title: NAT2 6A, a haplotype of the N-acetyltransferase 2 gene, is an important biomarker for risk of anti-tuberculosis drug-induced hepatotoxicity in Japanese patients with tuberculosis.
abstract: OBJECTIVE
  To investigate an association between N-acetyltransferase 2 (NAT2)-haplotypes/diplotypes and adverse effects in Japanese pulmonary tuberculosis patients.
  
  
  METHODS
  We studied 100 patients with pulmonary TB treated with anti-TB drugs including INH. The frequencies and distributions of single nucleotide polymorphisms, haplotypes, and diplotypes of NAT2 were determined by the PCR-restriction fragment length polymorphism method, and the results were compared between TB patients with and without adverse effect, using multivariate logistic regression analysis.
  
  
  RESULTS
  Statistical analysis revealed that the frequency of a variant haplotype, NAT2 6A, was significantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity [P = 0.001, odds ratio (OR) = 3.535]. By contrast, the frequency of a wild-type (major) haplotype, "NAT2 4", was significantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P < 0.001, OR = 0.265). There was no association between NAT2-haplotypes and skin rash or eosinophilia.
  
  
  CONCLUSIONS
  The present study shows that NAT2 is one of the determinants of anti-TB drug-induced hepatotoxicity. Moreover, the haplotypes, NAT2 4 and NAT2 6A, are useful new biomarkers for predicting anti-TB drug-induced hepatotoxicity.
authors.affiliation: Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
authors.forename: Norihide
authors.initials: N
authors.lastname: Higuchi
authors.forename: Naoko
authors.initials: N
authors.lastname: Tahara
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yanagihara
authors.forename: Kiyoyasu
authors.initials: K
authors.lastname: Fukushima
authors.forename: Naofumi
authors.initials: N
authors.lastname: Suyama
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Inoue
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Kohichiro
authors.initials: K
authors.lastname: Yoshiura
authors.forename: Norio
authors.initials: N
authors.lastname: Niikawa
authors.forename: Chun-Yang
authors.initials: CY
authors.lastname: Wen
authors.forename: Hajime
authors.initials: H
authors.lastname: Isomoto
authors.forename: Saburou
authors.initials: S
authors.lastname: Shikuwa
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Omagari
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mizuta
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsukamoto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000995:Antitubercular Agents / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D044466:Asian People; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human