title: A polymorphism in Toll-interleukin 1 receptor domain containing adaptor protein is associated with susceptibility to meningeal tuberculosis.
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.
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, Washington.|Institute for Systems Biology, Seattle, Washington.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Hawn
authors.affiliation: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.|Center for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Dunstan
authors.affiliation: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Guy E
authors.initials: GE
authors.lastname: Thwaites
authors.affiliation: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.|Center for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford.
authors.forename: Cameron P
authors.initials: CP
authors.lastname: Simmons
authors.affiliation: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.|Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Ho Chi Minh City, Vietnam.
authors.forename: Nguyen Thuong
authors.initials: NT
authors.lastname: Thuong
authors.affiliation: Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
authors.forename: Nguyen Thi Ngoc
authors.initials: NTN
authors.lastname: Lan
authors.affiliation: Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
authors.forename: Hoang Thi
authors.initials: HT
authors.lastname: Quy
authors.affiliation: Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Ho Chi Minh City, Vietnam.
authors.forename: Tran Thi Hong
authors.initials: TTH
authors.lastname: Chau
authors.affiliation: Hung Vuong Hospital, Ho Chi Minh City, Vietnam.
authors.forename: Nguyen T
authors.initials: NT
authors.lastname: Hieu
authors.affiliation: Institute for Systems Biology, Seattle, Washington.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Rodrigues
authors.affiliation: Institute for Systems Biology, Seattle, Washington.
authors.forename: Marta
authors.initials: M
authors.lastname: Janer
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.|Enodar BioLogic Corporation, Seattle, Washington.
authors.forename: Lue Ping
authors.initials: LP
authors.lastname: Zhao
authors.affiliation: Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Ho Chi Minh City, Vietnam.
authors.forename: Tran Tinh
authors.initials: TT
authors.lastname: Hien
authors.affiliation: 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.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Farrar
authors.affiliation: Institute for Systems Biology, Seattle, Washington.
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
mesh_terms: 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
chemical_list: D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors