Toll-like receptor (TLR) polymorphisms in African children: Common TLR-4 variants predispose to severe malaria.
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Toll-like receptor (TLR) polymorphisms in African children: Common TLR-4 variants predispose to severe malaria. / Mockenhaupt, Frank P; Cramer, Jakob; Hamann, Lutz; Stegemann, Miriam S; Eckert, Jana; Oh, Na-Ri; Otchwemah, Rowland N; Dietz, Ekkehart; Ehrhardt, Stephan; Schröder, Nicolas W J; Bienzle, Ulrich; Schumann, Ralf R.
In: P NATL ACAD SCI USA, Vol. 103, No. 1, 1, 2006, p. 177-182.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Toll-like receptor (TLR) polymorphisms in African children: Common TLR-4 variants predispose to severe malaria.
AU - Mockenhaupt, Frank P
AU - Cramer, Jakob
AU - Hamann, Lutz
AU - Stegemann, Miriam S
AU - Eckert, Jana
AU - Oh, Na-Ri
AU - Otchwemah, Rowland N
AU - Dietz, Ekkehart
AU - Ehrhardt, Stephan
AU - Schröder, Nicolas W J
AU - Bienzle, Ulrich
AU - Schumann, Ralf R
PY - 2006
Y1 - 2006
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 103
SP - 177
EP - 182
JO - P NATL ACAD SCI USA
JF - P NATL ACAD SCI USA
SN - 0027-8424
IS - 1
M1 - 1
ER -
