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: 6785310
• 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/6785310
• 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）： 内源性心脏激素系统（CHS）调节血压， 高血压引起的左心室肥厚（LVH）， 并延缓收缩性心力衰竭的进展。的“传入肢” CHS是指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”描述了这些激素在靶标中的生物作用 组织。血浆 cGMP 水平与传出血浆密切相关 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 和传出心脏激素信号传导途径以及基因-基因相互作用 这些基因型和 ACE 基因之间的差异，有助于个体间的 高血压心脏病的易感性存在差异。而且， 这些等位基因在特殊人群中的频率差异可能 解释非洲裔美国人对 LVH、发育的敏感性增加 心力衰竭的发生以及已确定的心力衰竭的进展。为了 解决这些假设，我们将识别未经治疗的患者 大约随机人群样本中的高血压和 LVH。 3,000 个科目。 然后我们将比较非洲人 CHS 的传入和传出功能 患有未经治疗的高血压和左心室的美国和白人受试者 肥大，并识别以减少为特征的表型 CHS 的传入或传出功能。我们将 对这些受试者进行测序以识别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 型心脏激素受体和 corin）。接下来我们将学习 这些基因型与流行性高血压、心脏 MRI 确定的关联 LVH 和两个种族中流行的高血压心肌病 队列。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。