Meta-Analysis-Based Preliminary Exploration of the Connection between ATDILI and Schizophrenia by GSTM1/T1 Gene Polymorphisms

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 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.

抗结核药物存在多种不良反应，其中包括抗结核药物性肝损伤（anti-tuberculosis drug-induced liver injury, ATDILI）与精神障碍。现有研究表明，谷胱甘肽S-转移酶（glutathione S-transferase, GST）基因参与了抗结核药物性肝损伤及精神分裂症（schizophrenia, SCZ）的发病过程，由此可见，GST基因或可作为连接ATDILI与SCZ的分子纽带。但针对GSTM1/T1基因多态性与这两种疾病的关联研究，所得结果却存在较大分歧。我们先后在PubMed、ISI Web of Science、EMBASE、中国知网（Chinese National Knowledge Infrastructure, CNKI）以及中国生物医学文献数据库（Chinese BioMedical Literature Database）中检索病例-对照关联研究，随后针对20项已发表的关联研究开展荟萃分析：其中检验GSTM1与ATDILI关联的研究共纳入3146名受试者，检验GSTT1与ATDILI关联的研究纳入2587名受试者，检验GSTM1与SCZ关联的研究纳入2283名受试者，检验GSTT1与SCZ关联的研究纳入1116名受试者，以此评估GSTM1/T1基因多态性与ATDILI及SCZ的关联强度。固定效应模型分析结果显示，携带GSTM1阳性基因型的个体发生ATDILI的风险显著降低（风险比（risk ratio, RR）=0.81，95%置信区间（confidence interval, CI）：0.75~0.88，P=0.004）；而随机效应模型与固定效应模型均表明，携带GSTT1阳性基因型仅与SCZ发病风险升高显著相关（RR=1.17，95%CI：1.04~1.32，P=0.01），但该基因型与ATDILI的关联无统计学意义（固定效应模型下P=0.82）。此外，依据威尼斯标准（Venice criteria），上述显著关联结果得到了中等强度证据的支持。本研究结果证实，GSTM1可作为连接ATDILI与SCZ的遗传纽带，同时提示携带GSTM1缺失基因型的受试者，可能同时罹患ATDILI与SCZ。