GSTM1 and GSTT1 genetic polymorphisms and their association with antituberculosis drug‑induced liver injury

Abstract

Antituberculosis (anti-TB) drugs are the most common cause of drug-induced liver injury (DILI). There are numerous studies revealing the associations between the polymorphisms of pharmacogenes and the risk of anti-TB DILI (ATDILI). In the present study, relevant studies regarding the pharmacogenes associated with ATDILI were systematically searched in PubMed and Scopus. A total of 24 genes associated with ATDILI were reported on and the top five reported genes in terms of frequency were revealed to be N-acetyltransferase 2, cytochrome P450 family 2 subfamily E member 1, glutathione S-transferases [glutathione S-transferase mu 1 (GSTM1) and glutathione S-transferase theta 1 (GSTT1)] and solute carrier organic anion transporter family member 1B1. As ATDILI may be the result of direct and indirect interactions, the encoded proteins were further analysed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) to observe the protein-protein interactions and the associations amongst these proteins. The results suggested that only GSTT1 and GSTM1 were central proteins associated with all the other analysed proteins. Therefore, the association between GSTT1 or GSTM1 and the risk of developing ATDILI were further analysed. The results revealed that a GSTM1 deletion genotype was significantly associated with risk of ATDILI [odds ratio (OR), 1.28; 95% confidence interval (CI), 1.08-1.51; P= 0.004], whereas the GSTT1 deletion genotype and GSTM1/GSTT1 dual-deletion genotype were not significantly associated with risk of ATDILI. Subgroup analysis based on ethnicity was performed and the results demonstrated a significant association between GSTM1 and ATDILI in South Asian individuals (OR, 1.48; 95% CI, 1.12-1.95; P=0.005), which has not been reported previously, to the best of our knowledge. In conclusion, GSTM1 was associated with ATDILI in South Asian individuals.

Variability of the Genes Involved in the Cellular Redox Status and Their Implication in Drug Hypersensitivity Reactions

“…Current evidence supports that GSTM1, GSTP1, GSTT1, TXNRD1, SOD1, and SOD2 enzymes may exert a role in the underlying mechanism of DHRs. Prominent findings include the association of GSTM1 null or SOD2 rs4880 and DHRs triggered by NSAIDs and β-lactam antibiotics [ 28 , 30 , 31 , 35 , 40 ], whereas other putative associations such as GSTP1 rs1695, GSTT1 null, SOD1 rs2070424, or TXNRD1 haplotype require further studies [ 26 , 28 , 29 , 31 , 32 , 36 , 37 , 38 ].…”

“…Drug-induced liver injury (DILI) is one of the most common DHRs and a recent updated meta-analysis has confirmed an association between GSTM1 null genotypes and susceptibility to antituberculosis-DILI in South Asian individuals [ 31 ]. GSTM enzymes exert an essential role in detoxifying ROS and xenobiotics and individuals holding GSTM1 null genotypes have shown an absence of GSTM activity [ 81 ].…”

“…Although this association was not confirmed in a Jewish population [ 29 ]. A certain number of studies have shown controversial results about the association between GSTT1 null variant and DILI [ 31 , 33 , 34 ]. Nonetheless, meta-analysis studies did not confirm that association [ 31 , 90 ].…”

“…A certain number of studies have shown controversial results about the association between GSTT1 null variant and DILI [ 31 , 33 , 34 ]. Nonetheless, meta-analysis studies did not confirm that association [ 31 , 90 ]. Lucena et al demonstrated an association of GSTM1-T1 double-null genotype and Spanish patients with co-amoxiclav hepatotoxicity [ 25 ].…”

CYP2E1, GSTM1, and GSTT1 genetic polymorphisms and their associations with susceptibility to antituberculosis drug-induced liver injury in Thai tuberculosis patients

“…Attesting the relationships between GSTs and other drug-metabolizing enzymes, a previous study by Chanhom et al. involving protein-protein interaction analysis has uncovered that there were direct links between NAT2 , CYP2E1, and GST s. From this finding, it has been hypothesized that genetic polymorphisms within those genes may be implicated in ATDILI [ 32 ]. To address this speculation, the combination analysis of CYP2E1 phenotypic polymorphisms and GSTs genetic polymorphisms was investigated.…”