Genetic determinants of RAA system and hypertension

产品说明：（改编自申请人摘要）尽管进行了大量的努力，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化是由遗传决定的，这一认识表明有可能鉴定出直接导致高血压发病的遗传变异。 通过使用中间表型（发现存在于一些但不是所有高血压受试者中的性状）细分高血压患者有可能大幅增加此类遗传方法的效力。这一建议有五个方面。 首先，在常规使用的“中间表型”分组我们的高血压患者，从而增加的可能性，随后的病理生理学连接到（一个）特定的基因（S）。 第二，是最先进的临床研究设施-一般临床研究中心（GCRC）-在其中执行详细的生理方案。 第三，他们将专注于使用候选基因与停药受试者中高血压中间表型表达的关联分析，同时继续使用受影响同胞对和家族连锁分析的技术。第四，是在这个群体中，当按中间表型分组时，遗传上位性的文件。 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与环境因素相互作用。 最后，有大量的主题已经被研究。 总的来说，我们有DNA，人口统计学数据，临床数据和一些生化数据，来自1215个家系的2400多个人，他们接受了检查，以确定住院GCRC研究的受试者资格。 这些谁经历了我们的密集的中间表型方案包括91个人从15个家系，145同胞的两个或两个以上的高血压同胞（193同胞对），175高血压“单例”和79血压正常的“单例”。 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相互关联; 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，以增加预防和/或干预的特异性。

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.