Discovery of Gene Variants and Mechanisms Underlying Salt-Sensitive Hypertension

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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.