within the TLR-9 Toll/IL-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 1.5- and 2.6-fold increased risks of severe malaria, respectively. These findings suggest TLR4-mediated responses to malaria in vivo and TLR-4 polymorphisms to be associated with disease manifestation.
authors.affiliation: Institute of Tropical Medicine Berlin, Charité-Universitätsmedizin Berlin, Spandauer Damm 130, 14050 Berlin, Germany.
authors.forename: Frank P
authors.initials: FP
authors.lastname: Mockenhaupt
authors.forename: Jakob P
authors.initials: JP
authors.lastname: Cramer
authors.forename: Lutz
authors.initials: L
authors.lastname: Hamann
authors.forename: Miriam S
authors.initials: MS
authors.lastname: Stegemann
authors.forename: Jana
authors.initials: J
authors.lastname: Eckert
authors.forename: Na-Ri
authors.initials: NR
authors.lastname: Oh
authors.forename: Rowland N
authors.initials: RN
authors.lastname: Otchwemah
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Dietz
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehrhardt
authors.forename: Nicolas W J
authors.initials: NW
authors.lastname: Schröder
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bienzle
authors.forename: Ralf R
authors.initials: RR
authors.lastname: Schumann
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers; D005260:Female; D020022:Genetic Predisposition to Disease; D005869:Ghana / Q000453:epidemiology; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense / Q000235:genetics; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D015995:Prevalence; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D051217:Toll-Like Receptor 9 / Q000235:genetics
chemical_list: D017931:DNA Primers; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495371:TLR9 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9