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

Abstract

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. 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 metaanalysis were performed based on each NAT2 genotype and risk of ATDILI cases and also new classification of the ultraslow 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 fixedeffect (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.