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Meta-Analysis
. 2019 Jan 15;39(1):BSR20180845.
doi: 10.1042/BSR20180845. Print 2019 Jan 31.

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

Saif Khan  1 , Raju K Mandal  2 , Abdulbaset Mohamed Elasbali  3 , Sajad A Dar  2 , Arshad Jawed  2 , Mohd Wahid  2 , Harishankar Mahto  4 , Mohtashim Lohani  5 , Bhartendu Nath Mishra  6 , Naseem Akhter  7 , Ali A Rabaan  8 , Shafiul Haque  9
Affiliations
Meta-Analysis

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

Saif Khan et al. Biosci Rep. .

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.

Keywords: Meta-analysis; NAT2; anti-tuberculosis drug; genetic model; hepatotoxicity.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1
Figure 1. PRISMA 2009 Flow-diagram showing the identification and selection process (inclusion/exclusion) of the pertinent studies for the present meta-analysis
Figure 2
Figure 2. Forest plot of ORs with 95% CI of INH-induced hepatotoxicity risk associated with the NAT2 481C>T gene polymorphism for the overall population
Note: Black square represents the value of OR and the size of the square indicates the inverse proportion relative to its variance. Horizontal line is the 95% CI of OR.
Figure 3
Figure 3. Forest plot of ORs with 95% CI of INH-induced hepatotoxicity risk associated with the NAT2 590G>A gene polymorphism for the overall population
Note: Black square represents the value of OR and the size of the square indicates the inverse proportion relative to its variance. Horizontal line is the 95% CI of OR.
Figure 4
Figure 4. Forest plot of ORs with 95% CI of INH-induced hepatotoxicity risk associated with the NAT2 857G>A gene polymorphism for the overall population
Note: Black square represents the value of OR and the size of the square indicates the inverse proportion relative to its variance. Horizontal line is the 95% CI of OR.
Figure 5
Figure 5. Trial sequence analysis of all the included studies dealing with NAT2 gene polymorphisms based on dominant genetic model: (A) 481C>T, (B) 590G>A, (C) 857G>A and INH-induced hepatotoxicity risk
See this image and copyright information in PMC

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