title: CYP2E1, GSTM1 and GSTT1 genetic polymorphisms and susceptibility to antituberculosis drug-induced hepatotoxicity: a nested case-control study.
abstract: OBJECTIVE
  The pathogenic mechanism of antituberculosis drug-induced hepatotoxicity (ATDH) is thought to involve drug-metabolizing enzymes including N-acetyl transferase2 (NAT2), cytochrome P4502E1 (CYP2E1) and glutathione S-transferase (GST) M1, T1. The associations between genetic polymorphisms of those genes and ATDH have been reported but with inconsistent results. Moreover, most studies were hospital-based retrospective studies and not prospective. We aimed to investigate possible associations of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms with ATDH using a more robust case-control study nested in a population-based prospective antituberculosis treatment cohort.
  
  
  METHODS
  A total of 4304 patients with smear-positive tuberculosis (TB) who received standard short-course chemotherapy were monitored for 6-9 months. Incidence density sampling method was adopted to select controls and 4 : 1 matched with each ATDH cases by age (± 5 years), sex, treatment history, disease severity and drug dosage. The CYP2E1, GSTM1 and GSTT1 polymorphisms were genotyped using PCR-RFLP and multiplex PCR methods. Conditional logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (CI), as well as corresponding P-values.
  
  
  CONCLUSIONS
  A total of 89 ATDH cases and 356 controls were included in this study. There was no statistically significant association between CYP2E1 RsaI c1/c1 genotype or DraI C/C genotype and ATDH (OR = 0·99, 95% CI:0·62-1·59; OR = 1·13, 95% CI: 0·40-3·20, respectively) compared with CYP2E1 RsaI c1/c2 or c2/c2 genotypes or DraI D/D genotype, or between GSTM1/GSTT1 null genotypes and ATDH (OR = 1·22, 95% CI: 0·76-1·96; OR = 0·96, 95% CI: 0·60-1·52, respectively) compared with non-null genotypes.
  
  
  CONCLUSIONS
  This is the first study of the involvement of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms in ATDH using a nested case-control population-based prospective cohort design. We could not confirm positive associations of genetic polymorphisms of CYP2E1 RsaI, CYP2E1 DraI, GSTM1 null and GSTT1 null with ATDH reported by various groups, in our Chinese TB population.
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China.
authors.forename: S-W
authors.initials: SW
authors.lastname: Tang
authors.forename: X-Z
authors.initials: XZ
authors.lastname: Lv
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: S-S
authors.initials: SS
authors.lastname: Wu
authors.forename: Z-R
authors.initials: ZR
authors.lastname: Yang
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Xia
authors.forename: D-H
authors.initials: DH
authors.lastname: Tu
authors.forename: P-Y
authors.initials: PY
authors.lastname: Deng
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.forename: D-F
authors.initials: DF
authors.lastname: Chen
authors.forename: S-Y
authors.initials: SY
authors.lastname: Zhan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000995:Antitubercular Agents / Q000009:adverse effects* / Q000627:therapeutic use; D044466:Asian People; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000235:genetics*; D015331:Cohort Studies; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D014376:Tuberculosis / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D003577:Cytochrome P-450 Enzyme System; D000072467:Cytochrome P450 Family 2; D005982:Glutathione Transferase; C110332:CYP2F1 protein, human; C413545:glutathione S-transferase T1