Pharmacogenetic association between NAT2 gene polymorphisms and isoniazid induced hepatotoxicity: trial sequence meta-analysis as evidence.

Saif Khan,Sajad A Dar,Mohtashim Lohani,Mohd Wahid,Arshad Jawed,Bhartendu Nath Mishra,Ali A Rabaan,Raju K Mandal,Naseem Akhter,Harishankar Mahto,Shafiul Haque,Abdulbaset Mohamed Elasbali

doi:10.1042/bsr20180845

Abstract

Hepatotoxicity is a severe problem generally faced by tuberculosis (TB) patients. It is a well-known adverse reaction due to anti-TB drugs in TB patients undergoing long-term treatment. The studies published previously have explored the connection of N-acetyltransferase 2 (NAT2) gene polymorphisms with isoniazid-induced hepatotoxicity, but the results obtained were inconsistent and inconclusive. A comprehensive trial sequence meta-analysis was conducted employing 12 studies comprising 3613 controls and 933 confirmed TB cases using the databases namely, EMBASE, PubMed (Medline) and Google Scholar till December 2017. A significant association was observed with individuals carrying variant allele at position 481C>T (T vs. C: P = 0.001; OR = 1.278, 95% CI = 1.1100–1.484), at position 590G>A (A vs. G: P = 0.002; OR = 1.421, 95% CI = 1.137–1.776) and at position 857G>A (A vs. G: P = 0.0022; OR = 1.411, 95% CI = 1.052–1.894) to higher risk of hepatotoxicity vis-à-vis wild-type allele. Likewise, the other genetic models of NAT2 gene polymorphisms have also shown increased risk of hepatotoxicity. No evidence of publication bias was observed. These results suggest that genetic variants of NAT2 gene have significant role in isoniazid induced hepatotoxicity. Thus, NAT2 genotyping has the potential to improve the understanding of the drug–enzyme metabolic capacity and help in early predisposition of isoniazid-induced hepatotoxicity.

Highlights

Mycobacterium tuberculosis is the single most prominent species responsible for tuberculosis (TB) disease
No evidence of publication bias was observed. These results suggest that genetic variants of N-acetyltransferase 2 (NAT2) gene have significant role in isoniazid induced hepatotoxicity
The last search performed was updated on December 2017 using the following keyword combinations: N-acetyltransferase 2 OR NAT2 OR gene AND tuberculosis induced hepatotoxicity OR TB induced hepatotoxicity

Summary

Introduction

Mycobacterium tuberculosis is the single most prominent species responsible for tuberculosis (TB) disease. It has been observed that many patients are at higher risk of developing hepatotoxicity during the course of anti-TB chemotherapy than others [3] This individual susceptibility could be associated with the genetic variation in the gene(s) involved in the drug metabolism, transport or excretion, or gene(s) that regulates the immune responses [4]. A meta-analysis combines multiple studies on the same alleles of genes to enhance the statistical power of the analysis and gives more accurate and reliable results of the genetic effects We executed this meta-analysis by combining all the eligible published studies to examine the comprehensive picture of the above said pharmacogenetic association and understand the role of NAT2 gene polymorphisms in INH-induced hepatotoxicity in TB patients. The current trial sequential meta-analysis of the published case–control reports will help in strengthening the postulated pharmcogenetic association of NAT2 genetic variants with INH-induced hepatotoxicity risk in TB patients

Materials and methods

Literature search strategy

Results

Methods

Discussion