Genetic determinants of RAA system and hypertension

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的主要机制仍然未知。很大一部分人群的血压变化是由遗传决定的，这一认识表明，确定直接导致高血压发病的遗传变异是可能的。通过使用中间表型来细分高血压患者-在一些但不是全部高血压患者中发现存在的特征-有可能大大增加这种遗传方法的功效。这一建议有五个方面。首先，常规使用“中间表型”对高血压患者进行亚组，从而增加将相应病理生理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-一般临床研究中心(GCRCs) -其中执行详细的生理协议。第三，他们将集中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技术。第四，是遗传上位的文件在这个群体时，亚组的中间表型。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的相互作用。最后，有大量的科目已经被研究过了。总的来说，我们有DNA、人口统计数据、临床数据和一些生化数据，来自1215个谱系的2400多名个体，这些个体被检查为住院GCRC研究的合格受试者。这些研究对象包括来自15个谱系的91个个体，145个有两个或更多高血压兄弟姐妹的兄弟姐妹（193对兄弟姐妹），175个高血压“单胎”和79个正常的“单胎”。该项目的总体目标有三个方面：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/或相关的基因；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。

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.