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01.12.2012 | Research | Ausgabe 1/2012 Open Access

Malaria Journal 1/2012

Toll-like receptor polymorphisms and cerebral malaria: TLR2 Δ22 polymorphism is associated with protection from cerebral malaria in a case control study

Zeitschrift:
Malaria Journal > Ausgabe 1/2012
Autoren:
Jennifer A Greene, Nadia Sam-Agudu, Chandy C John, Robert O Opoka, Peter A Zimmerman, James W Kazura
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1475-2875-11-47) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

JG performed genotyping, in vitro work, statistical analysis, and drafted manuscript. JXK and CCJ conceived and designed the study. PAZ was involved in data analysis. NSA conducted ELISAs. ROO was involved in study sample collection. All authors read and approved the final manuscript.

Abstract

Background

In malaria endemic areas, host genetics influence whether a Plasmodium falciparum-infected child develops uncomplicated or severe malaria. TLR2 has been identified as a receptor for P. falciparum-derived glycosylphosphatidylinositol (GPI), and polymorphisms within the TLR2 gene may affect disease pathogenesis. There are two common polymorphisms in the 5' un-translated region (UTR) of TLR2, a 22 base pair deletion in the first unstranslated exon (Δ22), and a GT dinucleotide repeat in the second intron (GTn).

Methods

These polymorphisms were examined in a Ugandan case control study on children with either cerebral malaria or uncomplicated malaria. Serum cytokine levels were analysed by ELISA, according to genotype and disease status. In vitro TLR2 expression was measured according to genotype.

Results

Both Δ22 and GTn polymorphisms were highly frequent, but only Δ22 heterozygosity was associated with protection from cerebral malaria (OR 0.34, 95% confidence intervals 0.16, 0.73). In vitro, heterozygosity for Δ22 was associated with reduced pam3cys inducible TLR2 expression in human monocyte derived macrophages. In uncomplicated malaria patients, Δ22 homozygosity was associated with elevated serum IL-6 (p = 0.04), and long GT repeat alleles were associated with elevated TNF (p = 0.007).

Conclusion

Reduced inducible TLR2 expression may lead to attenuated pro-inflammatory responses, a potential mechanism of protection from cerebral malaria present in individuals heterozygous for the TLR2 Δ22 polymorphism.
Zusatzmaterial
Additional file 1: Table S1. Cytokine association tests according to TLR2 genotype in Uganda children with cerebral malaria or uncomplicated malaria. (DOC 120 KB)
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Literatur
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