Genetic Determinants of Hypertension, LVH, and CHF

高血压、左心室肥厚和慢性心力衰竭的遗传决定因素

• 批准号: 7122065
• 负责人: Daniel L Dries
• 金额: $ 14.96万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-17 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7122065
• 关键词: African American; atrial natriuretic peptide; biological signal transduction; cardiovascular disorder epidemiology; caucasian American; clinical research; congestive heart failure; gene environment interaction; gene interaction; genetic susceptibility; heart function; hormone regulation /control mechanism; human subject; hypertension; muscle proteins; neuropeptide receptor; patient oriented research; peptide hormone; racial /ethnic difference; serine proteinases; ventricular hypertrophy

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.

描述（由申请人提供）： 内源性心荷尔蒙系统（CHS）调节血压， 响应高血压的左心室肥大（LVH）的发展， 并延迟了收缩性心力衰竭的进展。的“传入” CHS是指心肌释放心房和大脑的能力 脂肪肽（ANP和BNP）响应压力超负荷，并 “肢体”描述了这些激素在靶标的生物学作用 组织。 CGMP的血浆水平与传出密切相关 心脏激素的作用提供了一种经过验证的方法来测量 CHS在人类中的传出功能。我们假设这种基因环境 涉及与传入的关键成分有关的基因的相互作用 和发出的心脏激素信号通路和基因 - 基因相互作用 在这些基因型和王牌之间，有助于个人间 对高血压心脏病的敏感性变化。而且， 特殊人群中这些等位基因的频率的差异可能 解释非裔美国人对LVH的敏感性增加，发展 心力衰竭和既定心力衰竭的进展。为了 解决这些假设，我们将确定未经治疗的患者 在随机人群样本中的高血压和LVH。 3,000名受试者。 然后，我们将比较CHS在非洲中的传入和传出功能 具有未经治疗的高血压和左室的美国和高加索受试者 肥大，并确定以减少为特征的表型 CHS传入或传出功能的功能。我们将 序列这些受试者以识别候选基因中的序列变体 对心脏激素信号通路至关重要（ANP，BNP的基因 A型和C心血激素受体和Corin）。然后我们将学习 这些基因型与普遍的高血压的关联 LVH和两个种族中普遍的高血压心肌病 同伙。此外，我们将分析这些基因型与 晚期收缩性心力衰竭患者的预后。