Abstract
Toll-like receptors (TLRs) are critical mediators of the inflammatory response to malarial infection, and gene polymorphisms affecting TLR function may be partially responsible for inter-individual variation in disease manifestation. However, there are inconsistencies in the associations of common genetic variants of TLR4 (D299G) and TLR9 (T-1237C and T-1486C) with malaria outcome. A comprehensive search was conducted to identify relevant and independent Plasmodium falciparum-infected case-control studies, and meta-analysis including six studies for each SNP was performed to obtain more precise estimates of the pooled effects of these variants. The results showed significant associations of the -1486C allele with the risk of severe malaria in allele contrast (T vs. C, p = 0.004, OR = 1.26) and homozygous (TT vs. CC, p = 0.03, OR = 1.51) genetic models. There was no association between the D299G or T-1237C variants and uncomplicated or severe malaria using any of the genetic models tested. However, in stratified analysis, -1237C was associated with the risk of severe malaria in Indian adults (TT vs. TC, p = 0.06, OR = 2.13; TT vs. TC+CC, p <0.00001, OR = 2.65), suggesting that our results must be considered preliminary. The robustness of -1486C as a risk factor warrants investigation into its functionality in malaria pathogenesis. Further, the lack of an association with the T-1237C variant was weak, and future studies examining more detailed individual data from different ethnic groups are essential for confirmation of its genetic contribution to malaria.
Highlights
Malaria, one of the most deadly infectious diseases in humans, is caused by five species of Plasmodium (Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium knowlesi) with an estimated 198 million cases and 584,000 deaths in 20131
Toll-like receptors (TLRs) are critical mediators of the inflammatory response to malarial infection, and gene polymorphisms affecting TLR function may be partially responsible for inter-individual variation in disease manifestation
The criteria for inclusion in the meta-analysis were: I) independent P. falciparum-infected case-control or cohort studies conducted to evaluate the association of the TLR4D299G and/or TLR9T-1237C and T-1486C polymorphisms with the risk of severe malaria in order to exclude the possibility of repeated data from two or more studies from the same region, if any; II) sufficient published data on the genotypes or allele frequencies for determining odds ratios (OR) and confidence intervals (CIs); and III) the study was published as a full paper, not as a meeting abstract or review
Summary
One of the most deadly infectious diseases in humans, is caused by five species of Plasmodium (Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium knowlesi) with an estimated 198 million cases and 584,000 deaths in 20131. While TLR4 may interact with extra-cellular ligands (such as PfGPI; Plasmodium falciparum Glycosylphosphatidylinositol) as well as intracellular ligands as it is located both on the cell surface and on endosomes, TLR9 interacts only with intracellular ligands owing to its endosomal localization[8,10,11,12] Both TLR4 and TLR9 are influenced by hemozoin (Hz) from ruptured schizonts in malaria. Hz facilitates the entry of parasite DNA into the host cell and thereby stimulates TLR99, whereas, by interacting with host fibrinogen, Hz activates TLR4 in human monocytes[12] Since both TLR4 and TLR9 are localized to the endosome and stimulated by Hz, they may share a common influence on the clinical manifestation of malaria. Genetic association studies analyzing variants in TLR4 and TLR9 from different endemic regions have been conflicting
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