title: Susceptibility to tuberculosis is associated with TLR1 polymorphisms resulting in a lack of TLR1 cell surface expression.
abstract: Human TLR1 plays an important role in host defense against Mycobacterium tuberculosis. Our aim was to analyze the association of the loss of TLR1 surface expression and TLR1 SNPs with susceptibility to TB. TLR1neg and TLR1pos cells from healthy individuals were identified by flow cytometry and compared by sequencing. TLR1 expression was measured using quantitative real-time PCR and immunoblotting. TLR1 SNP analyses of healthy individuals and TB patients from EU-C and Ghana were performed, and association of the TLR1 genotypes with increased risk of developing TB was statistically evaluated. Lack of TLR1 surface expression accompanied by impaired function was strongly associated with TLR1 SNP G743A. Genotyping of EU-C controls and TB patients revealed an association of TLR1 743A/1805G alleles [OR 2.37 (95% CI 1.13, 4.93), P=0.0219; OR 2.74 (95% CI 1.26, 6.05), P=0.0059] as well as TLR1neg 743AA/1805GG versus TLR1pos genotypes 743AG/1805TG [OR 4.98 (95% CI 1.64, 15.15), P=0.0034; OR 5.70 (95% CI 1.69, 20.35), P=0.0015] and 743AG + GG/1805TG + TT [OR 3.54 (95% CI 1.29, 9.90), P=0.0086; OR 4.17 (95% CI 1.52, 11.67), P=0.0025] with increased susceptibility to TB. No association of G743A with TB was found in Ghana as a result of a low frequency of genotype 743AA. Our data gain new insights in the role of TLR1 in M. tuberculosis defense and provide the first evidence that TLR1 variants are associated with susceptibility to TB in a low-incidence country.
authors.affiliation: Institute of Immunology, Medical Faculty, Rheinisch-Westfaelische Technische Hochschule Aachen University, Aachen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Uciechowski
authors.forename: Heidi
authors.initials: H
authors.lastname: Imhoff
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
authors.forename: Christian G
authors.initials: CG
authors.lastname: Meyer
authors.forename: Edmund N
authors.initials: EN
authors.lastname: Browne
authors.forename: Detlef K
authors.initials: DK
authors.lastname: Kirsten
authors.forename: Anja K
authors.initials: AK
authors.lastname: Schröder
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schaaf
authors.forename: Adnan
authors.initials: A
authors.lastname: Al-Lahham
authors.forename: Ralf René
authors.initials: RR
authors.lastname: Reinert
authors.forename: Norbert
authors.initials: N
authors.lastname: Reiling
authors.forename: Hajo
authors.initials: H
authors.lastname: Haase
authors.forename: Adelheid
authors.initials: A
authors.lastname: Hatzmann
authors.forename: Daniela
authors.initials: D
authors.lastname: Fleischer
authors.forename: Nicole
authors.initials: N
authors.lastname: Heussen
authors.forename: Michael
authors.initials: M
authors.lastname: Kleines
authors.forename: Lothar
authors.initials: L
authors.lastname: Rink
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000954:Antigens, Surface / Q000032:analysis*; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D005869:Ghana / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D017720:Molecular Epidemiology; D009169:Mycobacterium tuberculosis; D020641:Polymorphism, Single Nucleotide; D051194:Toll-Like Receptor 1 / Q000032:analysis / Q000235:genetics*; D014376:Tuberculosis / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D055815:Young Adult
chemical_list: D000954:Antigens, Surface; D051194:Toll-Like Receptor 1