醛固酮靶基因TSC22D3、CNK3、ADRBK1变异与不同肾素亚型高血压及Na+相关血压变异关系的研究

Epithelial sodium channel (ENaC) is one of the key regulators in the homeostasis of Na+ and blood pressure. Aldosterone target genes, such as TSC22D3,CNK3,and ADRBK1 are involved in blood pressure regulation through participating in ENaC degradation and expression. Therefore, we put forward a hypothesis: the genetic variations of TSC22D3,CNK3,and ADRBK1 may be involved in the pathogenesis of hypertension. To test this hypothesis, and considering the different genetic mechanism of different renin level hypertension subtypes, we will take this study through (1) according to the renin level in seat and standardized state; subjects were divided into three groups: low renin, high rennin and normal renin hypertension subtypes (all n=1500). 1500 individuals with normal blood pressure were selected as the control group. After genotyping the tags-SNPs of TSC22D3,CNK3,and ADRBK1 gene in above mentioned subjects, we will take a case - control analysis between the genetic variations of aldosterone target gene TSC22D3,CNK3,and ADRBK1 and different renin level hypertension subtypes. (2) In patients can tolerate intravenous saline load test, we will investigate the relationship among genetic variations of TSC22D3,CNK3,ADRBK1 and Na+-related blood pressure, renin and aldosterone level. (3) The variations positive associated with hypertension found in the above mentioned study will be take in further vitro functional studies. To reveal the genetic mechanism of hypertension and provide new ideas to the effective prevention and treatment of hypertension, the present study proceed to investigate the relationship between the genetic variations of the aldosterone target gene and hypertension from the whole system and pathway level.

醛固酮与上皮细胞钠通道（ENaC）在血压调节中发挥重要作用。醛固酮靶基因TSC22D3、ADRBK1、CNK3通过调节ENaC功能参与血压调节，且我们前期研究发现此通路中2个基因变异与高血压相关，故我们提出假说：上述基因变异可能与高血压及Na+相关血压变异相关。为验证此假说，且考虑到不同肾素亚型高血压遗传机制不同，拟通过：1）纳入低肾素、高肾素、正肾素亚型高血压各1500例，对照组为1500血压正常者，采用TaqMan PCR法对上述基因的标签SNPs基因型鉴定，研究其与不同肾素亚型高血压关系；2）对能耐受者行静脉盐水负荷试验，研究基因变异在Na+相关血压变异中的作用；3）对阳性关联SNPs行体外功能实验。本研究从"不同亚型高血压遗传机制不同"角度出发，从整个系统和通路水平研究醛固酮靶基因变异与高血压关系，可为揭示高血压遗传机制奠定基础，为高血压有效防治提供新思路和治疗靶点

醛固酮与上皮细胞钠通道（ENaC）在钠水调节中发挥重要作用。醛固酮靶基因TSC22D3、CNK3、ADRBK1通过调节ENaC 通路参与血压调节。本研究从“不同亚型高血压遗传机制不同”角度出发，从整个系统和通路水平研究醛固酮靶基因变异与高血压关系，为揭示高血压遗传机制奠定基础。.该项目是通过比较醛固酮靶基因变异位点在低肾素、正常肾素、高肾素类型高血压患者的分布特点，探讨基因变异与不同肾素类型高血压的关联关系；通过对阳性关联SNPs在细胞分子水平进行验证。课题组对CNK3的rs4870285,rs9397716,rs9322467在高血压组及对照组共计2290份DNA中进行基因型分型，显示这三个位点在病例组与对照组之间没有统计学差异。利用TaqMan PCR技术对ADRBK1基因rs1894111, rs4930416, rs7127431, rs12286664 和rs3730147进行基因型鉴定并关联研究，示rs1894111位点CT+TT基因型可能是高血压的危险因素；rs1894111与汉族低肾素型高血压有关，其CC基因更易发生低肾素型高血压。就TSC22D3基因由于数据库中没有对人类有意义的TSC22D3的TagSNPs，为此，研究组采用典型病例组---低肾素高血压患者96个样本，进行以启动子、3个外显子功能区域以及3’-UTR区测序，发现在3’UTR区和Promoter区有4个新的SNP位点，但变异频率低。再次在96例高肾素高血压患者以及96例原发性醛固酮增多症确诊的高血压患者进行测序验证，三组间该基因变异位点分布无统计学差异。.通过该项目课题组建立了不同肾素亚型高血压的临床表型数据库及DNA样本库；探索了醛固酮靶基因TSC22D3、CNK3、ADRBK1基因变异与不同肾素亚型高血压的相关性，结果显示ADRBK1基因变异与原发性高血压关系密切；而CNK3基因多态性、TSC22D3基因变异与高血压机制需要进一步探讨。

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