Genetics of Human Hypertension

人类高血压的遗传学

• 批准号: 7496515
• 负责人: GORDON H WILLIAMS
• 金额: $ 69.81万
• 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/7496515
• 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)：基因革命的一个预期结果是更加个性化的治疗和预防策略。在过去的十年里，在高血压SCOR(HTN)的支持下，我们已经建立了一个大的队列，他们已经被仔细地描述了几个关键候选基因的表型和基因分型。我们有强有力的证据表明，这些基因中的一些确定了理论上应该对特定疗法有反应的同质亚群。合乎逻辑的下一步是测试这些预期。我们的重点是荷尔蒙因素导致HTN及其相关的心血管(CV)风险的遗传基础。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。两个是这项提案的重点。共同的特征是：1)当钠饮食改变时，醛固酮(ALDO)分泌调节异常，2)盐敏感型血压(BP)。第一种中间表型，占高血压患者的25%-30%，被称为无调制。它们的缺陷是当肾上腺和血管系统的钠摄入量改变时，组织血管生成的失调。他们有肾功能异常，但肾素水平正常。非调节剂与血管紧张素原的多态变异(ACT)和脂肪细胞衍生的亮氨酸氨基肽酶(ALAP)有关，ACT增加血管紧张素原的产生-功能突变的增加-脂肪细胞衍生的亮氨酸氨基肽酶(ALAP)减少血管紧张素Ⅱ的降解-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血管紧张素转换酶的水平。给予血管紧张素转换酶抑制剂可纠正非调制的病理生理学特征。我们小组最近才发现的第二种中间表型是更传统的盐敏感亚组的一部分：低肾素HTN。这些个体的ALDO水平不成比例地升高，而在非调节剂中观察到的ALDO水平降低，并且与-2肾上腺素能受体基因的多态有关。这种中间表型可能包括三分之一或更多的低肾素高血压患者。本提案的总体目标是从三个方面扩大这些初步调查结果。首先，在非调节因子中，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--非调节因子的一个主要特征。其次，对于这两种表型，我们将使用体内和体外技术来确定HTN风险增加的可能机制(S)。第三，对于非调节剂，我们将确定针对这些机制的治疗(S)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工具，在相当一部分高血压人群中使用机械和遗传驱动的方法进行个性化治疗。