title: N-acetyltransferase 2 (NAT2) genotype as a risk factor for development of drug-induced liver injury relating to antituberculosis drug treatment in a mixed-ethnicity patient group.
abstract: OBJECTIVE
  This study aims to assess whether NAT2 genotype affects susceptibility to moderate to severe liver injury in patients undergoing drug treatment for tuberculosis with isoniazid-containing regimens.
  
  
  METHODS
  Twenty-six patients of European or South Asian ethnicity, who had suffered liver injury during treatment with isoniazid-containing drug regimens and 101 ethnically matched controls were genotyped for the NAT2*5, NAT2*6, and NAT2*7 alleles. Genotyping for additional polymorphisms in the NAT gene region was also performed on 20 of the 26 cases. NAT2 genotype frequency between cases and controls was compared.
  
  
  RESULTS
  NAT2 genotypes predicting a slow acetylator phenotype were found to be associated with an increased risk of isoniazid-related liver injury (odds ratio (OR) = 4.25 (95% confidence interval (CI), 1.36-13.22); p = 0.012) with 85% of the cases being slow acetylators compared with 56% of the controls. There was no evidence for an increased risk for the slow acetylator genotype in patients with the most severe cases of liver injury, who underwent liver transplantation.
  
  
  CONCLUSIONS
  The NAT2 slow acetylator genotype appears to be a significant risk factor for moderate and severe drug- induced liver injury. However, the overall effect size is modest and generally in line with effects described previously for this genotype in milder drug-induced liver injury. Additional genetic risk factors may also contribute.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Ching-Soon
authors.initials: CS
authors.lastname: Ng
authors.forename: Abul
authors.initials: A
authors.lastname: Hasnat
authors.forename: Abdullah
authors.initials: A
authors.lastname: Al Maruf
authors.forename: Maizbha Uddin
authors.initials: MU
authors.lastname: Ahmed
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Day
authors.forename: Guruprasad P
authors.initials: GP
authors.lastname: Aithal
authors.forename: Ann K
authors.initials: AK
authors.lastname: Daly
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D001208:Asia / Q000453:epidemiology; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D004359:Drug Therapy, Combination; D005006:Ethnicity / Q000235:genetics; D005060:Europe / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D012307:Risk Factors; D014376:Tuberculosis / Q000188:drug therapy / Q000235:genetics
chemical_list: D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid