{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:39:31Z","timestamp":1787009971853,"version":"build-2736575974"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2005months of isoniazid, rifampin or rifabutin, pyrazinamide, and ethambutol, then 4\u2005months 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 903 participants in multivariable genetic association analyses,\n                      <jats:italic toggle=\"yes\">NAT2<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">NAT2<\/jats:italic>\n                      rapid acetylators, but not statistically significant at the 5% level. A\n                      <jats:italic toggle=\"yes\">GSTM1<\/jats:italic>\n                      polymorphism (rs412543) was associated with increased risk of treatment-related adverse events, including hepatotoxicity.\n                      <jats:italic toggle=\"yes\">SLCO1B1<\/jats:italic>\n                      polymorphisms were associated with increased risk of treatment-related hepatoxicity and treatment failure\/recurrence. Polymorphisms in\n                      <jats:italic toggle=\"yes\">NR1\/2<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">VTI1A<\/jats:italic>\n                      , and the genes\n                      <jats:italic toggle=\"yes\">METTL17<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">PRSS57<\/jats:italic>\n                      , but none achieved genome-wide significance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      In a clinical cohort representing three regions of Brazil,\n                      <jats:italic toggle=\"yes\">NAT2<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1097\/fpc.0000000000000552","type":"journal-article","created":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T05:00:10Z","timestamp":1728882010000},"page":"55-64","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":8,"title":["Pharmacogenetics of tuberculosis treatment toxicity and effectiveness in a large Brazilian cohort"],"prefix":"10.1097","volume":"35","author":[{"given":"Gustavo","family":"Amorim","sequence":"first","affiliation":[{"name":"Vanderbilt University Medical Center, Department of Biostatistics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Jaworski","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Department of 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C.","family":"Figueiredo","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Department of Medicine, Division of Infectious Diseases, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Turner","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Department of Medicine, Division of Infectious Diseases, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno B.","family":"Andrade","sequence":"additional","affiliation":[{"name":"Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Bahia"},{"name":"Instituto Brasileiro para Investiga\u00e7\u00e3o da Tuberculose, Funda\u00e7\u00e3o Jos\u00e9 Silveira"},{"name":"Instituto Gon\u00e7alo Moniz, Funda\u00e7\u00e3o Oswaldo Cruz"},{"name":"Universidade Salvador (UNIFACS), Laureate Universities"},{"name":"Escola Bahiana de Medicina e Sa\u00fade P\u00fablica (EBMSP)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Digna R.","family":"Velez Edwards","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Department of Obstetrics and Gynecology, Division of Quantitative Sciences, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adalberto R.","family":"Santos","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology Applied to Mycobacteria, Instituto Oswaldo Cruz"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria C.","family":"Rolla","sequence":"additional","affiliation":[{"name":"Instituto Nacional de Infectologia Evandro Chagas, Funda\u00e7\u00e3o Oswaldo Cruz, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy R.","family":"Sterling","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Department 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