Genetic determinants of aldosterone escape in heart failure

心力衰竭中醛固酮逃逸的遗传决定因素

• 批准号: 7575589
• 负责人: Larisa Humma Cavallari
• 金额: $ 6.44万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7575589
• 关键词: ABCB1 gene; Adverse effects; Affect; Aldosterone; Aldosterone Antagonists; Aldosterone Synthase; American; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Atrial Natriuretic Factor; CYP11B2 gene; Cardiac Volume; Data; Development; Disease Progression; Elderly; Exposure to; Frequencies; Functional disorder; Gene Proteins; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genotype; Glycoproteins; Goals; Heart failure; Hormones; Hospitalization; Investigation; Lead; Liquid substance; Mediating; N-propionylprocainamide; Outcome; P-Glycoprotein; Patients; Peptidyl-Dipeptidase A; Persons; Play; Proteins; Public Health; Renin; Renin-Angiotensin-Aldosterone System; Risk; Risk Factors; Role; Standards of Weights and Measures; System; Testing; genetic association; human CYP11B2 protein; hyperkalemia; improved; insight; older patient; response

DESCRIPTION (provided by applicant): Heart failure affects over 5 million Americans and is the leading cause for hospitalization in the elderly. The renin-angiotensin-aldosterone system (RAAS) plays a central role in heart failure development and progression. Angiotensin converting enzyme (ACE) inhibitors are cornerstone therapy to suppress the RAAS; however, aldosterone levels rise in a subset of patients despite continued ACE inhibitor treatment. This phenomenon, known as aldosterone escape, may have important consequences given the deleterious effects of aldosterone on fluid volume and cardiac remodeling. There are limited data on whether genes for proteins that regulate aldosterone secretion influence the risk for aldosterone escape. The focus of this proposal is to determine whether the genes for ACE, aldosterone synthase (CYP11B2), atrial natriuretic peptide (NPPA), and p- glycoprotein (ABCB1) contribute to aldosterone escape during ACE inhibitor therapy in heart failure. The long-term goal of this line of investigation is to determine whether genotype is predictive of response to aldosterone antagonists in heart failure. This study will test the hypothesis that the ACE, CYP11B2, NPPA, and/or ABCB1 genes are associated with aldosterone escape in heart failure. Our specific aims are (1) to determine whether the ACE, CYP11B2, NPPA, and/or ABCB1 genes are associated with aldosterone escape in heart failure by comparing ACE I/D, CYP11B2 T-344C, NPPA C-664G and T2238C, and ABCB1 C3435T genotype frequencies between heart failure patients with a circulating aldosterone level >150 pg/ml despite ACE inhibitor treatment and those with a lower level; and (2) to examine the mechanism underlying genetic associations with aldosterone escape by estimating the correlation between circulating aldosterone and both angiotensin II and atrial natriuretic peptide concentrations in ACE inhibitor-treated heart failure patients. The proposed study is important because insight into genetic contributions to aldosterone escape could ultimately lead to the ability to predict which patients are at risk for aldosterone-mediated disease progression despite standard therapy, in whom the additional therapy to antagonize aldosterone might be particularly beneficial. PUBLIC HEALTH RELEVANCE: Heart failure is the most common cause for hospitalization in the elderly. Aldosterone is a hormone that promotes heart failure development and progression. This study aims to determine whether a person's genetic makeup affects his or her risk for elevated aldosterone levels despite standard therapy in heart failure.

描述（由申请人提供）：心力衰竭影响超过 500 万美国人，是老年人住院的主要原因。肾素-血管紧张素-醛固酮系统（RAAS）在心力衰竭的发生和进展中发挥着核心作用。血管紧张素转换酶 (ACE) 抑制剂是抑制 RAAS 的基础疗法；然而，尽管持续接受 ACE 抑制剂治疗，部分患者的醛固酮水平仍会上升。鉴于醛固酮对体液容量和心脏重塑的有害影响，这种被称为醛固酮逃逸的现象可能会产生重要后果。关于调节醛固酮分泌的蛋白质基因是否影响醛固酮逃逸风险的数据有限。该提案的重点是确定 ACE、醛固酮合酶 (CYP11B2)、心房钠尿肽 (NPPA) 和 p-糖蛋白 (ABCB1) 的基因是否有助于心力衰竭 ACE 抑制剂治疗期间醛固酮逃逸。该研究的长期目标是确定基因型是否可以预测心力衰竭中醛固酮拮抗剂的反应。本研究将检验 ACE、CYP11B2、NPPA 和/或 ABCB1 基因与心力衰竭中醛固酮逃逸相关的假设。我们的具体目标是 (1) 通过比较 ACE I/D、CYP11B2 T-344C、NPPA C-664G 和 T2238C 来确定 ACE、CYP11B2、NPPA 和/或 ABCB1 基因是否与心力衰竭中醛固酮逃逸相关，以及循环醛固酮水平 >150 pg/ml 的心力衰竭患者之间的 ABCB1 C3435T 基因型频率尽管接受 ACE 抑制剂治疗且水平较低； (2) 通过评估接受 ACE 抑制剂治疗的心力衰竭患者的循环醛固酮与血管紧张素 II 和心房钠尿肽浓度之间的相关性，研究与醛固酮逃逸的遗传相关性的潜在机制。这项拟议的研究很重要，因为深入了解醛固酮逃逸的遗传因素可能最终能够预测哪些患者尽管接受了标准治疗，但仍面临醛固酮介导的疾病进展的风险，而拮抗醛固酮的额外治疗可能对这些患者特别有益。 公共卫生相关性：心力衰竭是老年人住院的最常见原因。醛固酮是一种促进心力衰竭发生和进展的激素。这项研究旨在确定一个人的基因构成是否会影响他或她在接受心力衰竭标准治疗的情况下醛固酮水平升高的风险。