Initiating Factors for Hypertension

描述(申请人提供)：发现与高血压相关的基因变异非常困难，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。我们认为，年轻的高血压前期个体对盐分负荷的急性利钠反应的差异将使检测与盐分负荷延迟排泄的遗传和激素/电解质关联成为可能，如果在稳态盐平衡下(或在代偿机制开始发挥作用后)进行研究，这一点将被掩盖。选定的神经体液因子将作为预测延迟利钠反应的潜在中间表型进行检验。一旦在受控基线条件下进行的急性盐水挑战发现了这些与盐相关的遗传关联，我们将在NHLBI家庭血压计划研究的大型多种族和民族受试者中测试已识别的基因变异是否与高血压相关。有人认为，对急性盐水负荷的急性激素或电解质反应不足是盐相关高血压的最早可检测到的启动因素，而且关注这一中间表型本身将提供比以前在高血压或血压研究中所提供的更大的力量。第一组接受检查的对象将是来自犹他州的480名北欧裔高加索人。在低盐饮食(每天50 mmol)的情况下，急性输注盐水会在与肾脏钠排泄直接相关的途径中引起激素和电解质的急剧变化，包括儿茶酚胺-多巴胺、肾素-血管紧张素-醛固酮、皮质醇和激肽释放酶系统。激素、电解质和水的排泄、近端和远端小管的重吸收以及相关的遗传多态性将通过贝叶斯通路网络进行分析，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控制盐和水排泄有关的基因。此外，我们将在一个单独的、大型的现有横断面数据集中(6,658名高血压患者和正常血压患者)，测试已识别的与钠挑战急性反应的效应器或调节器的遗传关联是否与高血压相关。在受控基线条件下急性钠和容量变化、延迟钠排泄和高血压的拟议系统和遗传学方法以前从未被研究过。所有其他这类研究都是关于钠平衡的主题，或者缺乏系统和遗传学方法。由此产生的数据，加上我们现有数据的丰富，将提供一个机会来测试关于预测延迟钠排泄的启动机制的新假说。公共卫生相关性：这项赠款寻求确定人类中决定对高盐摄入量的不良血压反应的主要异常。血液、尿液和DNA将在短时间内被注入钠和水的溶液中进行研究。结果可能会提出更好的预防或至少治疗高血压的方法。

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.