GENETICS OF HYPERTENSION AND ITS INTERMEDIATE PHENOTYPES

描述(逐字摘自申请者摘要)：高血压，过度的 这是大多数发达国家的共同特征，会增加罹患 心血管、脑血管和肾脏疾病。尽管如此，主要的 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 在基因决定的情况下，有一系列研究专注于识别基因 导致高血压发病机制的变异体。然而，标准 以“高血压”为表型的遗传连锁分析可能缺乏力量 这种疾病的多因素性质。一种克服这一挑战的方法 是将高血压患者细分为更同质的亚组。我们 根据五种中间表型提出分层：1) 血管紧张素-II对肾上腺和肾血管反应的非调节作用 钠摄入量的变化；2)尿激肽释放酶排泄的改变；3)低 血浆肾素活性对容量耗竭的反应；4)游离皮质醇增加 排泄；5)胰岛素抵抗。这些特征中的每一个都显示出 在高血压受试者中的患病率，可能与 高血压的病理生理学，最重要的是，显示出 遗传力。我们的总体目标是，定义潜在的 通过研究中间表型，亚洲人群中的高血压可能是 鼎足而三。首先，我们的农村中国人口将是 特征是收集了600个无关的中间表型数据 舒张压偏高且血压正常的个体 控制。第二，候选基因将根据潜在的 中间表型的生理学和编码的变异 这些潜在相关基因的序列将被识别出来。最后， 在候选基因中确定的多态将通过 由中间表型定义的病例对照分析。在追求这个目标的过程中 战略，我们的目的是减少肯定会影响到 之前对高血压的遗传学研究。事实上，拟议中的中间人 表型已经成功地用于西方的研究 与致病基因变异有关的种群。我们的建议意在 要利用安庆农村的特点拓展这项研究， 中国。与中国的城市相比，药物治疗并不容易 可在安庆农村使用，因此测量不容易出现治疗偏差。 此外，由于缺乏现成的交通工具，安庆留了下来 与世隔绝，相对同质。因此，遗传因素导致了 这一人群中的高血压可能不那么异质性，更容易发生 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.