{"doi":"10.1101/2023.08.30.23294860","title":"Pharmacogenetics of tuberculosis treatment toxicity and effectiveness in a large Brazilian cohort","abstract":"Abstract Background Genetic polymorphisms have been associated with risk of anti-tuberculosis 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 2015-2019, and who were evaluable 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 anti-tuberculosis 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. Conclusions 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.","journal":"medRxiv","year":2023,"id":393597,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9011,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1167658,"name":"James Jaworski","orcid":"0009-0009-2852-4088","position":1,"is_corresponding":false},{"id":689803,"name":"Marcelo Cordeiro‐Santos","orcid":"0000-0002-7140-7145","position":2,"is_corresponding":false},{"id":110663,"name":"Afranio Kritski","orcid":"0000-0002-5900-6007","position":3,"is_corresponding":false},{"id":689804,"name":"Marina C. Figueiredo","orcid":"0000-0002-0671-398X","position":4,"is_corresponding":false},{"id":340158,"name":"Megan Turner","orcid":"0000-0001-5180-2773","position":5,"is_corresponding":false},{"id":252301,"name":"Bruno B. Andrade","orcid":"0000-0001-6833-3811","position":6,"is_corresponding":false},{"id":55367,"name":"Digna R. Velez Edwards","orcid":"0000-0001-5293-0056","position":7,"is_corresponding":false},{"id":1167659,"name":"Adalberto Rezende Santos","orcid":"0000-0002-9514-4589","position":8,"is_corresponding":false},{"id":689805,"name":"Valéria C. Rolla","orcid":"0000-0002-0841-1408","position":9,"is_corresponding":false},{"id":240257,"name":"Timothy R. Sterling","orcid":"0000-0002-4822-6979","position":10,"is_corresponding":false},{"id":292655,"name":"David W. Haas","orcid":"0000-0002-5813-1594","position":11,"is_corresponding":false},{"id":708632,"name":"Gustavo Amorim","orcid":"0000-0002-2941-5360","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T01:19:05.913428Z","pmid":"37693472","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}