A Polymorphism in Toll‐Interleukin 1 Receptor Domain Containing Adaptor Protein Is Associated with Susceptibility to Meningeal Tuberculosis

University of Oxford, Oxford, England, United Kingdom
The Journal of Infectious Diseases (Impact Factor: 6). 10/2006; 194(8):1127-34. DOI: 10.1086/507907
Source: PubMed


Although meningitis is the most severe form of infection caused by Mycobacterium tuberculosis, the immunopathogenesis of this disease is poorly understood. We tested the hypothesis that polymorphisms in Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP), an adaptor protein that mediates signals from Toll-like receptors activated by mycobacteria, are associated with susceptibility to tuberculosis (TB).
We used a case-population study design in Vietnam with cord-blood control samples (n = 392) and case patients (n = 358) who had either pulmonary (n = 183) or meningeal (n = 175) TB.
The TIRAP single-nucleotide polymorphism (SNP) C558T was associated with increased susceptibility to TB, with a 558T allele frequency of 0.035 in control samples versus 0.074 in case patients (odds ratio [OR], 2.25; P < .001). Subgroup analysis revealed that SNP 558T was more strongly associated with susceptibility to meningeal TB (OR, 3.02; P < .001) than to pulmonary TB (OR, 1.55; P = .22). In comparison to the 558CC genotype, the 558TT genotype was associated with decreased whole-blood interleukin-6 production, which suggests that TIRAP influences disease susceptibility by modulating the inflammatory response.
These results provide the first evidence of an association of a TIRAP SNP with the risk of any disease and also suggest that the Toll-like receptor pathway influences susceptibility to meningeal and pulmonary TB by different immune mechanisms.

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    • "The synonymous Tirap SNP, C558T (Ala186 Ala), has also been linked to increased susceptibility to tuberculosis. Individuals with the 558TT genotype had decreased levels of interleukin-6 in whole-blood [140]. "
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    • "Our results are similar to those of some association studies of this variation in other populations, which also found no correlation of SNP with TB in Russian, Ghanaian, Indonesian (Nejentsev et al., 2008), and Vietnamese (Hawn et al., 2006) in a large scale of samples. For the SNP C558T, another study provided evidence showing that both the variant and the haplotype containing the T allele were more frequent in TB patients than in controls (Hawn et al., 2006). In our study, although both the T allele (OR = 1.55; "
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