title: Polymorphisms in TICAM2 and IL1B are associated with TB.
abstract: Human genetic susceptibility for tuberculosis (TB) has been demonstrated by several studies, but few have examined the multiple innate and adaptive immunity genes comprehensively, age-specific effects and/or resistance to Mycobacterium tuberculosis (Mtb) infection (resistors (RSTRs)). We hypothesized that RSTRs, defined by a persistently negative tuberculin skin test, may have different genetic influences than Mtb disease. We examined 29 candidate genes in pathways that mediate immune responses to Mtb in subjects in a household contact study in Kampala, Uganda. We genotyped 546 haplotype-tagging single-nucleotide polymorphisms (SNPs) in 835 individuals from 481 families; 28.7% had TB, 10.5% were RSTRs, and the remaining 60.8% had latent Mtb infection. Among our most significant findings were SNPs in TICAM2 (P = 3.6 × 10(-6)) and IL1B (P = 4.3 × 10(-5)) associated with TB. Multiple SNPs in IL4 and TOLLIP were associated with TB (P < 0.05). Age-genotype interaction analysis revealed SNPs in IL18 and TLR6 that were suggestively associated with TB in children aged ⩽ 10 years (P = 2.9 × 10(-3)). By contrast, RSTR was associated with SNPs in NOD2, SLC6A3 and TLR4 (nominal P < 0.05); these genes were not associated with TB, suggesting distinct genetic influences. We report the first association between TICAM2 polymorphisms and TB and between IL18 and pediatric TB.
authors.affiliation: Dept. of Epidemiology & Biostatistics, Case Western Reserve Univ., Cleveland, OH.
authors.forename: Noémi Borsay
authors.initials: NB
authors.lastname: Hall
authors.affiliation: Dept. of Epidemiology & Biostatistics, Case Western Reserve Univ., Cleveland, OH.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Igo
authors.affiliation: Uganda-CWRU Research Collaboration.
authors.forename: LaShaunda L
authors.initials: LL
authors.lastname: Malone
authors.affiliation: Dept. of Epidemiology & Biostatistics, Case Western Reserve Univ., Cleveland, OH.
authors.forename: Barbara
authors.initials: B
authors.lastname: Truitt
authors.affiliation: Dept. of Epidemiology & Biostatistics, Case Western Reserve Univ., Cleveland, OH.
authors.forename: Audrey
authors.initials: A
authors.lastname: Schnell
authors.affiliation: Dept. of Medicine, Case Western Reserve Univ., Cleveland, OH.
authors.forename: Li
authors.initials: L
authors.lastname: Tao
authors.affiliation: Uganda-CWRU Research Collaboration.
authors.forename: Brenda
authors.initials: B
authors.lastname: Okware
authors.affiliation: Uganda-CWRU Research Collaboration.
authors.forename: Mary
authors.initials: M
authors.lastname: Nsereko
authors.affiliation: Dept. of Medicine, Case Western Reserve Univ., Cleveland, OH.|Uganda-CWRU Research Collaboration.
authors.forename: Keith
authors.initials: K
authors.lastname: Chervenak
authors.affiliation: Dept. of Pediatrics, Oregon Health & Science University, Portland, OR.
authors.forename: Christina
authors.initials: C
authors.lastname: Lancioni
authors.affiliation: Dept. of Medicine, Univ. of Washington School of Medicine, Seattle, WA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Hawn
authors.affiliation: Uganda-CWRU Research Collaboration.|College of Health Sciences Makerere Univ. and Mulago Hospital, Kampala, Uganda.
authors.forename: Harriet
authors.initials: H
authors.lastname: Mayanja-Kizza
authors.affiliation: Uganda-CWRU Research Collaboration.|College of Health Sciences Makerere Univ. and Mulago Hospital, Kampala, Uganda.
authors.forename: Moses L
authors.initials: ML
authors.lastname: Joloba
authors.affiliation: Dept. of Medicine, Case Western Reserve Univ., Cleveland, OH.|Uganda-CWRU Research Collaboration.
authors.forename: W Henry
authors.initials: WH
authors.lastname: Boom
authors.affiliation: Dept. of Epidemiology & Biostatistics, Case Western Reserve Univ., Cleveland, OH.|Center for Proteomics & Bioinformatics, Case Western Reserve University, Cleveland OH.|Uganda-CWRU Research Collaboration.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Stein
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D014376:Tuberculosis / Q000453:epidemiology / Q000235:genetics*; D014454:Uganda / Q000453:epidemiology; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C508585:IL1B protein, human; D053583:Interleukin-1beta; C480228:TICAM2 protein, human