药物性肝损伤是抗结核治疗中最常见、最严重的不良反应之一，严重时可致肝坏死甚至危及生命，是治疗中断及失败的重要原因。目前尚缺乏统一、有效的临床诊断和预测指标。国内外研究表明，遗传因素对抗结核治疗中药物性肝损伤的发生起到重要的影响作用，但既往研究大多存在样本量少、分型通量低、缺乏系统性分析等不足，至今未找到其有效基因标记。本课题中我们将在与国际严重药物不良反应联盟前期合作研究结果基础上，进一步扩大收集抗结核用药导致严重肝损伤的病例及其相应对照样本，采用序列捕获及二代测序的手段，通过基于信号通路的多基因系统性分析策略，深入挖掘中国汉族人群抗结核药物引起肝损伤相关基因标记，进而对其进行大样本量验证及体内外功能机制研究，筛选出准确有效的基因标记，基于先前建立的基因分型芯片技术，研制中国汉族人群抗结核药引起肝损伤的预测技术体系，为结核病患者的个体化用药及未来预防性药物的开发提供理论依据。

Anti-Tuberculosis Drug-Induced Liver Injury (ATLI) is one of the most common and serious adverse reactions in anti-tuberculosis therapy. It usually causes the interruption or failure of the therapy and leads to hepatonecrosis or death in the worst cases. At present, there is a lack of unified and effective marker for clinical diagnosis and prediction. Previous studies revealed that genetic factors may play an important role in the occurrence of ATLI. However, effective genetic markers of ATLI have not been found so far due to the limitation of sample size, genotyping through-put and the lack of systematic analysis in previous reports. In this project, based on the collaboration results with the International Serious Adverse Event Consortium (iSAEC), we are going to expand the sample size of ATLI cases and matched control samples, comprehensively discover the genetic markers of ATLI in Chinese Han population through pathway-based multi-gene systematically association analysis method by target enrichment and next generation sequencing. Then, effective genetic markers will be furtherly verified by larger sample validation, in vitro and in vivo function study. Based on our previously established microarray genotyping method, a prediction system of ATLI in Chinese Han population will be developed, which will lay the foundation for the personalized medicine of anti-tuberculosis drug and future preventive drug discovery in Chinese Han population.