Abstract
Anti-tuberculosis drugs have some adverse effects such as anti-tuberculosis drug-induced liver injury (ATDILI) and mental disorders. The involvement of glutathione S-transferase (GST) genes in pathogenesis of ATDILI or schizophrenia (SCZ) has been reported. Therefore, GST genes may exemplify molecular connectors between ATDILI and SCZ. However, association studies of GSTM1/T1 polymorphisms with these two diseases have yielded conflicting results. After searching case-control association studies in PubMed, ISI Web of Science, EMBASE, Chinese National Knowledge Infrastructure (CNKI), and Chinese BioMedical Literature Database, we performed meta-analyses across a total of 20 published association studies on 3146 subjects for the association of GSTM1 and ATDILI, 2587 for the GSTT1-ATDILI association, 2283 for GSTM1-SCZ and 1116 for GSTT1-SCZ to test the associations of GSTM1/T1 polymorphisms with ATDILI and SCZ. The GSTM1 present genotype was significantly associated with decreased risks of ATDILI (risk ratio(RR): 0.81, 95% confidence interval (CI): 0.75–0.88, P < 0.0001) and SCZ (RR: 0.88, 95%CI: 0.80–0.96, P = 0.004) according to the fixed-effect model, while the GSTT1 present genotype was significantly associated only with a high risk of SCZ (RR: 1.17, 95%CI: 1.04–1.32, P = 0.01) according to both the random- and fixed-effect models, but not with ATDILI (P = 0.82) according to the fixed-effect model. Moreover, these significant results were supported with moderate evidence according to the Venice criteria. These results indicate that GSTM1 represents a genetic connection between ATDILI and SCZ, and suggest that ATDILI and SCZ may be co-occurring for the subjects with GSTM1 null genotype.
Highlights
Tuberculosis (TB) remains a devastating disease and the major leading cause of death worldwide
The current study is the first to explore the molecular connection between SCZ and anti-tuberculosis drug-induced liver injury (ATDILI) by glutathione S-transferase (GST) genes via large-scale meta-analyses [28]
We found that the glutathione S-transferase Mu-1 (GSTM1) present genotype was significantly associated with decreased risks of ATDILI (P < 0.0001) and SCZ (P = 0.004), whereas the glutathione S-transferase theta-1 (GSTT1) present genotype was only significantly associated with a high risk of SCZ (P = 0.01), but not ATDILI (P = 0.82); these significant results were supported by ‘moderate’ evidence according to the Venice criteria
Summary
Tuberculosis (TB) remains a devastating disease and the major leading cause of death worldwide. First-line therapeutic agents, such as isoniazid (INH), rifampin (RIF) and pyrazinamide (PZA) are effective treatments for TB [2]. These drugs can induce various adverse effects, among which anti-tuberculosis drug-induced liver injury (ATDILI) is the most common and serious side effect [3,4,5]. ATDILI, caused by the drugs’ reactive metabolites instead of their direct toxicities, has been widely suggested to be a Glutathione S-transferases (GSTs) related disease [6,7,8]. Several lines of evidence have suggested that GSTs can modulate the progress of SCZ, given that GSTs and glutathione-related enzymes can detoxify oxidative damage products [12,13,14]. GST genes are hypothesized to play an important role in both ATDILI and SCZ, acting as ‘molecular bridges’ between these two diseases
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