Initiating Factors for Hypertension

高血压的诱发因素

• 批准号: 7890573
• 负责人: Steven C. Hunt
• 金额: $ 69.27万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7890573
• 关键词: Acute; Aldosterone; Angiotensins; Arts; Biochemical; Blood; Blood Pressure; Candidate Disease Gene; Catecholamines; Caucasians; Caucasoid Race; Clinical Research; Complex; DNA; Data; Data Set; Detection; Distal; Dopamine; Electrolytes; Equilibrium; Ethnic group; European; Excretory function; Failure; Family; Financial compensation; Future; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Grant; Hormonal; Hormones; Human; Hydrocortisone; Hypertension; Individual; Individual Differences; Infusion procedures; Intake; Investigation; Kidney; Kininogenase; Lead; Masks; Measures; Methods; Modeling; National Heart, Lung, and Blood Institute; Pathway interactions; Pattern; Phase; Phenotype; Play; Population; Prevalence; Renin; Risk; Saline; Series; Siblings; Site; Sodium; Sodium Chloride; Sodium-Restricted Diet; System; Testing; Time; Tubular formation; Urine; Utah; Water; base; biological systems; computer based statistical methods; familial hypertension; genetic association; genetic variant; normotensive; offspring; phase 1 study; prevent; programs; public health relevance; response; salt balance; salt intake; saluretic; urinary; water solution

DESCRIPTION (provided by applicant): Discovery of gene variants associated with hypertension has been remarkably difficult, possibly because hypertension and blood pressure represent a complex interplay between initiating and compensating mechanisms. We propose that differences in the acute natriuretic responses to a saline load in young prehypertensive individuals will enable detection of genetic and hormonal/electrolyte associations with delayed excretion of the saline load which would be masked if studied under steady-state salt balance (or after compensatory mechanisms come into play). Selected neuro-humoral factors will be examined as potential intermediate phenotypes that predict delayed natriuretic responses. Once these salt-related genetic associations are uncovered by an acute saline challenge applied under controlled baseline conditions, we will test whether the identified gene variants are associated with hypertension in large multiracial and ethnic groups of subjects from the NHLBI Family Blood Pressure Program Study. It is proposed that deficiencies of acute hormonal or electrolyte responses to an acute saline load represent the earliest detectable initiating factors for salt-related hypertension, and that focusing on this intermediate phenotype will provide greater power than previously available in studies of hypertension or blood pressure, per se. The first group of subjects to be examined will be 480 Caucasians of Northern European descent from Utah. Acute saline infusions while on a low-salt diet (50 mmol/day) will elicit acute changes in hormones and electrolytes in pathways directly related to renal sodium excretion including the catecholamine-dopamine, renin-angiotensin-aldosterone, cortisol, and kallikrein systems. Hormone, electrolyte and water excretion, proximal and distal tubule reabsorption, and associated genetic polymorphisms will be analyzed by Bayesian pathway networks to model initial abnormal sodium responses and subsequent short-term compensation mechanisms. Candidate genes include those related to kidney control of salt and water excretion. Further, we will test whether the identified genetic associations with effectors or regulators of acute responses to sodium challenge are associated with hypertension in a separate, large, existing cross-sectional dataset (6,658 hypertensives and normotensives). The proposed systems and genetics approaches to acute sodium and volume changes under controlled baseline conditions, delayed sodium excretion and hypertension have not been previously studied. All other such studies have been on subjects in sodium balance or lack the systems and genetics approach. The resulting data together with the wealth of our existing data will provide an opportunity to test a new hypothesis about the initiating mechanisms that predict delayed sodium excretion. PUBLIC HEALTH RELEVANCE: This grant seeks to identify the primary abnormalities in humans that determine adverse blood pressure responses to high salt intake. Blood, urine, and DNA will be studied while individuals are infused with a sodium and water solution over a short period of time. Results may suggest better ways to prevent or to at least treat hypertension.

描述（由申请人提供）：与高血压相关的基因变异的发现非常困难，这可能是因为高血压和血压代表了启动和补偿机制之间的复杂相互作用。我们提出，年轻的高血压前个体的急性纳替纳二尿素反应的差异将使遗传和激素/电解质关联与盐水负荷延迟排泄，如果在稳态盐平衡下研究（或在补偿机制之后），则遗传和荷尔蒙/电解质关联延迟。选定的神经幽默因素将被检查为预测延迟发作性纳地酸反应的潜在中间表型。一旦这些与盐相关的遗传关联通过受控基线条件下应用的急性生理盐水挑战发现，我们将测试NHLBI家庭血压的大型多种族和族裔受试者中确定的基因变异是否与高血压有关。有人提出，急性激素或电解质对急性生理盐水负荷的反应代表了与盐相关高血压的最早可检测的启动因子，并且专注于这种中间表型将提供比以前在高压或血压研究中提供的更大的功率。要检查的第一组受试者将是犹他州北欧血统的480名高加索人。急性盐水输注时，低盐饮食（50 mmol/天）将引起与肾脏钠排泄直接相关的途径的急性变化，包括肾脏钠排泄物，包括儿茶酚胺 - 肾上腺素，肾素 - 血管固醇 - 甲求阿丁酮，皮质醇和Kallikrein Systems。激素，电解质和水排泄，近端和远端小管的吸收以及相关的遗传多态性将通过贝叶斯途径网络分析，以模拟初始的异常钠反应和随后的短期补偿机制。候选基因包括与肾脏和水排泄的肾脏控制有关的基因。此外，我们将测试在一个单独的，大的，现有的横截面数据集中（6,658种高血压和正常敏化剂）中，对钠挑战的效应子或急性反应的调节剂的遗传关联是否与高血压有关。在受控基线条件下，急性钠和体积变化，延迟排泄和高血压的急性钠和体积变化所提出的系统和遗传学方法先前尚未被研究。所有其他此类研究都涉及钠平衡中的受试者或缺乏系统和遗传学方法。最终的数据以及我们现有数据的财富将提供一个机会，以测试有关预测延迟钠排泄的启动机制的新假设。公共卫生相关性：该赠款旨在确定人类的主要异常，这些异常决定对高盐摄入的不良血压反应。将研究血液，尿液和DNA，而个体在短时间内注入了钠和水溶液。结果可能提出了预防或至少治疗高血压的更好方法。