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Antimicrob Agents Chemother. 2019 Jul 25;63(8). pii: e02692-18. doi: 10.1128/AAC.02692-18. Print 2019 Aug.

Genomewide Association Study Confirming the Association of NAT2 with Susceptibility to Antituberculosis Drug-Induced Liver Injury in Thai Patients.

Author information

1
Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
2
Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
3
Department of Biochemistry, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
4
Medical Genetics Center, Medical Life Sciences Institute, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand.
5
Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan mushiroda@riken.jp surakameth.m@dmsc.mail.go.th.
6
Fukujuji Hospital, Japan Anti-tuberculosis Association, Kiyose, Japan.
7
Chest Disease Institute, Department of Medical Services, Ministry of Public Health, Nonthaburi, Thailand.
8
TB/HIV Research Foundation, Chiangrai, Thailand.
9
Chiang Rai Prachanukroh Hospital, Ministry of Public Health, Chiangrai, Thailand.
10
Health Product Vigilance Center, Thai Food and Drug Administration, Ministry of Public Health, Nonthaburi, Thailand.
11
Buddhachinaraj Hospital, Phitsanulok, Thailand.
12
Rayong Hospital, Rayong, Thailand.
13
Mae-sort Hospital, Tak, Thailand.
14
Medical Genetics Center, Medical Life Sciences Institute, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand mushiroda@riken.jp surakameth.m@dmsc.mail.go.th.
15
Nopparatrajathanee Hospital, Department of Medicine, Ministry of Public Health, Nonthaburi, Thailand.
16
Thai Mueang Chaipat Hospital, Phang-nga, Thailand.
17
Hatyai Hospital, Songkhla, Thailand.
18
Thabo Crown Prince Hospital, Nong Khai, Thailand.

Abstract

Antituberculosis drug-induced liver injury (ATDILI) is a common side effect leading to tuberculosis (TB) treatment disruption. The mechanism of the disease remains poorly understood. We conducted a genomewide association study (GWAS) to investigate all possible genetic factors of ATDILI in Thai patients. This study was carried out in Thai TB patients, including 79 ATDILI cases and 239 tolerant controls from our network hospitals in Thailand. Nearly 1 million single-nucleotide polymorphisms (SNPs) were genotyped across the whole genome using an Illumina OmniExpress Exome BeadChip array. In the discovery stage, we identified strong association signals on chromosome 8 originating from the N-acetyltransferase (NAT2) region. The A allele of rs1495741, the top SNP in the intergenic region of NAT2 and PSD3 (14 kb from NAT2), was significantly associated with ATDILI (recessive model, odds ratio of 6.01 [95% confidence interval, 3.42 to 10.57]; P = 6.86E-11). This particular SNP was reported as a tag SNP for NAT2 inferred phenotypes. The AA, AG, and GG genotypes represented NAT2 slow acetylators, intermediate acetylators, and fast acetylators, respectively. The tag SNP genotypes demonstrated a concordance rate of 94.98% with NAT2 acetylator phenotypes. This GWAS shows that NAT2 is the most important risk factor for ATDILI in the Thai population.

KEYWORDS:

GWAS; NAT2; Thais; antituberculosis drug-induced liver injury

PMID:
31109976
PMCID:
PMC6658740
[Available on 2020-01-25]
DOI:
10.1128/AAC.02692-18

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