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[Preprint]. 2023 Sep 1:2023.08.30.23294860.
doi: 10.1101/2023.08.30.23294860.

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

Gustavo Amorim, James Jaworski, Marcelo Cordeiro-Santos, Afrânio L Kritski, Marina C Figueiredo, Megan Turner, Bruno B Andrade, Digna R Velez Edwards, Adalberto R Santos, Valeria C Rolla, Timothy R Sterling, David W Haas; Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil network

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

Gustavo Amorim et al. medRxiv. .

Update in

  • Pharmacogenetics of tuberculosis treatment toxicity and effectiveness in a large Brazilian cohort.
    Amorim G, Jaworski J, Yang J, Cordeiro-Santos M, Kritski AL, Figueiredo MC, Turner M, Andrade BB, Velez Edwards DR, Santos AR, Rolla VC, Sterling TR, Haas DW; Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil network. Amorim G, et al. Pharmacogenet Genomics. 2025 Feb 1;35(2):55-64. doi: 10.1097/FPC.0000000000000552. Epub 2024 Oct 15. Pharmacogenet Genomics. 2025. PMID: 39470346 Free PMC article.

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.

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