A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis

Abstract

Toll-like receptors (TLRs) and members of their signalling pathway play an important role in the initiation of the innate immune response to a wide variety of pathogens1,2,3. The adaptor protein TIRAP mediates downstream signalling of 5,6. We report a case-control genetic association study of 6106 individuals from Gambia, Kenya, United Kingdom, and Vietnam, with invasive pneumococcal disease, bacteraemia, malaria and tuberculosis. Thirty-three SNPs were genotyped, including TIRAP S180L. Heterozygous carriage of this variant was found to associate independently with all four infectious diseases in the different study populations (P=0.003, OR=0.59, 95%CI 0.42-0.83 for IPD; P=0.003, OR=0.40, 95%CI 0.21-0.77 for bacteraemia; P=0.002, OR=0.47, 95%CI 0.28-0.76 for malaria; P=0.008, OR=0.23 95%CI 0.07-0.73 for tuberculosis). Substantial support for a protective effect of S180L heterozygosity against infectious diseases was observed when the study groups were combined (N=6106, OverallCorrespondence should be addressed on genetics to AVSH (adrian.hill@well.ox.ac.uk) In the UK population, heterozygosity at TIRAP S180L was associated with protection from invasive pneumococcal disease (3×2 χ 2 =8.72, P=0.013, Table 1). An excess of mutant homozygotes amongst IPD cases (Table 1) was also observed in this UK population. TIRAP S180L was then examined in a separate group of UK individuals with thoracic empyema and a second control group. Although no association was observed between genotype and susceptibility to thoracic empyema overall (n=584, 3×2 χ 2 =0.63, P=0.73), analysis of the small subgroup of individuals with pneumococcal empyema revealed a non-significant trend towards association (3×2 χ 2 =5.05, P=0.080; Table 1). Interestingly, an excess of mutant homozygotes was again observed amongst this second group of IPD cases (Table 1).We then studied TIRAP S180L in a second population with invasive bacterial disease, comprising Kenyan children with well-defined bacteraemia. Although the mutant allele was found to be less common in the Kenyan population than in UK individuals, the same pattern of association was observed. The TIRAP S180L heterozygotes were significantly more common amongst community controls (5.9%), compared to individuals with bacteraemia (2.4%) (2×2 χ 2 =9.05, P=0.003; Table 1). The heterozygote protective effect of the S180L locus was also significant within the subgroup of 164 Kenyan children with pneumococcal bacteraemia (F exact =0.024, Table 1), thus replicating the findings in the UK studies.In the Gambian malaria case-control study, TIRAP S180L heterozygosity demonstrated a significant protective effect against both general malaria (Wald=8.35, P=0.004, Table 1) and severe malaria (Wald=8.706, P=0.003, Table 1). This result was replicated in a second malaria case-control study, this time in a Vietnamese population whose design included only cases of severe malaria: TIRAP S180L heterozygotes were again found to be more prevalent Finally, the possible effect of the TIRAP S180L polymorphism on ...

A polymorphism in human TLR2 is associated with increased susceptibility to tuberculous meningitis

“…25 A recent study has found that TIRAP S180L polymorphism was associated with infectious diseases including TB in Africa and the heterozygous carriage of this variant was protective against TB. 26 Owing to the central role of TLR2 in the recognition of TB, we hypothesized that TLR2 polymorphisms were associated with susceptibility to disseminated disease, in particular TBM.…”

The course of gastric cancer following surgery is associated with genetic variations of the interleukin-1 receptor antagonist and interleukin-1β

“…Regarding the inflammatory response, heterozygosity of the mannose binding lectin genotype predicts an advantage to fatal outcome of sepsis patients [28]. Furthermore, heterozygosity of the Toll-like receptor adaptor protein TIRAP/MAL has been associated with protection from tuberculosis, pneumococcal disease, and bacteremia [29]. Different molecular mechanisms for heterosis are discussed by Comings and MacMurray [30].…”

Tuberculosis infection: Insight from immunogenomics

“…A polymorphism in the TIRAP gene which changes a serine to a leucine at amino acid 180 (S180L, C539T) has been shown to impair TLR2-mediated NF-κB signaling in in vitro experiments [27]. The 180L variant was less able to bind TLR2 in comparison to the 180S variant.…”