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PMID: 16371473 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 103 ·No. 1 ·2006-01-03 ·Pages 177-82

Mockenhaupt FP, Cramer JP, Hamann L, Stegemann MS, Eckert J, Oh NR, Otchwemah RN, Dietz E, Ehrhardt S, Schröder NW, Bienzle U, Schumann RR

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.

MeSH Terms
Base Sequence Cell Line Child Child, Preschool DNA Primers Female Genetic Predisposition to Disease Ghana/epidemiology Humans Infant Malaria, Falciparum/epidemiology,genetics Male Molecular Sequence Data Mutagenesis, Site-Directed Mutation, Missense/genetics Odds Ratio Polymorphism, Genetic Prevalence Sequence Analysis, DNA Signal Transduction/genetics Toll-Like Receptor 2/genetics Toll-Like Receptor 4/genetics Toll-Like Receptor 9/genetics
Chemicals
DNA Primers TLR2 protein, human TLR4 protein, human TLR9 protein, human Toll-Like Receptor 2 Toll-Like Receptor 4 Toll-Like Receptor 9
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Mockenhaupt Frank P
Institute of Tropical Medicine Berlin, Charité-Universitätsmedizin Berlin, Spandauer Damm 130, 14050 Berlin, Germany.
Cramer Jakob P
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
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0506803102
Published
2006-01-03
Epub
2005-00-21
Pages
177-82
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1324982
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0506803102 PMC Full Text View journal details
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