cZNF609/mir-615-5p/靶基因信号通路参与高血压及脑卒中机制的分子流行病学研究

Recently, the research of endothelial dysfunction and epigenetics, which is closely related to the cardiovascular diseases, has become a hot spot. The cZNF609/mir-615-5p/target genes signaling pathway plays an important role in the proliferation and migration of vascular endothelial cells as well as participates in the pathological process of atherosclerosis. Our previous study found that in peripheral blood monocytes cZNF609 expression of ischemic stroke (IS) patients was significantly lower than that of the matched hypertension cases, whereas increased significantly in 5-7 days of stroke onset. The gene expression levels of Tie2 and IGF2 were down-regulated in IS patients, while the gene expression level of MEF2A was up-regulated in 5-7 days of stroke onset. The results showed that the signal pathway may be involved in hypertension and stroke and its process of prognosis. Based on previous experiments, we will explore the molecular mechanism of cZNF609/mir-615-5p/target gene signaling pathway in the pathogenesis of hypertension and stroke by detecting the gene expression and protein levels of mir-615-5p and target genes in a larger sample size. It provides new molecular markers for the clinical efficacy and prognosis of hypertension and stroke.

近年来，与心血管密切相关的内皮功能障碍及表观遗传学研究成为当前热点。其中，cZNF609/mir-615-5p/靶基因信号通路在血管内皮细胞生长、迁移和维持血管形态稳定中发挥重要作用，并参与动脉粥样硬化病理进程。本课题组前期研究发现，缺血性脑卒中人群外周血单核细胞中cZNF609表达水平显著低于高血压人群，而在脑卒中预后又恢复上调。此外，相对脑卒中首发人群，其预后阶段靶基因Tie2和IGF2水平下调，MEF2A水平上调。表明该信号通路可能参与高血压和脑卒中发病及预后过程。本课题拟在前期基础上，进一步增加健康对照，并扩大样本，检测mir-615-5p和靶基因mRNA及蛋白水平，同时分析靶基因遗传变异与血压变化及高血压和脑卒中的关系，探讨cZNF609/mir-615-5p/靶基因信号通路在高血压和缺血性脑卒中发病中的分子机制研究，为高血压及脑卒中临床疗效及预后评估提供新的分子标志物。

脑卒中作为我国首位死因严重威胁居民健康，高血压是其主要危险因素，发现新的易感基因和位点有助于了解高血压和脑卒中潜在遗传机制。本研究采用以人群为基础的大样本病例对照研究和队列研究相结合，系统探讨cZNF609/mir-615-5P/靶基因信号通路Tie2、MEF2A及IGF2基因遗传变异、表达水平与高血压和缺血性脑卒中的关系。结果显示，Tie2基因rs603085和IGF2基因rs3741211、rs10770125位点变异与高血压患病风险显著相关。IGF2基因rs10770125-rs2585单体型G-T与高血压低患病风险相关，rs3741211位点不同基因型收缩压水平存在差异，并在≤55岁的人群中降低了高血压的发病风险。此外，IGF2基因的rs2585与缺血性脑卒中患病风险存在正相关，rs3741211、rs2585与大动脉粥样硬化型脑卒中患病风险也存在正相关。MEF2A基因rs2292288-rs3743248单体型G-T以及IGF2基因rs10770125-rs2585单体型A-C/G-T与缺血性脑卒中患病风险增加相关。Tie2基因rs133480变异增加缺血性脑卒中发病和死亡风险。同时也发现cZNF609表达水平在高血压和缺血性脑卒中人群中均显著降低，其与收缩压和舒张压呈负相关。IGF2表达水平在缺血性脑卒中人群中降低，而Tie2表达水平显著升高。上述研究结果初步证实课题的科学假说，明确了cZNF609、Tie2、MEF2A、IGF2与高血压和缺血性脑卒中发生发展密切相关，在人群水平上阐明了cZNF609 /mir-615-5p /靶基因Tie2、MEF2A、IGF2对高血压和缺血性脑卒中发病的分子机制，为高血压及脑卒中的防治提供重要流行病学证据。