Genetics of Human Hypertension

描述（由申请人提供）：基因革命的预期结果是更个性化的治疗和预防策略。在过去的十年中，在高血压SCOR （HTN）的支持下，我们建立了一个大型队列，对几个关键候选基因进行了仔细的表型表征和基因分型。我们有强有力的证据表明，这些基因中的许多识别同质亚群，理论上应该对特定治疗有反应。合乎逻辑的下一步是测试这些期望。我们的重点是导致HTN及其相关心血管（CV）风险的激素因素的遗传基础。从这些研究中，我们已经确定了高血压人群的几种特定的中间表型。两个是本提案的重点。共同特征是：1)钠饮食改变时醛固酮（ALDO）分泌调节异常；2)盐敏感血压（BP）。第一种中间表型，包括25-30%的高血压患者，被称为非调节型。它们的缺陷是当钠摄入量在肾上腺和血管中改变时，组织ANGII产生失调。肾功能异常，但肾素水平正常。非调节剂与血管紧张素原（ACT）的多态性变异有关，后者增加了血管紧张素原的产生——一种功能突变的增加——以及脂肪细胞源性亮氨酸氨基肽酶（ALAP），后者减少了ANGII的降解——一种功能突变的丧失。因此，非调节剂可以通过两种方式增加ANGII的组织水平。非调节的病理生理特征通过给予ACE抑制剂得到纠正。第二种中间表型，最近才被我们的小组发现，是更传统的盐敏感亚组的一部分：低肾素HTN。与在非调节剂中观察到的ALDO水平降低相比，这些个体的ALDO水平不成比例地增加，并且与¿-2肾上腺素能受体基因的多态性有关。这种中间表型可能包括三分之一或更多的低肾素高血压。本建议的总目标是从三个方面扩大这些初步调查结果。首先，在非调节剂中，我们将确定两种主要基因变异与代谢综合征/胰岛素抵抗（非调节剂的一个主要特征）存在的关系。其次，对于这两种表型，我们将使用体内和体外技术确定HTN风险增加的可能机制。第三，对于非调节剂，我们将确定针对这些机制的治疗在降低血压方面比非特异性治疗（药物遗传学）更有效的可能性。因此，该项目的最终结果是开发出一种工具，用于在很大一部分高血压人群中使用机械和基因驱动的方法进行个体化治疗。

DESCRIPTION (provided by applicant): An anticipated outcome of the genetic revolution is more individualized treatment and prevention strategies. For the past decade supported by a SCOR in Hypertension (HTN) we have developed a large cohort who has been carefully characterized phenotypically and genotyped for several key candidate genes. We have strong evidence that a number of these genes identify homogeneous subgroups that theoretically should respond to specific therapies. The logical next step is to test these expectations. Our focus has been on the genetic underpinnings of hormonal factors leading to HTN and its associated cardiovascular (CV) risks. From these studies, we have identified several specific intermediate phenotypes of the hypertensive population. Two are the focus of this proposal. Common characteristics are: 1) an abnormality in the regulation of aldosterone (ALDO) secretion when sodium diet is modified and 2) salt sensitive blood pressure (BP). The first intermediate phenotype, comprising 25-30% of hypertensives, is termed non-modulation. Their defect is dysregulation of tissue ANGII production when Na intake is modified in the adrenal and the vasculature. They have abnormalities in renal function but normal renin level. Non-modulators are associated with polymorphic variants of angiotensinogen (ACT) that increases angiotensinogen production-a gain in function mutation- and adipocyte derived leucine aminopeptidase (ALAP) that reduces ANGII degradation- a loss of function mutation. Thereby in two ways non-modulators can increase tissue levels of ANGII. The pathophysiologic features of non-modulation are corrected by administrating an ACE inhibitor. The second intermediate phenotype, only recently identified by our group, is part of the more traditional salt sensitive sub-group: low renin HTN. These individuals have disproportionately increased ALDO levels in contrast to the reduced ALDO levels observed in non-modulators, and are associated with polymorphisms in the ¿-2 adrenergic receptor gene. This intermediate phenotype may comprise a third or more of low renin hypertensives. The overall goal of the present proposal is to expand on these preliminary findings in three ways. First, in non-modulators we will determine the relationship of the two major gene variants to the presence of the metabolic syndrome/insulin resistance-a major feature of non-modulation. Second, for both phenotypes, we will determine the likely mechanism(s) underlying the increased risk of HTN using in vivo and in vitro techniques. Third, for the non-modulators, we will determine the likelihood that therapy directed at these mechanism(s) will be more effective in reducing BP, than will non-specific therapy- pharmacogenetics. Thus, the ultimate outcome of this project is to develop tools for individualized therapy in a substantial fraction of the hypertensive population using mechanistically and genetically driven approaches.