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

• Published in: The Journal of infectious diseases Vol. 194; no. 8; pp. 1127 - 1134
• Main Authors: Hawn, Thomas R., Dunstan, Sarah J., Thwaites, Guy E., Simmons, Cameron P., Thuong, Nguyen Thuong, Lan, Nguyen Thi Ngoc, Quy, Hoang Thi, Chau, Tran Thi Hong, Hieu, Nguyen T., Rodrigues, Stephanie, Janer, Marta, Zhao, Lue Ping, Hien, Tran Tinh, Farrar, Jeremy J., Aderem, Alan
• Format: Journal Article
• Language: English
• Published: Chicago, IL The University of Chicago Press 15.10.2006; University of Chicago Press
• Subjects: Adult; Alleles; Asian Continental Ancestry Group - genetics; Bacteria; Bacterial diseases; Biological and medical sciences; Case-Control Studies; Cytokines; Disease susceptibility; Female; Fundamental and applied biological sciences. Psychology; Genetic Predisposition to Disease; Genotypes; Haplotypes; Human bacterial diseases; Humans; Infectious diseases; Male; Medical sciences; Meningeal tuberculosis; Microbiology; Mycobacterium tuberculosis; Polymorphism, Genetic; Pulmonary tuberculosis; Receptors; Receptors, Interleukin-1 - genetics; Toll like receptors; Toll-Like Receptors - genetics; Tuberculosis and atypical mycobacterial infections; Tuberculosis, Meningeal - genetics; Tuberculosis, Pulmonary - genetics; Vietnam; Vietnam; Infection; Sensitivity; Tuberculosis; Microbiology; Cytokine; Interleukin 1; Bacteriosis; Mycobacterial infection; Protein; Polymorphism
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/507907

BackgroundAlthough 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) MethodsWe 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 ResultsThe 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 ConclusionsThese 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