可溶性corin与血压盐敏感性的关系及遗传机制研究

Salt reduction is an important strategy for prevention and control of hypertension and cardiovascular diseases. Blood pressure responses to salt intake vary among individuals, which is defined as salt-sensitivity of blood pressure, but the mechanism of salt-sensitivity has not been fully understood. Studies conducted among animal models have identified that CORIN-deficiency induced sodium retention, and further led to salt-sensitive hypertension. Considering the effect of corin in blood pressure regulation, results from population study will provide scientific evidence for hypertension prevention and treatment. By far, the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study is the largest dietary intervention study. The proposed project is aimed to investigate the relationship and potential mechanism of corin and salt-sensitivity of blood pressure in the GenSalt study. The project will integrate population study, genome-wide association study and functional study. First, we will examine differences of corin and blood pressure between baseline examination (NaCl: 10-19 g/day) and low-sodium intervention stage (NaCl: 3 g/day) among 2604 participants and investigate the association of corin changes with salt-sensitivity of blood pressure. Second, we will conduct gene-environment interaction analysis to identify important variants or loci, which might modify the relationship between corin changes and salt-sensitivity of blood pressure. Third, functional study of identified variants or loci will be performed to illustrate their potential mechanism in blood pressure regulation. The proposed project is the first to investigate the relationship between corin and salt-sensitivity of blood pressure in humans. Findings from the current project will provide evidence on mechanism of blood pressure regulation, and will be of great significance on precision dietary intervention and hypertension management.

限盐是控制血压和防治心血管疾病的重要措施。盐敏感性存在个体差异，且机制尚未完全阐明。动物实验表明，Corin基因缺陷引起钠潴留，导致盐敏感性高血压，提示corin可能成为高血压防治的重要靶点。但有关corin和盐敏感性的人群证据十分缺乏。GenSalt研究为本课题组前期开展的全球规模最大的人群膳食盐干预试验。本项目拟在2604例研究对象中，观察由基线阶段（NaCl：10-19克/天）进入低盐膳食干预阶段（NaCl：3克/天）后，可溶性corin 和血压水平的变化，探讨corin水平变化与血压盐敏感性的关系；通过遗传-环境交互作用分析，明确基因与corin共同作用对血压调节的影响；并通过生物学功能研究，探索重要易感区域在血压调节中的分子机制。本研究首次在人群水平探讨可溶性corin与血压盐敏感性的关系，将为阐明血压调节的机制提供科学依据，对于制定精准化生活方式干预和降压治疗策略具有重要意义。

高血压是造成我国居民心血管疾病负担和死亡的首要危险因素，明确高血压的高危人群、开展针对高血压的人群防治是心血管疾病一级预防的有效手段。限盐是高血压防控的重要措施之一，然而不同特征人群对血压盐摄入的反应性存在差别，关注影响水盐代谢和血压调节的遗传和环境因素对于高血压防控、降低心血管疾病负担具有重要意义。.本项目依托于前期采用家系研究设计的GenSalt膳食干预和GenSalt随访资料开展研究，选择研究对象共1906名开展研究。首先，通过筛选corin蛋白编码基因和环鸟苷酸依赖的蛋白激酶（PRKG）相关基因的标签SNP 50个和213个位点，开展遗传与血压盐敏感性的关联分析，发现CORIN基因上的10个SNP可能与血压盐敏感性存在关联，随着PRKG1基因rs10997916位点T等位基因个数增加，血压的低盐敏感性下降。其次，利用长期随访数据分析发现，NADPH氧化酶相关基因NCF2与收缩压的长期变化相关。然后，通过系统综述及大样本人群数据分析的方法，明确了温度变化、配偶吸烟等影响血压水平和高血压患病的重要环境危险因素。本课题研究结果为针对个体和家庭开展高血压防控和人群干预提供了新的科学证据。.在本课题资助下，目前已经在国际高血压领域权威杂志Hypertension等发表英文论文6篇，本人为第一作者2篇、通讯作者1篇；获得教育部自然科学二等奖1项。