S Wattanapokayakit1, T Mushiroda2, H Yanai3, N Wichukchinda4, C Chuchottawon5, S Nedsuwan6, A Rojanawiwat4, S Denjanta6, T Kantima7, J Wongyai7, W Suwankesawong8, W Rungapiromnan8, R Kidkeukarun9, W Bamrungram10, A Chaiwong11, S Suvichapanich12, S Mahasirimongkol4, K Tokunaga12. 1. Medical Genetics Center, Medical Life Sciences Institute, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand; Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan. 2. Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 3. Fukujuji Hospital, Japan Anti-tuberculosis Association, Kiyose, Japan. 4. Medical Genetics Center, Medical Life Sciences Institute, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand. 5. Central Chest Institute of Thailand, Department of Medical Services, Ministry of Public Health, Nonthaburi, Thailand. 6. Chiangrai Prachanukroh Hospital, Department of Social and Preventive Medicine, Ministry of Public Health, Chiang Rai, Thailand. 7. TB/HIV Research Foundation, Chiang Rai, Thailand. 8. Health Product Vigilance Centre, Food and Drug Administration, Ministry of Public Health, Nonthaburi, Thailand. 9. Buddhachinaraj Hospital, Phitsanulok, Thailand. 10. Rayong Hospital, Rayong, Thailand. 11. Maesot Hospital, Tak, Thailand. 12. Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Abstract
BACKGROUND: Anti-tuberculosis drug-induced liver injury (AT-DILI) is one of the most common forms of drug-induced liver injury (DILI) in high tuberculosis (TB) burden countries. Among anti-tuberculosis drugs, isoniazid is the main cause of hepatotoxicity in patients with AT-DILI. OBJECTIVE: To investigate the association of AT-DILI with N-acetyltransferase 2 (NAT2) genotype status in Thai TB patients. METHODS: We enrolled 53 patients diagnosed with AT-DILI and 85 patients who tolerated anti-tuberculosis treatment as controls. Acetylator status was determined based on the inferred NAT2 haplotypes from four common single-nucleotide polymorphisms (SNPs) in Thais using Sanger sequencing. RESULTS: Phenotype frequencies of the NAT2 acetylator in AT-DILI patients were respectively 71.7%, 22.6% and 5.7% for slow, intermediate and rapid acetylators. Among slow, intermediate, and rapid acetylators in treatment tolerant controls, phenotype frequencies were respectively 22.4%, 62.4% and 15.3%. Slow NAT2 acetylators demonstrated a significant association with risk of AT-DILI. The odds ratio of comparing slow NAT2 acetylator in DILI patients and tolerance was 8.80 (95%CI 4.01-19.31, P = 1.53 × 10-8). CONCLUSIONS: Slow acetylator status in the NAT2 genotype is a significant risk factor for DILI in Thai patients with TB. This evidence provides confirmatory data in support of the role of NAT2 in AT-DILI in the Thai population.
BACKGROUND: Anti-tuberculosis drug-induced liver injury (AT-DILI) is one of the most common forms of drug-induced liver injury (DILI) in high tuberculosis (TB) burden countries. Among anti-tuberculosis drugs, isoniazid is the main cause of hepatotoxicity in patients with AT-DILI. OBJECTIVE: To investigate the association of AT-DILI with N-acetyltransferase 2 (NAT2) genotype status in Thai TB patients. METHODS: We enrolled 53 patients diagnosed with AT-DILI and 85 patients who tolerated anti-tuberculosis treatment as controls. Acetylator status was determined based on the inferred NAT2 haplotypes from four common single-nucleotide polymorphisms (SNPs) in Thais using Sanger sequencing. RESULTS: Phenotype frequencies of the NAT2 acetylator in AT-DILI patients were respectively 71.7%, 22.6% and 5.7% for slow, intermediate and rapid acetylators. Among slow, intermediate, and rapid acetylators in treatment tolerant controls, phenotype frequencies were respectively 22.4%, 62.4% and 15.3%. Slow NAT2 acetylators demonstrated a significant association with risk of AT-DILI. The odds ratio of comparing slow NAT2 acetylator in DILI patients and tolerance was 8.80 (95%CI 4.01-19.31, P = 1.53 × 10-8). CONCLUSIONS: Slow acetylator status in the NAT2 genotype is a significant risk factor for DILI in Thai patients with TB. This evidence provides confirmatory data in support of the role of NAT2 in AT-DILI in the Thai population.
Authors: Min Zhang; Shuqiang Wang; Bob Wilffert; Rongsheng Tong; Dick van Soolingen; Susan van den Hof; Jan-Willem Alffenaar Journal: Br J Clin Pharmacol Date: 2018-10-03 Impact factor: 4.335