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30万美国人死亡的主要原因或促成原因。大约28%的美国成年人患有难治性高血压（TRH）。降压药在TRH患者中的无效很可能是由于这些个体中调节血压的特定遗传变异。关键的问题是：哪些基因和基因变异影响高血压的风险？这些基因调节血压的分子机制是什么？这些问题的答案将为TRH患者提供靶向治疗。众所周知，钠是高血压的主要危险因素，基因多态性是血压对钠反应变化的基础；然而，很少有基因多态性被确定为使个体易患高血压。主要障碍包括在人体研究中难以控制膳食钠，以及在大量高盐人群中确定影响高血压风险的钠反应基因的可用性。为了解决这些关键问题和人类研究的问题，我们建议使用纯种，表型和基因分型，盐-na - ve狒狒种群。我们将使用一种策略的更新版本，我们成功地使用了一种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研究高血压表型。我们将使用现有的生物材料和从一组高血压不一致的狒狒中获得的数据，这些狒狒被喂食两种钠含量不同的饮食。结合新的基因组数据和网络分析，这个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：遗传多态性是灵长类动物血压对饮食钠反应变化的基础。我们将通过以下目标来解决这个问题：1)确定并优先考虑影响BP变异的候选基因和非编码rna (ncRNAs)；2)确定影响BP的关键网络基因的统计功能变异；3)验证影响血压的钠反应基因的功能变异；4)验证影响BP的网络中钠反应基因（和编码蛋白）的网络相互作用。人类和狒狒在生理和基因上的相似性将使研究结果从狒狒转移到人类身上。

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.