Pharmacogenetics of tuberculosis treatment toxicity and effectiveness in a large Brazilian cohort.

Autor:	Amorim G; Vanderbilt University Medical Center, Department of Biostatistics., Jaworski J; Vanderbilt University Medical Center, Department of Medicine, Division of Epidemiology., Yang J; Vanderbilt University Medical Center, Department of Biostatistics.; Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Cordeiro-Santos M; Fundação Medicina Tropical Dr. Heitor Vieira Dourado.; Universidade do Estado do Amazonas (UEA), Manaus., Kritski AL; Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Figueiredo MC; Vanderbilt University Medical Center, Department of Medicine, Division of Infectious Diseases, Nashville, Tennessee, USA., Turner M; Vanderbilt University Medical Center, Department of Medicine, Division of Infectious Diseases, Nashville, Tennessee, USA., Andrade BB; Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Bahia.; Instituto Brasileiro para Investigação da Tuberculose, Fundação José Silveira.; Instituto Gonçalo Moniz, Fundação Oswaldo Cruz.; Universidade Salvador (UNIFACS), Laureate Universities.; Escola Bahiana de Medicina e Saúde Pública (EBMSP).; Faculdade de Tecnologia e Ciências (FTC), Salvador, Bahia, Brazil., Velez Edwards DR; Vanderbilt University Medical Center, Department of Obstetrics and Gynecology, Division of Quantitative Sciences, Nashville, Tennessee, USA., Santos AR; Laboratory of Molecular Biology Applied to Mycobacteria, Instituto Oswaldo Cruz., Rolla VC; Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil and., Sterling TR; Vanderbilt University Medical Center, Department of Medicine, Division of Infectious Diseases, Nashville, Tennessee, USA., Haas DW; Vanderbilt University Medical Center, Department of Medicine, Division of Infectious Diseases, Nashville, Tennessee, USA.; Meharry Medical College, Department of Internal Medicine, Nashville, Tennessee, USA.
Jazyk:	angličtina
Zdroj:	Pharmacogenetics and genomics [Pharmacogenet Genomics] 2024 Oct 15. Date of Electronic Publication: 2024 Oct 15.
DOI:	10.1097/FPC.0000000000000552
Abstrakt:	Background: Genetic polymorphisms have been associated with risk of antituberculosis treatment toxicity. We characterized associations with adverse events and treatment failure/recurrence among adults treated for tuberculosis in Brazil. Methods: Participants were followed in Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil. We included persons with culture-confirmed drug-susceptible pulmonary tuberculosis who started treatment between 2015 and 2019, and who were eligible for pharmacogenetics. Treatment included 2 months of isoniazid, rifampin or rifabutin, pyrazinamide, and ethambutol, then 4 months of isoniazid and rifampin or rifabutin, with 24-month follow-up. Analyses included 43 polymorphisms in 20 genes related to antituberculosis drug hepatotoxicity or pharmacokinetics. Whole exome sequencing was done in a case-control toxicity subset. Results: Among 903 participants in multivariable genetic association analyses, NAT2 slow acetylator status was associated with increased risk of treatment-related grade 2 or greater adverse events, including hepatotoxicity. Treatment failure/recurrence was more likely among NAT2 rapid acetylators, but not statistically significant at the 5% level. A GSTM1 polymorphism (rs412543) was associated with increased risk of treatment-related adverse events, including hepatotoxicity. SLCO1B1 polymorphisms were associated with increased risk of treatment-related hepatoxicity and treatment failure/recurrence. Polymorphisms in NR1/2 were associated with decreased risk of adverse events and increased risk of failure/recurrence. In whole exome sequencing, hepatotoxicity was associated with a polymorphism in VTI1A, and the genes METTL17 and PRSS57, but none achieved genome-wide significance. Conclusion: In a clinical cohort representing three regions of Brazil, NAT2 acetylator status was associated with risk for treatment-related adverse events. Additional significant polymorphisms merit investigation in larger study populations, particularly regarding risk of treatment failure/recurrence. (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
Databáze:	MEDLINE
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