Genetic Determinants of Hypertension, LVH, and CHF

描述(由申请人提供)： 内源性心脏激素系统(CHS)调节血压， 高血压引起的左心室肥厚的发展， 延缓心力衰竭的进展。大脑的“传入肢体” CHS指的是心肌释放心房和脑的能力 钠尿肽(ANP和BNP)对压力超负荷的反应，以及 “传出肢体”描述了这些激素在靶体内的生物学作用。 组织。血浆cGMP水平与出血量密切相关 心脏激素的作用提供了一种有效的方法来测量 人类CHS的传出功能。我们假设基因环境 涉及与传入关键成分相关的基因的相互作用 和传出的心脏激素信号通路，以及基因-基因相互作用 在这些基因型和ACE基因之间，有助于个体间的遗传 高血压性心脏病易感性的变异。此外， 这些等位基因在特殊人群中的频率差异可能 解释非裔美国人对左心室肥厚、心脏发育的易感性增加 心力衰竭和已建立的心力衰竭的进展。为了 针对这些假设，我们将确定未经治疗的患者 高血压和左心室肥厚在随机抽样人群中的大约。3000名受试者。 然后我们将比较非洲社区卫生服务的传入和传出功能- 美国人和高加索人未经治疗的高血压和左心室 肥大，并鉴定表型特征为减少 社区卫生服务的传入或传出功能。我们会 对这些受试者进行测序以确定候选基因中的序列变异 对心脏激素信号通路至关重要(ANP、BNP、 A型和C型心脏激素受体，以及Corin)。然后我们会研究 这些基因与高血压流行的关系，心脏核磁共振测定 高血压心肌病在两个民族中的流行情况 一群人。此外，我们还将分析这些基因型与 晚期收缩性心力衰竭患者的预后。

DESCRIPTION (provided by applicant): The endogenous cardiac hormonal system (CHS) moderates blood pressure, the development of left-ventricular hypertrophy (LVH) in response to hypertension, and delays progression of systolic heart failure. The "afferent-limb" of the CHS refers to the ability of the myocardium to release atrial and brain natriuretic peptide (ANP and BNP) in response to pressure overload, and the "efferent- limb" describes the biological action of these hormones in target tissue. Plasma levels of cGMP are tightly correlated with the efferent actions of the cardiac hormones providing a validated method to measure the efferent function of the CHS in humans. We hypothesize that gene-environment interactions involving genes related to critical components of the afferent and efferent cardiac hormonal signaling pathways, and gene-gene interactions between these genotypes and the ACE-gene, contribute to inter-individual variation in susceptibility to hypertensive heart disease. Moreover, differences in the frequencies of these alleles in special populations may explain the increased susceptibility of African-Americans to LVH, development of heart failure, and progression of established heart failure. In order to address these hypotheses, we will identify patients with untreated hypertension and LVH in a random population sample of approx. 3,000 subjects. We will then compare the afferent and efferent function of the CHS in African- American and Caucasian subjects with untreated hypertension and leftventricular hypertrophy, and identify phenotypes characterized by reduced function of either the afferent or efferent function of the CHS. We will sequence these subjects to identify sequence variants in candidate genes critical to the cardiac hormonal signaling pathways (the gene for ANP, BNP, the type A and C cardiac hormone receptors, and corin). We will then study the association of these genotypes with prevalent hypertension, cardiac MRIdetermined LVH, and prevalent hypertensive cardiomyopathy in the two ethnic cohorts. In addition we will analyze the association of these genotypes with prognosis in patients with advanced systolic heart failure.