A polymorphism in toll-interleukin 1 receptor domain containing adaptor protein is associated with susceptibility to meningeal tuberculosis

Thomas R. Hawn, Sarah J. Dunstan, Guy E. Thwaites, Cameron P. Simmons, Nguyen Thuong Thuong, Nguyen Thi Ngoc Lan, Hoang Thi Quy, Tran Thi Hong Chau, Nguyen T. Hieu, Stephanie Rodrigues, Marta Janer, Lue Ping Zhao, Tran Tinh Hien, Jeremy J. Farrar, Alan Aderem

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Abstract

Background. 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). Methods. 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. Results. 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. Conclusions. 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.

Original languageEnglish
Pages (from-to)1127-1134
Number of pages8
JournalJournal of Infectious Diseases
Volume194
Issue number8
DOIs
Publication statusPublished - 15 Oct 2006
Externally publishedYes

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