TIRAP and Tuberculosis Meningitis
• JID 2006:194 (15 October) • 1127
M A J O R A R T I C L E
A Polymorphism in Toll-Interleukin 1 Receptor
Domain Containing Adaptor Protein Is Associated
with Susceptibility to Meningeal Tuberculosis
Thomas R. Hawn,1,2,aSarah J. Dunstan,6,9,aGuy E. Thwaites,6Cameron P. Simmons,6,9Nguyen Thuong Thuong,6,7
Nguyen Thi Ngoc Lan,5Hoang Thi Quy,5Tran Thi Hong Chau,7Nguyen T. Hieu,8Stephanie Rodrigues,2Marta Janer,2
Lue Ping Zhao,3,4Tran Tinh Hien,7Jeremy J. Farrar,6,9,10and Alan Aderem2
1Department of Medicine, University of Washington School of Medicine,
Thach Hospital for Tuberculosis and Lung Disease, and
and Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, and
Medicine, London, United Kingdom
2Institute for Systems Biology,
3Fred Hutchinson Cancer Research Center,
6Hospital for Tropical Diseases,
9Center for Clinical Vaccinology
10The London School of Hygiene and Tropical
4Enodar BioLogic Corporation, Seattle, Washington;
5Oxford University Clinical Research Unit and
8Hung Vuong Hospital, Ho Chi Minh City, Vietnam;
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 (
case patients () who had either pulmonary (n p 358n p 183
The TIRAP single-nucleotide polymorphism (SNP) C558T was associated with increasedsusceptibility
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 toP ! .001
meningeal TB (OR, 3.02;) than to pulmonary TB (OR, 1.55;P ! .001
genotype, the 558TT genotype was associated with decreased whole-blood interleukin-6 production,whichsuggests
that TIRAP influence disease susceptibility by modulating the inflammato y response.
These results provide the firs evidence of an association of a TIRAP SNP with the risk of any
disease and also suggest that the Toll-like receptor pathway influence susceptibility to meningeal and pulmonary
TB by different immune mechanisms.
Although meningitis is the most severe form of infection caused by Mycobacterium tuberculosis,
) andn p 392
) or meningeal () TB.n p 175
). In comparison to the 558CC
P p .22
Despite the discovery of the tuberculosis bacillus 1100
years ago and the availability of effective drugs for 150
years, there remain a number of formidable challenges
for controlling Mycobacterium tuberculosis (Mtb) in-
Received 24 February 2006; accepted 16 June 2006; electronically published
12 September 2006.
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
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.
aT.R.H. and S.J.D. contributed equally to the work.
Reprints or correspondence: Thomas R. Hawn, Box 356523, University of
Washington School of Medicine, 1959 NE Pacific St., Seattle WA 98195 (thawn@
The Journal of Infectious Diseases
? 2006 by the Infectious Diseases Society of America. All rights reserved.
fection . The development of a more-effective vac-
cine is a high worldwide priority and depends on a
thorough understanding of the host response to infec-
tion. Furthermore, tuberculosis (TB) causes different
types of human disease, including localized pulmonary
disease, extrapulmonary disease—such as meningitis—
and miliary or disseminated disease. It is not known at
present which host genetic, environmental, and bac-
terial virulence factors influenc the different clinical
presentations of TB. Tuberculous meningitis (TBM) is
an especially devastating form of TB that causes death
or severe neurological defici in more than one-half of
persons affected . Advances in genomic technology
and immunology are creating new opportunities to un-
derstand the influenc of human genetic variation on
the pathophysiological characteristics of TB.
The molecular mechanisms that influenc the de-
velopment of a protective immune response to Mtb are
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1134 • JID 2006:194 (15 October) • Hawn et al.
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