Characterisation of GSTM1 and GSTT1 genetic variability and its role in the development of drug-induced hepatotoxicity in patients with drug-susceptible pulmonary tuberculosis

Objectives. Both glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) are enzymes detoxifying various xenobiotics. In patients with tuberculosis (TB) receiving isoniazid, GSTM1 and GSTT1 null genotypes may potentially increase the risk of drug-induced hepatotoxicity (DIH). However, data on the impact of specific genetic variants is limited. This study characterised GSTM1 and GSTT1 genetic variability and assessed its relationship with DIH in patients with drug-susceptible pulmonary TB.

Materials and methods. The study included 35 patients admitted to the Centre of Tuberculosis and Lung Diseases, Riga East University Hospital. DIH status was determined based on serum aminotransferase levels before and 10–12 days after treatment initiation. GSTM1 and GSTT1 genes were sequenced using a custom next-generation sequencing protocol targeting exons and untranslated (UTR) regions with flanking sequences. Sequencing data were processed using the Galaxy platform. Statistical analyses were performed using IBM SPSS Statistics 29.0.0.

Results. Sequencing data for the GSTM1 and GSTT1 genes were generated for 15 (42.9%) and 32 (91.4%) patients, respectively; they were classified as GSTM1+ and GSTT1+ genotype carriers with at least one sequenceable allele. In total, 21 GSTM1 variant (three exonic, 17 intronic, one 3'UTR) and 15 GSTT1 variants (two exonic, 12 intronic, one 3'UTR) were identified. The GSTT1 variants were not further analysed due to low inter-patient variability. After adjusting for biological sex, age and baseline serum alanine aminotransferase levels, neither GSTM1/GSTT1 genotypes nor the investigated GSTM1 variants (exonic: rs1056806, rs1065411; intronic: rs11101983, rs113639525, rs72989301, rs737497; upstream: rs412543) were significant predictors of DIH, observed in 14.3% (5/35) of patients.

Conclusions. This study provides novel insights into GSTM1 and GSTT1 genetic variability in patients with TB. While the incidence of DIH aligns with previous reports, no significant relationship was observed between the GSTM1/GSTT1 genotypes or the investigated GSTM1 variants and the development of this adverse drug reaction.