GENETICS OF HYPERTENSION AND ITS INTERMEDIATE PHENOTYPES

描述（来自申请人摘要的逐字）：高血压，一种非常严重的高血压， 大多数发达国家的一个共同特征，增加了 心脑血管和肾脏疾病。然而，主要 大多数患者血压升高的决定因素尚不清楚。 认识到血压变化的相当大一部分是由于 基因决定的，一条研究路线集中在识别基因 导致高血压发病的变异。但标 使用“高血压”作为表型的遗传连锁分析可能缺乏动力， 这种疾病的多因素性克服这一挑战的方法 将高血压患者细分为更同质的亚组。我们 提出基于五种中间表型的分层：1） 肾上腺和肾血管对血管紧张素II反应的非调节 钠摄入量变化; 2）尿激肽释放酶排泄改变; 3）低 血浆肾素活性对血容量减少的反应; 4）游离皮质醇增加 排泄;和5）胰岛素抵抗。这些特征中的每一个都显示出 高血压受试者的患病率，可能与 高血压的病理生理学，最重要的是， 遗传性我们的总体目标是，确定 通过研究中间表型，可以在亚洲人群中发现高血压， 分为三个部分。首先，我们的中国农村人口将 其特征在于收集600个无关的中间表型数据， 舒张压高的个体和100名血压正常的个体 对照第二，候选基因将根据潜在的 中间表型的生理学，以及编码中的变异 将鉴定这些潜在相关基因的序列。最后， 在候选基因中鉴定的多态性将通过 由中间表型定义的病例对照分析。为了达成这 战略，我们的目的是减少异质性，这肯定会影响 以前的高血压遗传研究。实际上，所提出的中间体 表型已经成功地用于西方研究 人口牵连致病性遗传变异。我们的建议是 利用安庆农村的特点， 中国与中国城市地区相比， 可用在农村安庆，所以测量是不容易治疗偏差。 此外，由于缺乏现成的交通工具，安庆一直保持 孤立且相对同质。因此，遗传因素有助于 在这一人群中，高血压的异质性较低， 检测到

DESCRIPTION (Verbatim from Applicant's Abstract): Hypertension, an exceedingly common trait in most developed countries, imparts an increased risk of cardiovascular, cerebrovascular and renal diseases. Nevertheless, the primary determinants of elevated blood pressure in most patients are unknown. Recognizing that a sizable portion of variation in blood pressure is genetically determined, one line of research has focused on identifying genetic variants that contribute to the pathogenesis of hypertension. However, standard genetic linkage analysis using "hypertension" as a phenotype may lack power due to the multifactorial nature of the disorder. A way to overcome this challenge is to subdivide hypertensive subjects into more homogenous subgroups. We propose stratification on the basis of five intermediate phenotypes: 1) non-modulation of adrenal and renal vascular responses to angiotensin II with changes in sodium intake; 2) altered urinary kallikrein excretion; 3) low plasma renin activity response to volume depletion; 4) increased free cortisol excretion; and 5) insulin resistance. Each of these traits shows an increased prevalence in hypertensive subjects, can be plausibly linked to the pathophysiology of hypertension and, most importantly, shows evidence of heritability. Our overall goal, to define the underlying genetics of hypertension in an Asian population by studying intermediate phenotypes, can be divided into three parts. First, our rural Chinese population will be characterized by the collection of intermediate phenotype data on 600 unrelated individuals with high diastolic blood pressure and on 100 normotensive controls. Second, candidate genes will be chosen according to the underlying physiology of the intermediate phenotypes, and variations in the coding sequences of these potentially relevant genes will be identified. Finally, polymorphisms identified in the candidate genes will be tested through case-control analyses defined by the intermediate phenotypes. In pursuing this strategy, our intention is to reduce the heterogeneity that has surely impacted previous genetic studies of hypertension. Indeed, the proposed intermediate phenotypes have already been used successfully in studies of Western populations to implicate causative genetic variants. Our proposal is intended to expand this research by taking advantage of characteristics of rural Anqing, China. In contrast to urban areas of China, drug therapy is not readily available in rural Anqing, so measurements are not prone to treatment bias. Further, due to lack of readily available transportation, Anqing has remained isolated and relatively homogeneous. Thus, the genetic factors contributing to hypertension in this population may be less heterogeneous and more readily detected.