Influence of glutathione S-transferase M1 and T1 homozygous null mutations on the risk of antituberculosis drug-induced hepatotoxicity in a Caucasian population.
OBJECTIVE
Genetic variations in enzymes of isoniazid metabolism confer an increased risk for antituberculosis drug-induced hepatotoxicity in Asian populations. The present study was aimed at investigating the possible association of antituberculosis drug-induced hepatotoxicity with polymorphisms at the glutathione S-transferase (GST) gene in a Caucasian population.


METHODS
A prospective case-control study was nested in a cohort of patients with active tuberculosis who were treated with a combination of isoniazid, rifampicin and pyrazinamide. Cases constituted patients with antituberculosis drug-induced hepatotoxicity (n=35), and controls constituted patients without any evidence of this complication (n=60). Homozygous null polymorphisms at GST loci M1 and T1 were analysed from genomic DNA from all participants.


RESULTS
The GSTT1 homozygous null polymorphism was significantly associated with antituberculosis drug-induced hepatotoxicity [odds ratio (OR) 2.60, 95% confidence interval (CI) 1.08-6.24, P=0.03]. No significant association was observed between the GSTM1 homozygous null polymorphism and antituberculosis drug-induced hepatotoxicity (OR 0.73, 95% CI 0.31-1.73, P=0.48).


CONCLUSIONS
The GSTT1 homozygous null polymorphism may be a risk factor of antituberculosis drug-induced hepatotoxicity in Caucasians.
Leiro
Virginia
V
Servicio de Neumología, Hospital Xeral-Cíes de Vigo (CHUVI), Vigo, Pontevedra, Spain. virginia.leiro.fernandez@sergas.es
Fernández-Villar
Alberto
A
Valverde
Diana
D
Constenla
Lucía
L
Vázquez
Rafael
R
Piñeiro
Luis
L
González-Quintela
Arturo
A
D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000995:Antitubercular Agents / Q000009:adverse effects*; D001219:Aspartate Aminotransferases / Q000097:blood; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D004359:Drug Therapy, Combination; D005260:Female; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011718:Pyrazinamide / Q000009:adverse effects; D012293:Rifampin / Q000009:adverse effects; D044465:White People / Q000235:genetics
D000410:Alanine Transaminase; D000995:Antitubercular Agents; D001219:Aspartate Aminotransferases; D005982:Glutathione Transferase; D007538:Isoniazid; D011718:Pyrazinamide; D012293:Rifampin; C413545:glutathione S-transferase T1