Genetics of Hypertension

描述（由申请人提供）：高血压是世界上最常见的慢性疾病，仅在美国就有7200万人患有高血压。其中90%的人患上了高血压，原因不明，也被称为原发性高血压。虽然众所周知，遗传学在原发性高血压的易感性中起着重要作用，但导致原发性高血压的基因/遗传因素的特性在很大程度上仍然未知。这是促进我们对原发性高血压病因了解的最大单一限制因素。利用大鼠高血压遗传模型，我们在大鼠基因组中找到了一个793.5 kb的区域，该区域负责控制BP。大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性的分析表明，该基因的选择性变异也与人类原发性高血压有关。这一观察结果表明需要进一步研究这种新基因的功能，这是我们建议的具体目标之一。另一个目标是通过在最短的大鼠基因组片段中捕获BP效应，进一步对关键的793.5kb区域进行遗传剖析，以获得该优先候选基因和/或其他QTL效应物的候选性的进一步证据，并构建转基因同源菌株来测试QTL效应。我们的建议的意义在于，它可能处于揭示原发性高血压病因的一个新的遗传因素的边缘。公共卫生相关性：众所周知，遗传是导致高血压的一个重要因素，高血压会导致心血管相关疾病。本提案中描述的研究工作有助于改善我们目前对控制血压的基因身份的有限理解。通过成功完成所描述的工作所获得的知识，预计将明确指出至少一个以前未被怀疑引起高血压的遗传因素。

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.