Genetics of Human Hypertension

人类高血压的遗传学

• 批准号: 7322763
• 负责人: GORDON H WILLIAMS
• 金额: $ 69.35万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7322763
• 关键词: AR gene; Adipocytes; Adrenal Glands; Adrenergic Receptor; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Angiotensins; Appendix; Argentina; Blood Pressure; Candidate Disease Gene; Cell Line; Cells; Characteristics; Clinical; Coronary heart disease; Data; Data Set; Defect; Diabetes Mellitus; Diet; Double-Blind Method; Family history of; France; Frequencies; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Hormonal; Human; Human Genetics; Hypertension; Hypotension; In Vitro; Individual; Insulin Resistance; Intake; Intervention; Italy; LDL Cholesterol Lipoproteins; Leucine Aminopeptidase; Mediating; Metabolic syndrome; Mutation; Netherlands; Numbers; Obesity; Outcome; Pathway interactions; Pharmacogenetics; Phenotype; Population; Prevention strategy; Production; Protocols documentation; Randomized; Rattus; Receptor Gene; Recruitment Activity; Regulation; Renal function; Renin; Rest; Risk; Role; Secondary to; Sodium; Sodium Chloride; Sodium-Restricted Diet; Source; Structure; Subgroup; Switzerland; Techniques; Testing; Tissues; Triglycerides; Variant; Zona Glomerulosa; cardiovascular risk factor; cohort; concept; expectation; genetic association; hypercholesterolemia; in vivo; kidney cell; loss of function mutation; low renin hypertension; normotensive; receptor; response; salt intake; salt sensitive; tool; translational study

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.

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（HTN）的SCOR支持下，我们已经开发了一个大型队列，该队列已经仔细表征了几个关键候选基因的表型和基因型。我们有强有力的证据表明，这些基因中的一些确定同质亚群，理论上应该对特定的治疗作出反应。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个特定的中间表型。两个是本提案的重点。共同特点是：1）当改变钠饮食时醛固酮（ALDO）分泌调节的异常和2）盐敏感性血压（BP）。第一中间表型，包括25-30%的高血压，被称为非调制。它们的缺陷是当肾上腺和脉管系统中的Na摄入被改变时，组织ANGII产生失调。他们有肾功能异常，但正常的肾素水平。非调节剂与血管紧张素原（ACT）的多态性变体和脂肪细胞衍生的亮氨酸氨肽酶（阿拉普）相关，所述血管紧张素原（ACT）的多态性变体增加血管紧张素原产生-功能突变的获得-所述脂肪细胞衍生的亮氨酸氨肽酶减少ANGII降解-功能突变的丧失。因此，非调节剂可以通过两种方式增加组织中ANGII的水平。非调节的病理生理学特征通过施用ACE抑制剂来纠正。第二个中间表型，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水平不成比例地升高，并且与± 2肾上腺素能受体基因的多态性相关。这种中间表型可能包括三分之一或更多的低肾素高血压。本提案的总体目标是以三种方式扩大这些初步调查结果。首先，在非调节剂中，我们将确定两个主要基因变异与代谢综合征/胰岛素抵抗的存在的关系-非调节的主要特征。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比非特异性治疗-药物遗传学更有效降低BP的可能性。因此，该项目的最终结果是开发工具，在很大一部分高血压人群中使用机械和遗传驱动的方法进行个体化治疗。