Are genetic variations in glutathione S‐transferases involved in anti‐tuberculosis drug‐induced liver injury? A meta‐analysis

Abstract

What is known and Objective As a crucial protective role in the detoxifying mechanisms of drugs, glutathione S‐transferases (GSTs) may affect an individual patient's susceptibility to anti‐tuberculosis drug‐induced liver injury (ATLI). However, the results of studies investigate the association between GSTM1, GSTT1 and GSTP1 polymorphisms and risk of ATLI are inconclusive. A meta‐analysis on this topic was performed. Methods PubMed, EMBASE, ISI web of science and the Chinese National Knowledge Infrastructure (CNKI) were systematically searched to identify relevant studies. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated. Heterogeneity among articles and publication bias were also tested. Results and discussion After excluding one study as an outlier, the null GSTM1 genotype was associated with an increased risk of ATLI (OR = 1.270, 95% CI (1.014‐1.590, P = .038), especially in East Asians (OR = 1.501, 95% CI (1.303‐1.730). With similar exclusion, the null GSTT1 genotype increased the risk of ATLI in the total population (OR = 1.169, 95% CI: 1.028‐1.330) and in Indians (OR = 1.732, 95% CI: 1.229‐2.416). No statistically significant association was observed between the mutant GSTP1 genotype with risk of ATLI, which may need more rigorous and uniform case‐control or cohort studies for more robust inferences. What is new and conclusion This up‐to‐date meta‐analysis strongly suggests associations of GSTM1 and GSTT1 polymorphisms with ATLI. The results show the increased risk of ATL1 with the null GSTM1 and GSTT1 genotype on ATLI development. No such association is shown with the mutant GSTP1 genotype.

Collagen type XVIII alpha 1 chain (COL18A1) variants affect the risk of anti‐tuberculosis drug‐induced hepatotoxicity: A prospective study

“…Clearly, it is urgent to explore new biomarkers for diagnosis of ATDH. With the development of molecular detection methods, genetic factors are gradually well‐recognized and considered as the crucial elements in the pathogenesis, prediction, diagnosis and treatment of many diseases 14‐16 . Nowadays, a growing body of evidence proves that single nucleotide polymorphisms (SNPs), such as pregnane X receptor ( PXR ) rs7643645 17,18 and phase I cytochrome P450 enzyme ( CYP2E1 ), 8 play important roles in the prediction, diagnosis, and treatment of ATDH.…”

Clinical and Genetic Risk Factors for Drug-Induced Liver Injury Associated with Anti-Tuberculosis Treatment—A Study from Patients of Portuguese Health Centers

“…For these genes, conflicting results have been published. Considering recent meta-analyses, two support the roles of CYP2E1, GSTM1, and GSTT1 in AT-DILI [ 19 , 20 ], one does not implicate GSTT1 [ 21 ], and in another CYP2E1 could only be implicated in East Asian populations [ 18 ]. In a trans-ethnic meta-analysis from Nicoletti et al, CYP2E1 was not associated with AT-DILI [ 46 ].…”

“…Glutathione S-Transferases (GSTs) are phase II metabolizing enzymes with an important role in the detoxification of metabolites resulting from the biotransformation of xenobiotics by phase I enzymes [ 17 ]. Copy number variations (CNV) consisting in the deletion of Glutathione S-Transferase theta 1 ( GSTT1 ) and Glutathione S-Transferase Mu 1 ( GSTM1 ) have been associated with AT-DILI, although with controversial results [ 20 , 21 ].…”

N-Acetyl Cysteine as an Adjunct in the Treatment of Tuberculosis

“…According to studies on genetic polymorphisms of oxidant-antioxidant systems, mutations leading to reduced antioxidant enzymes or increased prooxidant enzymes resulted in increased susceptibility to anti-TB DILI [81,84,85]. A loss of function mutation on MAFK encoding MafK (small Maf basic leucine zipper proteins) increased susceptibility to anti-TB DILI [81] (Figure 1).…”

“…Tuberculosis Research and Treatment of GSTM1 and GSTT1, glutathione S-transferase encoding genes, with anti-TB DILI [85]. NAC prevented anti-TB drug-induced hepatotoxicity in animal studies [82,83] (Table 3).…”