不同干扰素应答慢性乙型肝炎患者的基因组DNA甲基化谱差异分析  

Differential analysis of DNA methylation profile between responder and nonresponder of interferon treatment in chronic hepatitis B patients

作　　者：邬敏[1,2] 张小楠[1] 陈捷亮[2] 袁正宏[1,2] 

机构地区：[1]上海市(复旦大学附属)公共卫生临床中心,上海201508 [2]复旦大学基础医学院教育部/卫生部医学分子病毒学重点实验室,上海200032

出　　处：《微生物与感染》2014年第4期217-223,共7页Journal of Microbes and Infections

基　　金："十二五"国家科技重大专项(2012ZX10002007-001-002)

摘　　要：α干扰素,包括长效干扰素——聚乙醇化α干扰素(PEG-IFNα),是临床用以治疗慢性乙型肝炎的首选药物。但干扰素治疗通常只能在有限的患者中获得完全应答。目前干扰素治疗应答相关指标预测的灵敏度与特异度远未令人满意,因此继续寻找潜在的与干扰素疗效预测相关的分子标记仍是一个十分有意义的工作。为探讨慢性乙型肝炎患者基因组DNA甲基化状态与干扰素治疗疗效的关系,本研究采用RocheNimbleGen人甲基化DNA免疫共沉淀-芯片(MeDIP-chip)技术,分析20例不同干扰素疗效慢性乙型肝炎患者的血浆基因组启动子甲基化谱差异,并利用MeDIP-定量聚合酶链反应(MeDIP-qPCR)检验部分基因启动子区域DNA甲基化的水平。结果显示,与快速应答组相比,无应答组中有588个基因启动子区甲基化水平存在显著差异(P<0.05)。这些基因主要涉及多个信号通路,即钙离子信号通路、细胞周期调节通路、肝脏代谢相关通路等。MeDIP-qPCR验证与芯片结果的一致性超过80%。本研究为探讨差异甲基化基因在干扰素应答中的作用及发现潜在的预测干扰素疗效的血液分子标记奠定了基础。Interferonα （IFN‐α） therapy remains a mainstay of treatment of chronic hepatitis B .However , sustained remission rates remain relatively low ,and the search for factors important for response to therapy continues .In order to study the relationship between the genomic DNA methylation profile and response to interferon therapy in chronic hepatitis B ,pretreatment plasma samples of 20 patients with chronic hepatitis B （CHB） receiving pegylated interferon α （PEG‐IFNα） treatment were subjected to DNA methylation analyses using Roche‐NimbleGen Human DNA Methylation 2 .1M Deluxe Promoter v2 Array .Methylated＆amp;nbsp;DNA immunoprecipitation‐quantitative polymerase chain reaction （MeDIP‐qPCR ） was used to further validate the methylation status of specific genes . A total of 588 genes were found to show differential methylation in interferon nonresponse group as compared with the rapid response group .These differential methylated genes were involved in several signaling pathways ,such as the calcium signaling pathway ,cell cycle and liver metabolism .The methylation levels of several genes in the two groups were confirmed by MeDIP‐qPCR ,consistent with the results of the MeDIP‐chip study . Our data provide a foundation for future study on the functions of differential methylated genes in interferon response as well as the discovery of new molecular markers for predicting prognosis of interferon therapy in CHB patients .

关 键 词：乙型肝炎病毒 干扰素 甲基化 DNA免疫共沉淀-芯片 

分 类 号：R512.62[医药卫生—内科学]