基于转录组学的抗结核药物肝损伤生物标志研究

李晨; 王彦琴; 霍倩; 帅怡; 陶功华; 洪新宇; 肖萍

doi:10.19428/j.cnki.sjpm.2023.22327

基于转录组学的抗结核药物肝损伤生物标志研究

Transcriptional analysis on biomarkers of liver injury induced by anti-tuberculosis drugs

摘要

摘要:
目的利用转录组芯片技术探索抗结核的药物肝损伤（DILI）的生物标志。
方法对上海市定点医院首次接受抗结核药物治疗的152例病例进行6个月的跟踪研究。在第0、2、4、8、12、24周采集血液样本，根据临床生化指标将研究人群分为肝损伤病例（DILI组，34例）和对照病例（对照组，118例），对两组间各影响因素进行单因素分析。采取1∶1匹配的病例对照研究，对13对DILI组/对照组病例的RNA样本进行全转录组mRNA芯片测序，通过Hotelling’s T²值排序法和STEM基因趋势分析软件筛选差异表达基因（DEGs），对DEGs进行功能富集和通路分析。
结果在152例接受抗结核药物治疗的临床病例中，患者体质量是抗结核药物肝毒性发生的危险因素。基于13对DILI组/对照组6个时间点的mRNA芯片分析，Hotelling’s T²值排序法筛选到513个DEGs，富集在基因本体（GO）的32条注释和KEGG基因数据库的10个通路中。STEM基因趋势分析软件筛选到1个差异表达模式，富集在GO的2条生物过程注释。其中关键基因AIM2、CD86、CXCL10和非编码RNA SCARNA10、SNHG10、SNORD105为抗结核药物肝毒性发生的潜在生物标志。
结论对抗结核DILI人群的生物标志研究，识别了与肝毒性发生相关的生物学途径，并获得一组与DILI相关的关键基因，为DILI发生机制研究及寻找更加早期、敏感的肝毒性发生生物标志提供了参考。

Abstract:
Objective The study utilized human transcriptome microarray to explore biomarkers for diagnosing drug-induced liver injury （DILI） caused by anti-tuberculosis drugs.
Methods A 6-month follow-up study was conducted on 152 patients treated with anti-tuberculosis drugs in designated hospitals in Shanghai. The blood samples were collected at the 0， 2， 4， 8， 12 and 24 weeks after treatment. According to the clinical biochemical indicators， the research subjects were divided into DILI cases （34 cases） and Control cases （118 cases）. Single factor analysis was conducted on the influencing factors between the two groups. In a 1∶1 matched DILI-control study， RNA samples of 13 pairs of cases were sequenced by the whole transcript expression mRNA array. Differentially expressed genes （DEGs） were screened by Hotelling's T² value sequencing and the expression trend analysis of genes by STEM （short-time series expression miner）， and the functional enrichment and pathway analysis of DEGs were carried out.
Results In total 152 clinical cases， weight of patients was a risk factor for the occurrence of hepatotoxicity caused by anti-tuberculous drugs. Based on the analysis results of mRNA array， 513 DEGs were screened by Hotelling's T² value sequencing method， which were enriched in 32 annotations of GO （Gene Ontology） analysis and 10 pathways of KEGG （Kyoto encyclopedia of genes and genomes） analysis. One differential expression pattern was screened by STEM， which was enriched in 2 biological process notes of GO. Among them， the key genes AIM2， CD86， CXCL10 and non-coding RNAs SCARNA10， SNHG10 and SNORD105 are potential biomarkers of DILI caused by anti-tuberculosis drugs.
Conclusion In this research for biomarkers conducted on cases with liver injury caused by anti-tuberculosis drugs， biological pathways associated with hepatotoxicity are identified and a series of key genes related with drug-induced liver injury are found， which provides the basis for mechanism study and searching for earlier and more sensitive biomarkers.

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