UGT1A1和CYP2E1基因多态性与一线抗结核药物所致肝损伤易感性研究  

Association between UGT1A1 and CYP2E1 gene polymorphisms and susceptibility of first-line anti-tuberculous drug induced liver injury

作　　者：孙勤[1] 刘轾彬[1] 沙巍[1] 肖和平[1] SUN Qin LIU Zhi-bin SHA Wei XIAO He-ping(Clinic and Research Center of Tuberculosis, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shang- hai 200433, Chin)

机构地区：[1]同济大学附属上海市肺科医院结核病临床研究中心上海市结核(肺)重点实验室,200433

出　　处：《中国防痨杂志》2017年第10期1073-1079,共7页Chinese Journal of Antituberculosis

基　　金：国家自然科学基金青年项目（81400006）;上海市浦江人才计划（16PJD041）;国家科技重大专项（2014ZX09507008）

摘　　要：目的 探讨Ⅰ相药物代谢酶的细胞色素P450 2E1 （CYP2E1）和Ⅱ相药物代谢酶的尿苷二磷酸葡萄糖醛酸转移酶1A1 （UGT1A1）基因多态性与抗结核药物所致肝损伤（ATDILI）易感性的相关性.方法 收集2012年3月至2015年12月期间在上海市肺科医院住院的经一线抗结核药物治疗后发生肝损伤的患者461例（为ATDILI组）,与同期住院未发生肝损伤的患者466例（为非ATDILI组）;对两组患者的临床信息进行统计分析,同时采集两组患者的外周静脉血进行基因组DNA提取和基因分析;采用生物信息统计学方法筛选出与CYP2E1和UGT1A1基因14个标签单核苷酸多态性位点（tagSNP;Hardy-Weinberg平衡P值＞0.001,最小等位基因频率＞0.1,r2＞0.8）,应用SNPscanTM多重SNP分型技术对研究对象DNA样本进行基因分型,分析这些位点基因型和单倍型在ATDILI组和非ATDILI组之间的频率及分布差异,分析在显性、隐性和加性遗传模型下各个SNP位点与ATDILI易感性的关联性.结果 所有位点的等位基因频率分布均符合Hardy-Weinberg平衡.ATDILI组UGT1A1基因rs4148323位点AA基因型频率（1.7％,8/461）明显低于非ATDILI组（4.3％,20/466）,显示携带rs4148323位点AA基因型可降低ATDILI患病的风险（OR=0.37,95％CI=0.16～0.86,P=0.020）;在隐形遗传模型下,携带该位点AA基因型可明显降低ATDILI患病的风险（OR=0.39,95％CI=0.17～0.90,P=0.023）;在加性遗传模型下,携带该位点突变型A等位基因可明显降低ATDILI患病风险（OR=0.79,95 ％％CI=0.63～0.99,P=0.040）.单倍型分析显示：ATDILI组UGT1A1基因ATG单倍型频率（0.19）明显低于非ATDILI组（0.22）,说明携带ATG单倍型可明显降低ATDILI患病的风险（OR=0.79,95 ％CI=0.63～0.99,P=0.045）.未发现其他位点与ATDILI的相关性.结论 UGT1A1基因为中国汉族人群ATDILI的易感基因.Objective To explore the association between a phase Ⅰ drug metabolizing enzyme encoding gene Cytodrome P450 2E1 （CYP2E1） and a phase Ⅱ drug metabolizing enzyme encoding gene UDP-glucuronosyltransferase 1 （UGT1A1） and susceptibility of first-line anti-tuberculous drug induced liver injury （ATDILI）.Methods Four hundred and sixty-one patients with ATDILI and 466 patients with non-ATDILI who were hospitalized in Shanghai Pulmonary Hospital from March 2012 to December 2015 were included in this study.The clinical characteristics of the two groups were compared.A whole blood sample was collected from each patient for genomic DNA extraction and genotype analysis.Fourteen tagSNPs of UGT1A1 and CYP2E1 gene were selected using systematic bioinformatic analysis （Hardy-Weinberg Equilibrium （HWE）-P〉0.001,Minimum-allele Frequency 〉0.1,r2〉0.8）.We performed a population based case-control study to genotype the 14 tagSNPs of UGT1A1 and CYP2E1 gene using SNPscanTM technology.The genotype and haplotype frequencies were detected and compared between the two groups.Three genetic models including dominant,recessive and additive model were used to analyze the association between all the selected SNPs polymorphisms and susceptibility of ATDILI.Results All the alleles frequencies of these SNPs were in HWE.We found that in ATDILI group,the frequency of UGT1A1 rs4148323 AA genotype （1.7%,8/461） was significantly lower than that in non ATDILI group （4.3%,20/466）,which indicated that the rs4148323 A/A carriers had a decreased risk for developing ATDILI （OR=0.37,95%CI=0.16-0.86,P=0.020）.In recessive model,rs4148323 A/A was also associated with a decreased risk for ATDILI （OR=0.39,95 %CI=0.17-0.90,P=0.023）.In additive model,allele of rs4148323 minor A was found to be associated with risk reduction with ATDILI （OR =0.79,95 % CI=0.63 0.99,P=0.040）.Haplotype analysis showed the frequency of ATG haplotype of UGT1A1 gene in ATDILI group （0.19） were significantly lower than that in non ATDILI gr

关 键 词：结核 药物性肝损伤 多态性 单核苷酸 疾病遗传易感性 

分 类 号：R734.2[医药卫生—肿瘤]