title: Genetic variations of NAT2 and CYP2E1 and isoniazid hepatotoxicity in a diverse population.
abstract: OBJECTIVE
  TB is a serious global public health problem. Isoniazid, a key drug used to treat latent TB, can cause hepatotoxicity in some patients. This pilot study investigated the effects of genetic variation in NAT2 and CYP2E1 on isoniazid-induced hepatotoxicity in TB contacts in British Columbia, Canada.
  
  
  METHODS
  DNA re-sequencing was used to establish the spectrum of genetic variation in the exons, promoter and conserved regions of NAT2 in all subjects. For CYP2E1, the CYP2E1*1C polymorphism was genotyped by PCR-RFLP. Association tests of NAT2 variants and haplotypes, as well acetylator types were performed.
  
  
  RESULTS
  We enrolled 170 subjects on isoniazid treatment (23 cases and 147 controls). Systematic re-sequencing of NAT2 revealed 18 known and 10 novel variants.
  
  
  CONCLUSIONS
  No single genetic variant of NAT2 and CYP2E1 showed a significant association with isoniazid-induced hepatotoxicity in this highly heterogeneous population. There was evidence of a trend for increasing hepatotoxicity risk across the rapid, intermediate and slow acetylator groups (p = 0.08).
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: So
authors.initials: S
authors.lastname: Yamada
authors.forename: Mila
authors.initials: M
authors.lastname: Tang
authors.forename: Kathryn
authors.initials: K
authors.lastname: Richardson
authors.forename: Julius
authors.initials: J
authors.lastname: Halaschek-Wiener
authors.forename: Matthew
authors.initials: M
authors.lastname: Chan
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Cook
authors.forename: J Mark
authors.initials: JM
authors.lastname: Fitzgerald
authors.forename: R Kevin
authors.initials: RK
authors.lastname: Elwood
authors.forename: Angela
authors.initials: A
authors.lastname: Brooks-Wilson
authors.forename: Fawziah
authors.initials: F
authors.lastname: Marra
mesh_terms: D000107:Acetylation; D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000235:genetics; D000995:Antitubercular Agents / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D001955:British Columbia / Q000453:epidemiology; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005006:Ethnicity; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010865:Pilot Projects; D012907:Smoking; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D004247:DNA; D019392:Cytochrome P-450 CYP2E1; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid