人巨细胞病毒感染及其编码的microRNA与高血压人群脑卒中发病风险的前瞻性研究

Stroke has now been the leading cause of death in China, becoming a serious public health problem. It has been demonstrated that human cytomegalovirus (HCMV) infection is associated with stroke in previous studies, although the association between HCMV and stroke are still not validated in prospective study. In addition, a recent study demonstrated a novel link between HCMV infection and essential hypertension and revealed that an HCMV-encoded miRNA, hcmv-miRNA-UL112, was highly expressed in hypertensive patients. However, there is a relatively scarcity regarding the association between incident stroke and HCMV and their encoded miRNA in patients with hypertension. Therefore, we will perform a nested case-control study to validate the association in hypertensive patients who were free from cardiovascular disease using our cohort population (n=5107). During a median of 9-year follow-up period, we will identify more than 300 cases of newly stroke. Using risk-set sampling, we will select controls from among hypertensive patients who remained from stroke and matched them to case patients. HCMV-DNA level and HCMV-encoded miRNA expression will be detected by real-time quantitative polymerase chain reaction and TaqMan probe.Baeline characteristics were compared between case patients and controls using conditional Logistic-regression analysis. The present study would prompt a clue for further study about the etiology and mechanism of stroke. At the same time, we will add an important molecular epidemiological evidence to the literature for screening the high-risk hypertensive patients.

脑卒中已成为我国国民第一位死因，是重要的公共卫生问题。人群横断面研究显示，人巨细胞病毒（human cytomegalovirus，HCMV）感染与脑卒中相关，但是尚未有前瞻性研究证实。近期研究发现HCMV感染与高血压相关，HCMV编码miRNA-UL112的上调可能是高血压的触发因素。但目前在高血压人群中，HCMV感染及其编码的miRNA与脑卒中发病的关系未见相关报道。本研究拟利用已建立的高血压队列人群（n=5107），采用匹配巢式病例对照研究设计，以随访的新发脑卒中为病例组，同时采用危险集抽样随机选取与之匹配的非脑卒中患者为对照组，通过荧光实时定量PCR、TaqMan探针分别检测HCMV-DNA及其编码miRNA的差异表达，运用多元条件Logistic回归等统计方法分析HCMV感染及其编码的miRNA与脑卒中发病的关系。期望通过本项目，为脑卒中的病因及发病机制提供新线索。

全球范围内，脑卒中是大多数西方国家继冠心病和癌症之后的第三位死亡原因。但是近年来，脑卒中已成为我国居民死亡的首要原因。目前，全国每年因该病支出超过670亿元人民币，给国家和众多家庭造成沉重的经济负担。人群横断面研究显示，人巨细胞病毒（human cytomegalovirus，HCMV）感染与脑卒中相关，但是尚未有前瞻性研究证实。本项目采用巢式病例对照研究设计，选择基线无心脑血管疾病病史的5107例高血压患者（年龄≥35岁）为研究对象，经平均8.4年随访，发生510例新发脑卒中，发病率为12.97/1000人年。随机选取300例新发脑卒中作为病例组，采用危险集抽样（risk-set samping）方法，按照1:1比例在同一队列人群中选取对照组。结果发现，脑卒中患者HCMV阳性率远远高于对照组（12.7% vs. 5.7%; P=0.023）。通过多元条件Logistic回归分析，HCMV血清抗体阳性显著增加脑卒中发病风险（OR: 1.437, 95% CI: 1.023-2.020; P=0.037），进一步调整其他危险因素这种关联依旧存在（OR及95%CI：1.464,1.003-2.137；P=0.048）。进一步对脑卒中亚型分析发现，在调整其他潜在的混杂因素后，HCMV与出血性脑卒中相关联（OR: 1.718, 95% CI: 1.042-2.832），而与缺血性脑卒中并没有关联（OR: 0.450, 95% CI: 0.142-1.428）。另外，研究发现HCMV感染率在冠心病住院患者中明显高于对照组（28.6% vs 4.8%，P=0.023），且HCMV编码的miR-UL-112-5p在病例组与对照组间差异表达明显，可能是HCMV致心血管疾病的触发作用；同时，病例对照研究结果提示我国东北人群补体成分5的单核苷酸rs17611基因多态性与缺血性脑卒中相关；利用人群资料分析美国JNC-8指南关于老年人群高血压的靶标不适合我国人群。本课题的研究结果将为脑卒中发病机制提供新的研究方向，同时为包括脑卒中在内的心脑血管疾病的预防和管理提供潜在的新的治疗靶点，具有很好的科学价值和推广意义。. 项目共发表5篇学术论文，其中包括SCI收录3篇，标志着我国这一研究领域居于世界前沿。