Initiating Factors for Hypertension

描述（由申请人提供）：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，年轻高血压前期个体对盐负荷的急性利尿钠反应的差异将能够检测遗传和激素/电解质与盐负荷排泄延迟的相关性，如果在稳态盐平衡下进行研究（或之后），这种相关性将被掩盖。补偿机制开始发挥作用）。选择的神经体液因子将作为预测迟发性利钠反应的潜在中间表型进行检查。一旦这些与盐相关的遗传关联被在受控基线条件下应用的急性盐水挑战所揭示，我们将在来自NHLBI家庭血压项目研究的大型多种族和种族受试者群体中测试所识别的基因变异是否与高血压相关。有人提出，急性激素或电解质反应的急性盐负荷的不足代表最早可检测的起始因素盐相关的高血压，并专注于这个中间表型将提供更大的权力比以前提供的高血压或血压的研究，本身。第一组受试者为480名来自犹他州的北方欧洲血统的高加索人。在低盐饮食（50 mmol/天）下进行急性生理盐水输注将引起与肾钠排泄直接相关的途径中激素和电解质的急性变化，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。将通过贝叶斯通路网络分析激素、电解质和水排泄、近端和远端小管重吸收以及相关遗传多态性，以模拟初始异常钠反应和后续短期代偿机制。候选基因包括那些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、现有的横断面数据集（6，658名高血压患者和血压正常者）中测试所确定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。所提出的系统和遗传学方法，在控制基线条件下的急性钠和容量的变化，延迟钠排泄和高血压尚未进行过研究。所有其他此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。由此产生的数据与我们现有的丰富数据一起，将提供一个机会来检验一个新的假设，即预测延迟钠排泄的启动机制。

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.