title: Factors associated with anti-TB drug-induced hepatotoxicity and genetic polymorphisms in indigenous and non-indigenous populations in Brazil.
abstract: Anti-tuberculosis (TB) drugs are responsible for the occurrence of several adverse drug reactions (ADRs), including hepatotoxicity. The aim was to estimate the incidence of hepatotoxicity and its association with genetic polymorphisms and clinical-epidemiological factors by comparing indigenous and non-indigenous TB patients. We investigated clinical-epidemiological variables, serum levels of liver enzymes and NAT2, CYP2E1 and GSTM1 polymorphisms. A non-conditional logistic regression was used to identify the factors associated with hepatotoxicity. Odds ratios were used as the association measures. The incidence of hepatotoxicity was 19.7% for all patients. The risk of hepatotoxicity was almost four times higher in indigenous patients, comparing to non-indigenous. We identified a new nonsynonymous single nucleotide polymorphism of NAT2 in indigenous patients. In total, 54.6% of the patients expressed a slow acetylation phenotype profile. The frequency of the null genotype of GSTM1 was higher in non-indigenous patients (p = 0.002), whereas no significant differences in relation to polymorphisms of CYP2E1 were observed between the groups. Hepatotoxicity was associated with patients older than 60 and indigenous (OR = 26.0; 95%CI:3.1-217.6; OR = 3.8; 95%CI:1.3-11.1, respectively). Furthermore, hepatotoxicity was associated with a slow acetylation profile in indigenous patients (OR = 10.7; 95%CI:1.2-97.2). Our findings suggest that there are distinct acetylation profiles in the Brazilian population, emphasizing the importance of pharmacogenetic analyses for achieving personalized therapeutic schemes and better outcomes.
authors.affiliation: Escola Nacional de Saúde Pública, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Heinrich
authors.affiliation: Laboratório de Genética Humana, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Verônica M
authors.initials: VM
authors.lastname: Zembrzuski
authors.affiliation: Faculdade de Ciências da Saúde, Universidade Federal da Grande Dourados, Dourados, MS, Brazil.
authors.forename: Marcos M
authors.initials: MM
authors.lastname: Ota
authors.affiliation: Faculdade de Medicina, Universidade Federal de Mato Grosso do Sul, Campo Grande, MS, Brazil.
authors.forename: Flavia P
authors.initials: FP
authors.lastname: Sacchi
authors.affiliation: Laboratório de Biologia Molecular Aplicada a Micobactérias, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Raquel L F
authors.initials: RL
authors.lastname: Teixeira
authors.affiliation: Laboratório de Genética Humana, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil; Escola de Ciências da Saúde, Universidade do Grande Rio, Duque de Caxias, RJ, Brazil.
authors.forename: Pedro H
authors.initials: PH
authors.lastname: Cabello Acero
authors.affiliation: Escola Nacional de Saúde Pública, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Geraldo Marcelo
authors.initials: GM
authors.lastname: Cunha
authors.affiliation: Escola Nacional de Saúde Pública, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Reinaldo
authors.initials: R
authors.lastname: Souza-Santos
authors.affiliation: Faculdade de Ciências da Saúde, Universidade Federal da Grande Dourados, Dourados, MS, Brazil; Fundação Oswaldo Cruz, Mato Grosso do Sul, Campo Grande, MS, Brazil.
authors.forename: Julio
authors.initials: J
authors.lastname: Croda
authors.affiliation: Escola Nacional de Saúde Pública, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil. Electronic address: paulobasta@gmail.com.
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Basta
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000995:Antitubercular Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D001938:Brazil / Q000453:epidemiology; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D015994:Incidence; D007223:Infant; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000453:epidemiology; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; D019392:Cytochrome P-450 CYP2E1; D005982:Glutathione Transferase; C478900:NAT2 protein, human
keywords: Adverse drug reactions; Hepatotoxicity; Indigenous; Pharmacogenetics; Tuberculosis