Discovery of Gene Variants and Mechanisms Underlying Salt-Sensitive Hypertension

描述(由申请人提供)：高血压是每年超过30万美国人的主要或主要致死原因。大约28%的美国成年人患有难治性高血压(TRH)。TRH患者血压(BP)药物无效很可能是由于调节这些患者血压的特定遗传变异所致。关键问题是：哪些基因和基因变异会影响高血压的风险？那么，这些基因调节BP的分子机制是什么？这些问题的答案将为TRH患者提供有针对性的治疗。众所周知，钠是高血压的主要危险因素，遗传多态是血压对钠反应变化的基础；然而，很少有基因多态被确定为易患高血压的个体。主要障碍包括在人体研究中难以控制饮食中的钠，以及可获得大量的盐缺乏人群来识别影响高血压风险的钠反应基因。为了解决这些关键问题和人类研究中的问题，我们建议使用一个系谱、表型和基因分型的盐碱型狒狒种群。我们将使用一种策略的更新版本，我们成功地使用该策略来识别调节血清高密度脂蛋白胆固醇的遗传变异，并利用我们独特的狒狒种群数据来确定高血压表型。我们将使用可用的生物材料和数据，这些材料和数据来自一组与高血压不一致的狒狒，他们被喂养了两种不同的钠含量的饮食。结合新的基因组数据和网络分析，这一独特的数据集将使我们能够识别受高钠饮食干扰的BP功能网络。我们假设：遗传多态是灵长类动物血压对饮食钠反应差异的基础。我们将通过以下目标来解决这一问题：1)确定影响BP变异的候选基因和非编码RNA(NcRNAs)的优先顺序；2)确定影响BP的关键网络基因中的统计功能变量；3)验证影响BP的钠响应基因的功能变量；以及4)验证影响BP的网络中钠响应基因(和编码蛋白)的网络相互作用。人类和狒狒之间在生理和基因上的相似之处将允许将研究结果从狒狒转化为人类。

DESCRIPTION (provided by applicant): Hypertension is a primary or contributing cause of death for more than 300,000 Americans annually. Approximately 28% of U.S. adults have treatment-resistant hypertension (TRH). The ineffectiveness of blood pressure (BP) medications in TRH individuals is very likely due to specific genetic variants regulating BP in these individuals. Critical questions are: What genes and gene variants influence risk of hypertension? And, what are the molecular mechanisms by which these genes regulate BP? The answers to these questions will provide targeted therapies for individuals with TRH. It is well-established that sodium is a major risk factor for hypertension and that genetic polymorphisms underlie variation in BP response to sodium; however, few genetic polymorphisms have been identified that predispose an individual to hypertension. Major obstacles include difficulty controlling dietary sodium in human studies and availability of large, salt-na¿ve human populations to identify sodium-responsive genes that influence hypertension risk. To address these critical questions and the issues with human studies, we propose to use a pedigreed, phenotyped and genotyped, salt-na¿ve baboon population. We will use an updated version of a strategy that we successfully employed to identify genetic variants regulating serum HDL cholesterol and exploit our unique baboon population data for hypertension phenotypes. We will use available biomaterials and data obtained from a panel of baboons discordant for hypertension that were fed two diets differing in sodium content. Combined with new genomic data and network analyses, this unique dataset will allow us to identify BP functional networks that are perturbed by a high-sodium diet. We hypothesize that: Genetic polymorphisms underlie variation in BP response to dietary sodium in primates. We will address this with the following Aims: 1) Identify and prioritize candidate genes and noncoding RNAs (ncRNAs) that influence variation in BP; 2) Identify statistical functional variants in critical network genes that influence BP; 3) Validate functional variants in sodium-responsive genes influencing BP; and 4) Validate network interactions of sodium-responsive genes (and encoded proteins) in networks influencing BP. Physiologic and genetic similarities between humans and baboons will allow translation of findings from baboon to human.