GENETICS OF HYPERTENSION

高血压的遗传学

• 批准号: 2223833
• 负责人: GORDON H WILLIAMS
• 金额: $ 91.98万
• 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/2223833
• 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; 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.

尽管进行了密集的努力，但主要异常 基本高血压的发病机理仍然未知。 知道的 人群血压变化的很大一部分是 遗传确定的表明识别的可能性 直接导致高血压发病机理的突变。 通过使用中间表型，性状，细分高血压患者 在某些但不是全部的高血压主题中发现的是 有可能大大增加这种遗传的能力 方法。 在此类中间表型中，有四种似乎显示 大多数诺言：1）尿尿kallikrein排泄改变； 2）高架 红细胞钠反向转移； 3）肾上腺不调制 以及对血管紧张素II的肾血管反应随钠的变化 进气4）低血浆肾素活性对体积消耗的反应。 这 这些中间表型的每个基础的生理学表明 一组潜在的候选基因，包括肾素的基因 血管紧张素系统，肾顶钠/氢抗胞毒蛋白，基因 调节反毒剂的活动，以及 Kallikrein Gene家族。 为了及时完成研究 时尚，兄弟姐妹对将在三个临床中心中的每个中心进行评估 - 马萨诸塞州波士顿，巴黎，法国和盐湖城，犹他州。 所有患者都会 执行标准方案以表征中间表型 每个兄弟姐妹对。 然后，我们将基因型兄弟姐妹对及其 具有候选基因标记的父母以确定等位基因 兄弟对在候选基因基因座的同胞对相同。 使用这些数据，我们将测试一个或多个突变的假设 候选基因有助于基本高血压的发病机理 通过在高血压兄弟姐妹对中进行连锁分析。 力量 通过对兄弟姐妹对进行分层的分析将增加分析 中间表型的存在或不存在。 通过类似方法， 候选基因座与中间表型本身之间的联系 将被调查。 可以预见的是，至少我们将 能够排除许多候选locis在 高血压的发病机理。 识别与任何一个 要研究的候选基因将为解开 这种常见疾病的发病机理。