Genetic interaction between NAT2, GSTM1, GSTT1, CYP2E1, and environmental factors is associated with adverse reactions to anti-tuberculosis drugs.
BACKGROUND
Adverse drug reactions (ADRs) associated with anti-tuberculosis (anti-TB) drug regimens have considerable impact on anti-TB treatment, potentially leading to unsuccessful outcomes. Nevertheless, the risk factors that play a role in anti-TB drug-induced ADRs are not well established. It is well documented that genetic polymorphisms in drug-metabolizing enzymes (DMEs) result in considerably complex variability in anti-TB drug disposition. In addition, the impact of pharmacogenetic variation on the metabolism of anti-TB drugs may be modifiable by environmental exposure. Thus, an assessment of pharmacogenetic variability combined with biomarkers of environmental exposure may be helpful for demonstrating the effect of the gene-environment interaction on susceptibility to ADRs induced by anti-TB drug therapy.


OBJECTIVE
The aim of the study was to investigate the impact of the interaction between environmental risk factors and pharmacogenetic polymorphisms in four common DMEs--N-acetyltransferase 2 (arylamine N-acetyltransferase) [NAT2], glutathione S-transferase theta 1 [GSTT1], glutathione S-transferase mu 1 [GSTM1], and cytochrome P450 2E1 [CYP2E1]--on commonly reported ADRs to first-line anti-TB drugs in 129 patients receiving homogeneous TB treatment.


METHODS
TB patients monitored during drug treatment were divided into subgroups according to the presence or absence of ADRs. Additionally, the patients' clinical and demographic characteristics were collected in order to identify the environmental factors that are potential triggers for ADRs induced by anti-TB drug treatment. Pharmacogenetic variability was determined by gene sequencing, TaqMan® assays, or polymerase chain reaction.


RESULTS
The findings of this study suggest that the NAT2 slow acetylator haplotype, female sex, and smoking are important determinants of susceptibility to ADRs induced by anti-TB drugs. Patients carrying multiple, but not single, polymorphisms in the NAT2, GSTM1, GSTT1, and CYP2E1 genes were found to have an increased risk of ADRs, as revealed by gene-gene interaction analysis. Moreover, we also identified meaningful gene-environment interaction models that resulted in the highest levels of ADR risk.


CONCLUSIONS
The study findings provide evidence of the clinical impact of the interaction between pharmacogenetic variability and environmental factors on ADRs induced by anti-TB drug therapy. Predictive pharmacogenetic testing and a comprehensive clinical history would therefore be helpful for identification and careful monitoring of patients at high risk of this complication.
Laboratrio de Farmacogenmica e Epidemiologia Molecular, Universidade Estadual de Santa Cruz, Ilhus, Brazil.
Gustavo N O
GN
Costa
Luiz A V
LA
Magno
Cinthia V N
CV
Santana
Cibele
C
Konstantinovas
Samuel T
ST
Saito
Moara
M
Machado
Giuliano
G
Di Pietro
Luciana
L
Bastos-Rodrigues
Débora M
DM
Miranda
Luiz A
LA
De Marco
Marco A
MA
Romano-Silva
Fabrício
F
Rios-Santos
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*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors; D014376:Tuberculosis / Q000188:drug therapy* / Q000235:genetics*; D055815:Young Adult
D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; D019392:Cytochrome P-450 CYP2E1; D005982:Glutathione Transferase; C478900:NAT2 protein, human; C413545:glutathione S-transferase T1