KLFs信号通路遗传变异与高血压和脑卒中关系的分子流行病学研究

It is found that the variations of KLFs and FOXO1 gene are significantly associated with the degree of carotid atherosclerosis. Herein we raise the scientific hypothesis that FOXO1 and KLFs may participate in the pathogenesis of hypertension and stroke. Recently our study found that there are significant differences between the expression levels of FOXO1 and 8 kinds of KLFs mRNA in peripheral blood mononuclear cells of ischemic stroke patients and hypertensive subjects, and the differential FOXO1 and 7 KLFs mRNA are significantly associated with the prognosis of ischemic stroke. On this basis, we would conduct a case-control study to evaluate the association of the variants in FOXO1 and 8 kind KLFs candidate and hypertension, stroke as well as its prognosis and further verify the positive loci in a follow-up study. The expected results would help to test the hypothesis and to establish a new foundation for elucidating the etiology of hypertension and stroke. The findings would provide a theoretical basis and sensitive index for disease control and drug target screening.

脑卒中为目前我国居民首位死因，高血压是其首要可干预危险因素。动物研究提示，锌指蛋白转录因子（KLFs）及其信号调控蛋白叉头转录因子1（FOXO1）可调控转化生长因子β1调节内皮细胞生长，参与血管发育与重塑以及血压调节。研究发现，KLFs与FOXO1基因变异与颈动脉粥样硬化程度密切相关。本课题以FOXO1与KLFs可能参与高血压并发脑卒中的发病机制为科学假说。我们近期研究发现缺血性脑卒中患者和高血压对象外周单核细胞FOXO1和8种KLFs mRNA表达水平存在显著差异；且FOXO1及7种KLFs mRNA与缺血性卒中预后显著关联。在此基础上，本课题拟采用病例-对照研究分析FOXO1和8种KLFs遗传变异与高血压及其并发脑卒中的关系，并通过随访研究加以验证。研究结果将有助于验证本课题的科学假说，为进一步阐明高血压并发脑卒中的病因机制；并为疾病防制和药物靶点筛选提供理论依据和敏感指标。

脑卒中是我国伤残调整生命年的首要原因，而高血压是其首要归因危险因素。研究表明锌指转录因子蛋白（KLFs）及其信号调控蛋白叉头转录因子1（FOXO1）可参与血管发育、重塑及血压调节，可能参与缺血性脑卒中和高血压的发病机制。本课题基于人群结合病例-对照研究和队列研究探讨KLFs和FOXO1 外周血白细胞mRNA表达水平及遗传变异与缺血性脑卒中、高血压及远期预后的关系。结果显示，经两阶段缺血性脑卒中病例对照研究验证，KLF3、KLF4、KLF5、KLF12和KLF13 mRNA表达水平与缺血性脑卒中患病风险存在关联。联合多个基因mRNA表达水平构建评分相较于传统危险因素而言，可显著提升缺血性脑卒中的判别效能。KLF4、KLF5和KLF12 mRNA表达水平可能与空腹血糖、总胆固醇和低密度脂蛋白胆固醇存在相关性。KLF3基因中rs7147 A>G变异、KLF4基因中rs2236599 C>T变异、KLF5基因中rs11841945 G>C变异和KLF12基因中rs1998571 C>G、rs1426 T>C变异与缺血性脑卒中患病存在关联。KLF12基因的 mRNA表达水平及遗传变异（rs12874102 A>G变异、rs9543429 C>T变异、rs7993625 C>T变异）与缺血性脑卒中的预后状况均存在关联。另外，KLF4、KLF12和KLF13 mRNA表达水平与高血压患病及血压水平存在关联，KLF3、KLF5和KLF12基因遗传变异与高血压患病存在关联，KLF5和KLF12基因遗传变异与高血压发病存在关联，KLF12基因遗传变异与高血压病例全因死亡及新发脑卒中存在关联，KLF3和KLF12遗传变异与血压值存在关联。本课题结果将为阐明缺血性脑卒中及高血压的病因机制提供科学依据，并有助于为缺血性脑卒中及高血压的临床诊治及预后评价研究提供新的思路和敏感指标。