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J Infect Dis. 2006 Oct 15;194(8):1127-1134. doi: 10.1086/507907. Epub 2006 Sep 12.

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

Author information

1
Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
2
Institute for Systems Biology, Seattle, Washington.
3
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
4
Center for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford.
5
Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Ho Chi Minh City, Vietnam.
6
Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7
Hung Vuong Hospital, Ho Chi Minh City, Vietnam.
8
Fred Hutchinson Cancer Research Center, Seattle, Washington.
9
Enodar BioLogic Corporation, Seattle, Washington.
10
The London School of Hygiene and Tropical Medicine, London, United Kingdom.
#
Contributed equally

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.

PMID:
16991088
PMCID:
PMC4333200
DOI:
10.1086/507907
[Indexed for MEDLINE]
Free PMC Article

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