Juan Manuel Cubillos-Angulo1,2,3, María B Arriaga1,2,3, Elisângela C Silva4,5, Beatriz L A Müller4,6, Daniela M P Ramalho4, Kiyoshi F Fukutani1,3, Pryscila F C Miranda4, Adriana S R Moreira4, Antonio Ruffino-Netto7, Jose R Lapa E Silva4, Timothy R Sterling8, Afrânio L Kritski4, Martha M Oliveira9, Bruno B Andrade1,3,8,10,11,12. 1. Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia. 2. Faculdade de Medicina, Universidade Federal da Bahia, Salvador, Bahia. 3. Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Fundação José Silveira, Salvador, Bahia. 4. Programa Acadêmico de Tuberculose, Faculdade de Medicina e Complexo Hospitalar HUCFF-IDT, Universidade Federal do Rio de Janeiro. 5. Recognize the Biology Laboratory, Center of Bioscience and Biotechnology, State University of North Fluminense Darcy Ribeiro. 6. Laboratório de Genômica Funcional e Bioinformática, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro. 7. Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Brazil. 8. Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee. 9. Centro de Desenvolvimento Tecnológico em Saúde, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. 10. Wellcome Centre for Infectious Disease Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa. 11. Universidade Salvador (UNIFACS), Laureate University, Salvador, Bahia, Brazil. 12. Escola Bahiana de Medicina e Saúde Pública, Salvador, Bahia, Brazil.
Abstract
BACKGROUND: The role of genetic polymorphisms in latent tuberculosis (TB) infection and progression to active TB is not fully understood. METHODS: We tested the single-nucleotide polymorphisms (SNPs) rs5743708 (TLR2), rs4986791 (TLR4), rs361525 (TNFA), rs2430561 (IFNG) rs1143627 (IL1B) as risk factors for tuberculin skin test (TST) conversion or development of active TB in contacts of active TB cases. Contacts of microbiologically confirmed pulmonary TB cases were initially screened for longitudinal evaluation up to 24 months, with clinical examination and serial TST, between 1998 and 2004 at a referral center in Brazil. Data and biospecimens were collected from 526 individuals who were contacts of 177 active TB index cases. TST conversion was defined as induration ≥5 mm after a negative TST result (0 mm) at baseline or month 4 visit. Independent associations were tested using logistic regression models. RESULTS: Among the 526 contacts, 60 had TST conversion and 44 developed active TB during follow-up. Multivariable regression analysis demonstrated that male sex (odds ratio [OR]: 2.3, 95% confidence interval [CI]: 1.1-4.6), as well as SNPs in TLR4 genes (OR: 62.8, 95% CI: 7.5-525.3) and TNFA (OR: 4.2, 95% CI: 1.9-9.5) were independently associated with TST conversion. Moreover, a positive TST at baseline (OR: 4.7, 95% CI: 2.3-9.7) and SNPs in TLR4 (OR: 6.5, 95% CI: 1.1-36.7) and TNFA (OR: 12.4, 95% CI:5.1-30.1) were independently associated with incident TB. CONCLUSIONS: SNPs in TLR4 and TNFA predicted both TST conversion and active TB among contacts of TB cases in Brazil.
BACKGROUND: The role of genetic polymorphisms in latent tuberculosis (TB) infection and progression to active TB is not fully understood. METHODS: We tested the single-nucleotide polymorphisms (SNPs) rs5743708 (TLR2), rs4986791 (TLR4), rs361525 (TNFA), rs2430561 (IFNG) rs1143627 (IL1B) as risk factors for tuberculin skin test (TST) conversion or development of active TB in contacts of active TB cases. Contacts of microbiologically confirmed pulmonary TB cases were initially screened for longitudinal evaluation up to 24 months, with clinical examination and serial TST, between 1998 and 2004 at a referral center in Brazil. Data and biospecimens were collected from 526 individuals who were contacts of 177 active TB index cases. TST conversion was defined as induration ≥5 mm after a negative TST result (0 mm) at baseline or month 4 visit. Independent associations were tested using logistic regression models. RESULTS: Among the 526 contacts, 60 had TST conversion and 44 developed active TB during follow-up. Multivariable regression analysis demonstrated that male sex (odds ratio [OR]: 2.3, 95% confidence interval [CI]: 1.1-4.6), as well as SNPs in TLR4 genes (OR: 62.8, 95% CI: 7.5-525.3) and TNFA (OR: 4.2, 95% CI: 1.9-9.5) were independently associated with TST conversion. Moreover, a positive TST at baseline (OR: 4.7, 95% CI: 2.3-9.7) and SNPs in TLR4 (OR: 6.5, 95% CI: 1.1-36.7) and TNFA (OR: 12.4, 95% CI:5.1-30.1) were independently associated with incident TB. CONCLUSIONS: SNPs in TLR4 and TNFA predicted both TST conversion and active TB among contacts of TB cases in Brazil.
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