TGF-β1及其受体的抑制分子信号通路对高血压及脑卒中的作用及机制研究

At present, stroke is the leading cause of the death for the Chinese population and hypertension is the main risk factor for stroke. Animal studies suggest that transforming growth factor β1 (TGF- β1) and its receptors are involved in vascular growth and remodeling which plays an important role in blood pressure homeostasis. Previous research reported EMILIN1 and FBN1, which encoding vascular elasticity fibrin and regulating the function of TGF- β1, and TGF- β1 receptor genes were significantly associated with hypertension as well as TGF- β1 and systolic and diastolic blood pressure were positively correlated. The results indicate that TGF- β1 may be involved in the pathogenesis of human hypertension. Our pre-experimental analysis found that the TGF- β1 expression level showed a significant elevation with a trend in the normotensive, hypertension and stroke population. On this basis, we put forward the scientific hypothesis: TGF- β1 may be involved in the process of hypertensive cerebral stroke and inhibition of TGF- β1 would help to control blood pressure and reduce the risk of stroke disease. This project will conduct a study combining a case-control and a cohort studies, to analyze the relationship between the TGF- β1, its receptor inhibiting protein HtrA1 and AGTR2 and the genetic variants and the changes of blood pressure, hypertension and stroke. The expected results would lay a foundation for the etiological mechanism of hypertension and its complication of stroke and provide scientific basis for the disease prevention and drug targets screening.

目前脑卒中为国人首位死因，高血压是其主要危险因素。血管发育与重塑对血压稳态具有重要作用，有动物研究提示转化生长因子β1 (TGF-β1)与其受体参与其中。前期研究报道编码血管弹性纤维蛋白且对TGF-β1有调控作用的EMILIN1、FBN1及TGF-β1受体基因变异与高血压存在显著关联，且TGF-β1与收缩压和舒张压呈正相关，表明TGF-β1可能参与人体高血压发病机制。预实验分析发现正常人群、高血压和脑卒中人群TGF-β1呈现趋势性升高，在此基础上，我们提出科学假说：TGF-β1可能参与高血压并发脑卒中进程，抑制TGF-β1水平将有助于控制血压而降低脑卒中发病风险。本课题以病例-对照研究和队列研究相结合，分析TGF-β1及其受体抑制蛋白HtrA1、AGTR2表达水平、基因变异与血压变化、高血压和脑卒中的关系，为阐明高血压及其并发脑卒中的病因机制建立新思路，并为疾病防制和药物靶点筛选提供依据。

本课题通过高血压和脑卒中的病例-对照研究和队列研究，对TGF-β1抑制分子信号通路HtrA1、AGTR1、AGTR2、BDNF和TGFBR3基因变异与高血压及其并发脑卒中的关系进行探讨，研究结果显示，在血压正常人群中TGF-β1水平与收缩压和舒张压均存在显著相关存在，在高血压人群中，TGF-β1水平呈高表达状态，提示但其功能可能受到抑制。队列研究分析发现，HtrA1基因rs2268350 位点变异显著影响脑卒中发病风险，与吸烟、饮酒间存在显著交互作用，且与吸烟的交互作用显著影响外周血单核细胞HtrA1 mRNA表达。遗传关联分析发现，AGTR1基因rs1492100和rs2933249变异与高血压发病风险显著相关；rs1492100与缺血性脑卒中发病风险增加存在显著关联，亚组分析发现，在女性人群中rs10935724与脑卒中发病风险显著相关；在男性、不吸烟、饮酒人群中，rs2933249、rs1492100和rs10935724变异分别与脑卒中发病风险增加呈正关联；在年龄>55岁的人群、吸烟人群中，AGTR2基因rs5194、rs3736556位点变异分别与高血压患病风险存在显著正相关；BDNF基因rs10835210、rs6265位点变异与高血压患病风险存在负关联，而rs1519480、rs10835210和rs1229106位点变异与缺血性脑卒中患病风险升高相。此外，对TGF-β1及其受体基因关联分析发现，TGFBR3基因rs12032588 G>T变异与高血压患病风险增加相关，对TGFBR1（前期研究）和TGFBR3高血压相关风险等位基因加权计算遗传风险评分（GRS）分析发现，高血压的患病风险随GRS上升而显著增加；队列研究中发现，TGFBR1基因rs10512263、TGFBR2基因rs3773645、TGFBR3基因rs1804506和TGFBRAP1基因rs17030766位点变异均可增加缺血性脑卒中发病风险，上述关联在较大样本的病例对照人群中得到进一步重复验证。这些研究结果在人群水平上验证了本课题的科学假说，研究发现表明高血压人群中TGF-β1调节血压的功能受到抑制，TGF-β1受体基因和TGF-β1抑制分子信号通路多基因变异不同程度参与了高血压和缺血性脑卒中的发病机制；结果将有助于深入探讨高血压及其并发脑卒中的分子机制。