Genetic determinants of RAA system and hypertension

RAA系统和高血压的遗传决定因素

• 批准号: 7010655
• 负责人: GORDON H WILLIAMS
• 金额: $ 40.01万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7010655
• 关键词: aldosterone; angiotensin /renin /aldosterone hypertension; angiotensin II; cardiovascular disorder epidemiology; clinical research; dietary sodium; disease /disorder classification; familial hypertension; family genetics; gene environment interaction; genetic polymorphism; genetic susceptibility; genotype; hormone regulation /control mechanism; human data; human genetic material tag; kallikreins; kidney function; linkage mapping; phenotype; renal tubular transport; saluresis

DESCRIPTION: (Adapted from the applicant's abstract) Despite intensive efforts, the primary mechanism(s) responsible for the pathogenesis of essential hypertension remain unknown. The knowledge that a large fraction of the populations' variation in blood pressure is genetically determined suggests the possibility of identifying the genetic variants which directly contribute to the pathogenesis of hypertension. Subdividing hypertensive patients by using intermediate phenotypes - traits which are found to be present in some, but not all, hypertensive subjects - has the potential to increase substantially the power of such genetic approaches. There are five aspects to this proposal. First, in the routine use of the "intermediate phenotype" to subgroup our hypertensive patients and thereby increase the likelihood of linking the consequent pathophysiology to (a) specific gene(s). Second, are the state-of-the-art clinical research facilities - General Clinical Research Centers (GCRCs) - in which to perform the detailed physiologic protocols. Third, they will concentrate on using association analysis of candidate genes with expression of intermediate phenotypes of hypertensive in subjects off medications, while continuing to use the techniques of affected sibling pairs and family linkage analyses. Fourth, is the documentation of genetic epistasis in this population when sub- grouped by intermediate phenotype. Thus, they expect to be able to tease out the polygenes contributing to hypertension and subsequently investigate how they interact with each other and with environmental factors. Finally, there are a large number of subjects who have already been studied. In total, we have DNA, demographic data, clinical data, and some biochemical data from over 2400 individuals belonging to 1215 pedigrees who were examined to qualify subjects for the inpatient GCRC studies. Those who have undergone our intensive intermediate phenotyping protocol include 91 individuals from 15 pedigrees, 145 sibships of two or more hypertensive siblings (193 sibling pairs), 175 hypertensive "singletons" and 79 normotensive "singleton". The overall objectives of this project are threefold: 1) to determine if the four potential intermediate phenotypes are associated with each other; 2) to identify the gene(s) associated and/or linked to these intermediate phenotypes; and 3) to determine the likelihood of genotype predicting phenotype for increased specificity for prevention and/or intervention.

描述：（改编自申请人的摘要）尽管付出了巨大的努力，但原发性高血压发病机制的主要机制仍然未知。 大部分人群的血压变异是由基因决定的这一知识表明，有可能确定直接导致高血压发病机制的遗传变异。 通过使用中间表型（发现在一些但不是全部高血压受试者中存在的特征）对高血压患者进行细分，有可能大幅增强此类遗传方法的功效。该提案有五个方面的内容。 首先，在常规使用“中间表型”对高血压患者进行分组时，从而增加将随后的病理生理学与特定基因联系起来的可能性。 其次，是最先进的临床研究设施 - 普通临床研究中心 (GCRC) - 可以在其中执行详细的生理方案。 第三，他们将集中精力使用候选基因与停药受试者高血压中间表型表达的关联分析，同时继续使用受影响的兄弟姐妹对和家庭连锁分析的技术。第四，是按中间表型分组时该群体中遗传上位性的记录。 因此，他们希望能够梳理出导致高血压的多基因，并随后研究它们如何相互作用以及它们与环境因素的相互作用。 最后，还有大量已经研究过的课题。 总的来说，我们拥有来自 1215 个家系的 2400 多名个体的 DNA、人口统计数据、临床数据和一些生化数据，这些个体经过检查以确定是否有资格参加住院 GCRC 研究。 接受我们强化中间表型分析方案的人包括来自 15 个谱系的 91 名个体、两个或更多高血压兄弟姐妹的 145 名同胞（193 名兄弟姐妹）、175 名高血压“单身人士”和 79 名血压正常“单身人士”。 该项目的总体目标有三个：1）确定四种潜在的中间表型是否彼此相关； 2) 鉴定与这些中间表型相关和/或连锁的基因； 3) 确定基因型预测表型的可能性，以提高预防和/或干预的特异性。