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15 October 2006

Volume 194, Number 8
The Journal of Infectious Diseases 2006;194:1127–1134
© 2006 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2006/19408-0014$15.00
DOI: 10.1086/507907
MAJOR ARTICLE

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

Thomas R. Hawn,1,2,a

Sarah J. Dunstan,6,9,a

Guy E. Thwaites,6

Cameron P. Simmons,6,9

Nguyen Thuong Thuong,6,7

Nguyen Thi Ngoc Lan,5

Hoang Thi Quy,5

Tran Thi Hong Chau,7

Nguyen T. Hieu,8

Stephanie Rodrigues,2

Marta Janer,2

Lue Ping Zhao,3,4

Tran Tinh Hien,7

Jeremy J. Farrar,6,9,10 and

Alan Aderem2

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

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 ( ) and case patients ( ) who had either pulmonary ( ) or meningeal ( ) 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; ). Subgroup analysis revealed that SNP 558T was more strongly associated with susceptibility to meningeal TB (OR, 3.02; ) than to pulmonary TB (OR, 1.55; ). 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.

Received 24 February 2006; accepted 16 June 2006; electronically published 12 September 2006.

Reprints or correspondence: Thomas R. Hawn, Box 356523, University of Washington School of Medicine, 1959 NE Pacific St., Seattle WA 98195 ().

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  • Presented in part: “Determinants of Host Resistance, Susceptibility or Immunopathology to Pathogens: Integrating Knowledge from Experimental Models to Human Disease” Keystone Meeting, Keystone, CO, 6–11 January 2006 (abstract 133).

    Financial support: National Institute of Health (grants to T.R.H., L.P.Z., and A.A.); Dana Foundation (grant to T.R.H.); Wellcome Trust of Great Britain (grant to J.J.F.).

    Potential conflicts of interest: none reported.

  • T.R.H. and S.J.D. contributed equally to the work.

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