GENETICS OF HUMAN HYPERTENSION

人类高血压的遗传学

• 批准号: 3366887
• 负责人: GORDON H WILLIAMS
• 金额: $ 87.5万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-01 至 1996-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3366887
• 关键词: aldosterone; alleles; angiotensin II; antiport; biological transport; complementary DNA; creatinine; diagnosis design /evaluation; dietary calcium; dietary potassium; dietary sodium; erythrocytes; excretion; familial hypertension; gene expression; gene mutation; genetic disorder diagnosis; genetic markers; genetic polymorphism; genotype; haptoglobins; human subject; hydrogen transport; in situ hybridization; ion transport; kidney circulation; linkage mapping; lithium; nutrition related tag; pathologic process; phenotype; plasma; polymerase chain reaction; renal tubular transport; secretion; siblings; sodium channel; transfection /expression vector; urine

Despite intensive efforts, the primary abnormalities responsible for the pathogenesis of essential hypertension remain unknown. The knowledge that a large fraction of the population's variation in blood pressure is genetically-determined suggests the possibility of identifying the mutations which directly contribute to the pathogenesis of hypertension. Subdividing hypertension patients by using intermediate phenotypes, traits which are found to be present in some, but not all, hypertensive subjects, has the potential to substantially increase the power of such genetic approaches. Among such intermediate phenotypes, four to appear to show the most promise: 1) altered urinary kallikrein excretion; 2) elevated erythrocyte sodium-lithium countertransport; 3) non-modulation of adrenal and renal vascular responses to angiotensin II with changes in sodium intake; and 4) low plasma renin activity response to volume depletion. The physiology which underlies each of these intermediate phenotypes suggests a battery of underlying candidate genes, including genes of the renin- angiotensin system, the renal apical sodium/hydrogen antiporter, genes which regulate the activity of the antiporter, and members of the kallikrein gene family. In order to complete the study in a timely fashion, sibling pairs will be evaluated at each of three clinical centers -Boston, MA, Paris, France and Salt Lake City, UT. All patients will undergo a standard protocol to characterize the intermediate phenotype in each of the sibling pairs. We will then genotype sibling pairs and their parents with candidate gene markers in order to determine the alleles shared identically by descent by the sibling pairs at candidate gene loci. Using these data, we will test the hypothesis that mutations in one or more candidates genes contribute to the pathogenesis of essential hypertension by performing linkage analysis in hypertensive sibling pairs. The power of the analysis will be increased by stratifying sibling pairs for the presence or absence of intermediate phenotypes. By analogous methods, linkage between candidate loci and the intermediate phenotypes themselves will be investigated. It is anticipated that, at a minimum, we will be able to exclude a number of candidate locis as having a role in the pathogenesis of hypertension. Identification of linkage with any of the candidate genes to be studied would provide a major step toward unravelling the pathogenesis of this common disorder.

尽管付出了巨大的努力，导致 原发性高血压的发病机制仍不清楚。 这些知识 人群血压变化的很大一部分是 基因决定表明有可能识别 基因突变直接导致高血压的发病。 利用中间表型、特征对高血压患者进行细分 发现存在于一些但不是全部高血压受试者中， 有潜力大幅增加这种基因的力量 接近。 在这些中间表型中，有四种表现出 最有希望的是：1）改变尿激肽释放酶的排泄； 2）升高 红细胞钠锂逆向转运； 3) 肾上腺的非调节 和肾血管对血管紧张素 II 的反应随钠的变化 摄入量； 4) 对血容量减少的低血浆肾素活性反应。 这 这些中间表型背后的生理学表明 一系列潜在的候选基因，包括肾素基因 血管紧张素系统，肾尖钠/氢逆向转运蛋白，基因 调节逆向转运蛋白的活动，以及 激肽释放酶基因家族。 为了及时完成学业 时尚，兄弟姐妹对将在三个临床中心中的每一个进行评估 -马萨诸塞州波士顿、法国巴黎和犹他州盐湖城。 所有患者都会 进行标准方案来表征中间表型 每对兄弟姐妹。 然后我们将对兄弟姐妹及其他们进行基因分型 具有候选基因标记的父母以确定等位基因 候选基因位点上的兄弟姐妹对在血统上具有相同的共享性。 使用这些数据，我们将检验一个或多个突变的假设 候选基因有助于原发性高血压的发病机制 通过对高血压兄弟姐妹进行连锁分析。 的力量 通过对兄弟姐妹对进行分层来增强分析 中间表型的存在或不存在。 通过类似的方法， 候选基因座和中间表型本身之间的联系 将被调查。 预计我们至少将 能够排除一些候选位点，因为它们在 高血压的发病机制。 识别与任何的链接 待研究的候选基因将为解开谜题迈出重要一步 这种常见疾病的发病机制。