Genetic variation of TLR-4, TLR-9 and TIRAP genes in Iranian malaria patients

Abstract

BackgroundToll-like receptors (TLRs) recognize pathogen-associated molecular patterns and their activation leads to the induction of effector genes involving inflammatory cytokines that may have contribute to controlling parasite growth and disease pathogenesis. The current immunogenetic study was designed to analyse the key components of innate immunity, TLRs and TIRAP (Toll-interleukin-1 receptor domain-containing adaptor protein), also known as MAL (MYD88 adaptor-like), in Iranian patients with mild malaria.MethodsThe tlr-4 (D299G and T399I), tlr-9 (T-1486C and T-1237C) and tirap (S180L) genes were assessed in 640 Baluchi individuals (320 Plasmodium falciparum-infected and 320 non-infected, median age of 28 years) from malaria-endemic regions using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods.ResultsCommon tlr-4 SNPs and promoter SNPs of tlr-9 were distributed among P. falciparum-infected and non-infected groups (P > 0.05) that showed no association of these variants with mild clinical manifestation. The comparison of the tirap S180L genotypes between patients with mild malaria and those healthy individuals showed that the frequency of heterozygosity was significantly higher in infected than non-infected individuals (33.8 vs. 25.6; OR, 1.479; 95% CI, 1.051-2.081; P = 0.024). The result also revealed a significant association of tirap S180L (P < 0.05) with development of mild malaria, which is common in Baluchi populations, who are living in malaria hypoendemic region of Iran but not in African populations (0%-6%).ConclusionThese data point towards the need for addressing the exact role of TLRs in contributing to human genetic factors in malaria susceptibility/resistance/severity within different malaria settings in the world.

Polymorphisms in the Fc Gamma Receptor IIIA and Toll-Like Receptor 9 Are Associated with Protection against Severe Malarial Anemia and Changes in Circulating Gamma Interferon Levels

“…There is accumulating evidence on the potential role of TLR9 polymorphisms in clinical malaria (13,30,65). Consistent with our study, two separate studies, carried out in Brazil and Iran, have recently revealed no impact of individual TLR9 (Ϫ1237T/C) promoter polymorphism on susceptibility to mild malaria in their respective populations (30,65).…”

“…Consistent with our study, two separate studies, carried out in Brazil and Iran, have recently revealed no impact of individual TLR9 (Ϫ1237T/C) promoter polymorphism on susceptibility to mild malaria in their respective populations (30,65). Moreover, the TLR9 (Ϫ1237TT) genotype has only been associated with low parasitemia but not increased susceptibility to clinical malaria in Ghanaian children aged 3 to 11 years (40).…”

A meta-analysis of TLR4 and TLR9 SNPs implicated in severe malaria

“…Although some studies have reported no association between T-1486C and malaria susceptibility or severity 7,20,22,24,27,30 , we observed that the -1486C allele was a risk factor for severe malaria and high parasite load, which is in line with previous findings 21,24 . Moreover, -1486C has been associated with an increased risk of low birth weight in term infants born to P. falciparum-infected pregnant women 25 .Consistent with these findings, the meta-analysis of the T-1486C variant revealed a significant association with SM under the allele contrast (T vs. C) and homozygous (TT vs. CC) genetic models.…”

“…In addition, our recent observation of opposing associations of the -1237C allele with different sub-clinical severe malarial phenotypes such as single organ dysfunction (SOD) vs. multi-organ dysfunction (MODS) 2 suggests that phenotype misclassification in malaria could also lead to a reduction in the power to detect the contribution of this variant. This may explain the lack of observed associations between the T-1237C variant and susceptibility or resistance to malaria 22,27,29,30 , in addition to other factors. Therefore, future studies examining large sample sizes of malaria-infected patients categorized into required phenotype classes from different ethnic populations and belonging to different age groups are eagerly awaited for confirmation.…”

“…However, we did not find any association between this polymorphism and severe malaria, even after stratifying the meta-analysis by age and ethnicity, though a substantial amount of heterogeneity was observed in children (data not shown). Moreover, many genetic association studies of the TLR4 D299G variant show no evidence for its association with malaria, either in terms of malarial susceptibility or resistance [26][27][28] . These observations strongly suggest that the TLR4 D299G polymorphism is a nonbiomarker for malaria.…”