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

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Malaria Journal (Impact Factor: 3.11). 02/2012; 11(47):47. DOI: 10.1186/1475-2875-11-47
Source: PubMed


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).
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.
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).
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.

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    • "Although, the early and robust inflammatory response is important for controlling acute blood-stage infection , superfluous or deregulated inflammation may have the consequence of severe malaria (Erdman et al., 2008). Consequently, association of genetic variations in TLR2 (5′UTR I/D), TLR4 (D299G and T399I) and TLR9 (T-1237C and T-1486C) (Greene et al., 2012; Gbédandé et al., 2013; Mockenhaupt et al., 2006b; Sawian et al., 2012), and change in their expression/responses with disease manifestation of malaria (Esposito et al., 2012; Franklin et al., 2009; Loharungsikul et al., 2008) emphasize the role of these TLRs in malaria pathogenesis. However, genetic association studies investigating the possible effect of these variants on severe malaria in different endemic regions are conflicting (Mockenhaupt et al., 2006b; Leoratti et al., 2008; Sam-Agudu et al., 2010; Zakeri et al., 2011; Esposito et al., 2012; Sawian et al., 2012). "
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    • "Despite priming of TLR2 responses during P. falciparum infections (McCall et al., 2007) and its function as heterodimeric partner in recognition via TLR1 and TLR6 (Takeuchi et al., 2001), the lack of association of TLR2 variants with malaria suggests that either the selected TLR2 variants for screening are less in frequency; few populations have been investigated or have no definite role. Investigation of insertion/ deletion polymorphism in the 5' UTR of TLR2 gene in Odisha, which has been found to be at greater than 10 % prevalence in different malaria endemic region (Greene et al., 2009) has shown that the deletion variant (D allele) in heterozygous state to be the risk factor for cerebral malaria (Dhangadamajhi et al., unpublished data) and is in contrast to previous observation in Ugandan population (Greene et al., 2012). However, the significant association of genetic variant responsible for reduced CD36 expression with mild malaria in this endemic region (Das et al., 2009) and the recent finding of CD36 as a coreceptor for TLR2 (Hoebe et al., 2005) indicates that the outcome might be altered depending on the prevalence of both these variants and caution should be taken while repeating this study. "
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