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NAT2 ultra-slow acetylator and risk of anti-tuberculosis drug-induced liver injury: a genotype-based meta-analysis

Suvichapanich, Supharata,*; Fukunaga, Koyab,*; Zahroh, Hilyatuzd,*; Mushiroda, Taiseib; Mahasirimongkol, Surakamethf; Toyo-oka, Lichtf; Chaikledkaew, Usag; Jittikoon, Jiraphunh; Yuliwulandari, Rikad,e; Yanai, Hidekic; Wattanapokayakit, Sukanyaf; Tokunaga, Katsushia

Pharmacogenetics and Genomics: July 2018 - Volume 28 - Issue 7 - p 167–176
doi: 10.1097/FPC.0000000000000339

Background NAT2 slow acetylator is a confirmed risk of anti-tuberculosis drug-induced liver injury (ATDILI). However, NAT2 ultra-slow acetylators, a new refinement among NAT2 slow acetylators, have been recently proposed. The patients with NAT2 genotypes of *6A/*6A, *6A/*7B and *7B/*7B are referred to in this group.

Objective We aim to prove an association of the NAT2 ultra-slow acetylators with the risk of ATDILI.

Materials and methods Systematic review and meta-analysis were performed based on each NAT2 genotype and risk of ATDILI cases and also new classification of the ultra-slow acetylators up to 31 October 2016. Meta-analysis of 18 studies with 822 ATDILI cases and 4630 controls was carried out in the RevMan software, version 5.3 with fixed-effect (low heterogeneity) and random effect (moderate to high heterogeneity) methods.

Results The strong associations between each NAT2 slow acetylator genotypes and ATDILI were confirmed in meta-analysis except for NAT2*5B/*5B [odds ratio (OR): 1.69; 95% confidence interval (CI): 0.96–2.95; P=0.0679]. The NAT2 ultra-slow acetylators contribute to higher risk of ATDILI (OR: 3.60; 95% CI: 2.30–5.63; P=1.76E−08) than all NAT2 slow acetylators (OR: 2.80; 95% CI: 2.20–3.57; P=5.73E−18) as well as fast acetylators. Additional in-vitro study using isoniazid as a substrate supports the existence of ultra-slow acetylator alleles (NAT2*6A and NAT2*7B).

Conclusion This is the first meta-analysis of NAT2 and the risk of ATDILI at the genotypic level. The result demonstrated that NAT2 ultra-slow acetylator genotypes will have the most effect on the increased risk of ATDILI.

aDepartment of Human Genetics, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo

bLaboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama

cFukujuji Hospital, Japan Anti-tuberculosis Association (JATA), Kiyose, Japan

dGenetics Research Centre

eDepartment of Pharmacology, Faculty of Medicine, YARSI University, Jakarta, Indonesia

fDepartment of Medical Sciences, Medical Genetics Center, Medical Life Sciences Institute, Ministry of Public Health, Nonthaburi

gDepartment of Pharmacy, Social Administrative Pharmacy Excellence Research Unit

hDepartment of Biochemistry, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand

*Supharat Suvichapanich, Koya Fukunaga and Hilyatuz Zahroh contributed equally to the writing of this article.

Correspondence to Surakameth Mahasirimongkol, Department of Medical Sciences, Medical Genetics Center, Medical Life Sciences Institute, Ministry of Public Health, Nonthaburi 11000, Thailand Tel: +66 295 10000 x98096; fax: +66 296 59757; e-mail:

Received October 30, 2017

Accepted April 27, 2018

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