A polymorphism in Toll-interleukin 1 receptor domain containing adaptor protein is associated with susceptibility to meningeal tuberculosis.
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.
Hawn
Thomas R
TR
Department of Medicine, University of Washington School of Medicine, Seattle, Washington.|Institute for Systems Biology, Seattle, Washington.
Dunstan
Sarah J
SJ
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.|Center for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford.
Thwaites
Guy E
GE
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
Simmons
Cameron P
CP
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.|Center for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford.
Thuong
Nguyen Thuong
NT
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.|Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Ho Chi Minh City, Vietnam.
Lan
Nguyen Thi Ngoc
NTN
Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
Quy
Hoang Thi
HT
Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
Chau
Tran Thi Hong
TTH
Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Ho Chi Minh City, Vietnam.
Hieu
Nguyen T
NT
Hung Vuong Hospital, Ho Chi Minh City, Vietnam.
Rodrigues
Stephanie
S
Institute for Systems Biology, Seattle, Washington.
Janer
Marta
M
Institute for Systems Biology, Seattle, Washington.
Zhao
Lue Ping
LP
Fred Hutchinson Cancer Research Center, Seattle, Washington.|Enodar BioLogic Corporation, Seattle, Washington.
Hien
Tran Tinh
TT
Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Ho Chi Minh City, Vietnam.
Farrar
Jeremy J
JJ
Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.|Center for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford.|The London School of Hygiene and Tropical Medicine, London, United Kingdom.
Aderem
Alan
A
Institute for Systems Biology, Seattle, Washington.
D000328:Adult; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009169:Mycobacterium tuberculosis; D011110:Polymorphism, Genetic; D017472:Receptors, Interleukin-1 / Q000235:genetics*; D051193:Toll-Like Receptors / Q000235:genetics*; D014390:Tuberculosis, Meningeal / Q000235:genetics*; D014397:Tuberculosis, Pulmonary / Q000235:genetics*; D014744:Vietnam
D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors