To systematically study the susceptible genetic markers for liver injury induced by anti-tuberculosis drugs in the Chinese population, 109 genes related to drug metabolism, transport and immunity were captured by Haloplex capture technique from DNA samples of 41 patients with liver injury induced by anti-tuberculosis drugs and 39 healthy controls, and sequenced completely. Association study was conducted using Plink software. To verify the significant candidate SNPs, the χ 2 study was expanded to the control group from the 1000-person Genome Project of the East Asian population. SIFT and Polyphen2 software were used to predict the functional significance of the associated SNPs. Our results identified the UGT1A4 rs2011404 (χ 2 = 4.6809, P = 0.0305) as a susceptible genetic marker for liver injury induced by anti-tuberculosis drugs, and rs2011404 mutation might contribute to UGT1A4 protein dysfunction. This study has provided a potentially useful reference for establishing the precision medicine in rational uses of anti-tuberculosis drugs in the clinic.
为系统性研究中国人群中抗结核药物引发肝损伤的易感基因标记,本研究以41例抗结核药物引发肝损伤的病人和39例健康对照为研究对象,采用Haloplex捕获测序的方法对其基因组中药物代谢、转运和免疫相关通路的109个基因进行靶向测序。用Plink软件对DNA突变位点与肝损伤的发生进行关联分析,以千人基因组计划东亚人群作为对照组,对显著性位点进行验证,并用SIFT和Polyphen2软件对预测显著关联的位点进行功能预测。结果发现UGT1A4 rs2011404 (χ 2 = 4.6809, P =0.0305)是抗结核药物引发的肝损伤的易感基因标记,且rs2011404突变可能引起UGT1A4蛋白的功能障碍。本研究为临床上对抗结核药物的合理用药提供了有益的参考。.
Keywords: UGT1A4; anti-tuberculosis drug; association study; liver injury.