Genetics of Hypertension

描述(申请人提供)：高血压是全世界最常见的慢性疾病，仅在美国就有7200万人受到这种疾病的影响。在这些人中，90%的人患有不明原因的高血压，也称为原发性高血压。虽然众所周知，遗传学在导致原发性高血压的易感性方面发挥了重要作用，但导致原发性高血压的基因/遗传因素的特性仍然很大程度上是未知的。这是推进我们对原发性高血压病因的理解的唯一最大的速率限制因素。利用高血压的大鼠遗传模型，我们在大鼠基因组上定位了一个793.5 kb的区域，负责控制BP。老鼠的这个区域和人类的同源区域包含两个基因，其中只有一个包含显著的变异。对人类单核苷酸多态的分析表明，该基因的特定变异也与人类原发性高血压有关。这一观察结果明确了进一步研究这种新基因功能的必要性，这构成了我们提案的具体目标之一。另一个目的是进一步从基因上剖析793.5kb的关键区域，通过在最短的大鼠基因组片段中捕获BP效应来获得该优先候选基因和/或其他QTL效应的进一步证据，并构建转基因-同源品系来测试QTL效应。我们的建议的意义在于，它可能即将揭开原发性高血压病因学中一种新的遗传因素的面纱。公共卫生相关性：众所周知，基因是导致高血压发展的一个重要因素，高血压会导致心血管相关疾病。这项提案中描述的研究工作是为了改善我们目前对控制血压的基因的身份的认识，这一认识非常有限。通过成功完成所描述的工作而获得的知识预计将确定至少一个以前没有被怀疑会导致高血压的遗传因素。

DESCRIPTION (provided by applicant): Hypertension is the most common chronic medical condition worldwide and in the US alone 72 million people are affected with the condition. Of these, 90% developed hypertension for no known reasons, also called as Essential hypertension. Although it is well known that genetics play a major role in conferring susceptibility to develop essential hypertension, the identities of the genes/genetic factors that are causally responsible for essential hypertension remain largely unknown. This is the single biggest rate-limiting factor in advancing our understanding of the etiology of essential hypertension. Using a rat genetic model for hypertension, we have located a 793.5 kb region on the rat genome as responsible for controlling BP. This region in rats and the orthologous regions in humans, contains two genes, only one of which contains significant variations. Analysis of single nucleotide polymorphisms in humans indicates that select variants of this gene are also associated with human essential hypertension. This observation defines the need to further investigate the function of this novel gene, which constitutes one of the specific aims of our proposal. The other aims are to further genetically dissect the critical 793.5kb region to obtain further evidence for the candidacy of this prioritized candidate gene and/or other QTL effectors by trapping the BP effect within the shortest possible rat genomic segment and to construct a transgenic-congenic strain to test the QTL effect. The significance of our proposal is that it is potentially on the verge of unraveling a novel genetic factor in the etiology of Essential Hypertension. PUBLIC HEALTH RELEVANCE: Genetics is well recognized to be an important factor that contributes to the development of hypertension, which leads to cardiovascular related illnesses. The research work described in this proposal pertains to improve our current, significantly limited understanding of the identities of genes that control blood pressure. Knowledge gained through successful completion of the work described is expected to pin-point at least one genetic factor that has not been previously suspected to cause hypertension.