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| Natura: | Artículo científico |
| Lingua: | en |
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Pharmacogenetics and genomics
2025
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| Accesso online: | https://pubmed.ncbi.nlm.nih.gov/39470346/ |
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| author | Amorim, Gustavo Jaworski, James Yang, Jing Cordeiro-Santos, Marcelo Kritski, Afrânio L Figueiredo, Marina C Turner, Megan Andrade, Bruno B Velez Edwards, Digna R Santos, Adalberto R Rolla, Valeria C Sterling, Timothy R Haas, David W |
| author_facet | Amorim, Gustavo Jaworski, James Yang, Jing Cordeiro-Santos, Marcelo Kritski, Afrânio L Figueiredo, Marina C Turner, Megan Andrade, Bruno B Velez Edwards, Digna R Santos, Adalberto R Rolla, Valeria C Sterling, Timothy R Haas, David W Amorim, Gustavo Jaworski, James Yang, Jing Cordeiro-Santos, Marcelo Kritski, Afrânio L Figueiredo, Marina C Turner, Megan Andrade, Bruno B Velez Edwards, Digna R Santos, Adalberto R Rolla, Valeria C Sterling, Timothy R Haas, David W |
| collection | PubMed - marine biology |
| contents | Pharmacogenetics of tuberculosis treatment toxicity and effectiveness in a large Brazilian cohort. Amorim, Gustavo Jaworski, James Yang, Jing Cordeiro-Santos, Marcelo Kritski, Afrânio L Figueiredo, Marina C Turner, Megan Andrade, Bruno B Velez Edwards, Digna R Santos, Adalberto R Rolla, Valeria C Sterling, Timothy R Haas, David W Humans Antitubercular Agents Brazil Male Female Adult Arylamine N-Acetyltransferase Middle Aged Polymorphism, Single Nucleotide Tuberculosis, Pulmonary Glutathione Transferase Tuberculosis Pharmacogenetics Prospective Studies Cohort Studies Treatment Outcome Pregnane X Receptor Liver-Specific Organic Anion Transporter 1 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. 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. 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. 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. |
| format | Artículo científico |
| id | pubmed_39470346 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | Pharmacogenetics and genomics |
| record_format | pubmed |
| spellingShingle | Pharmacogenetics of tuberculosis treatment toxicity and effectiveness in a large Brazilian cohort. Amorim, Gustavo Jaworski, James Yang, Jing Cordeiro-Santos, Marcelo Kritski, Afrânio L Figueiredo, Marina C Turner, Megan Andrade, Bruno B Velez Edwards, Digna R Santos, Adalberto R Rolla, Valeria C Sterling, Timothy R Haas, David W Humans Antitubercular Agents Brazil Male Female Adult Arylamine N-Acetyltransferase Middle Aged Polymorphism, Single Nucleotide Tuberculosis, Pulmonary Glutathione Transferase Tuberculosis Pharmacogenetics Prospective Studies Cohort Studies Treatment Outcome Pregnane X Receptor Liver-Specific Organic Anion Transporter 1 Pharmacogenetics of tuberculosis treatment toxicity and effectiveness in a large Brazilian cohort. Amorim, Gustavo Jaworski, James Yang, Jing Cordeiro-Santos, Marcelo Kritski, Afrânio L Figueiredo, Marina C Turner, Megan Andrade, Bruno B Velez Edwards, Digna R Santos, Adalberto R Rolla, Valeria C Sterling, Timothy R Haas, David W Humans Antitubercular Agents Brazil Male Female Adult Arylamine N-Acetyltransferase Middle Aged Polymorphism, Single Nucleotide Tuberculosis, Pulmonary Glutathione Transferase Tuberculosis Pharmacogenetics Prospective Studies Cohort Studies Treatment Outcome Pregnane X Receptor Liver-Specific Organic Anion Transporter 1 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. 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. 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. 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. |
| title | Pharmacogenetics of tuberculosis treatment toxicity and effectiveness in a large Brazilian cohort. |
| topic | Humans Antitubercular Agents Brazil Male Female Adult Arylamine N-Acetyltransferase Middle Aged Polymorphism, Single Nucleotide Tuberculosis, Pulmonary Glutathione Transferase Tuberculosis Pharmacogenetics Prospective Studies Cohort Studies Treatment Outcome Pregnane X Receptor Liver-Specific Organic Anion Transporter 1 |
| url | https://pubmed.ncbi.nlm.nih.gov/39470346/ |