A2-/B-adrenergic Receptor Polymorphisms in Heart Failure

心力衰竭中的 A2-/B-肾上腺素能受体多态性

• 批准号: 6892774
• 负责人: Stephen B Liggett
• 金额: $ 36.89万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6892774
• 关键词: African American; Hispanic Americans; alpha adrenergic receptor; beta adrenergic receptor; beta antiadrenergic agent; blood tests; caucasian American; clinical trials; disease /disorder onset; family genetics; gene environment interaction; gene interaction; genetic polymorphism; genetic susceptibility; heart catheterization; heart failure; heart function; human subject; human therapy evaluation; longitudinal human study; patient care management; patient oriented research; pharmacogenetics; phenotype; prognosis; receptor expression; therapy design /development

Adrenergic receptor (AR) function is critical for homeostasis in heart failure. Presynaptic alpha-2-AR control norepinephrine release from sympathetic nerves, while beta-1-and beta-2-AR expressed on cardiomyocytes increase inotropy and chronotropy. However, the expression and function of ARs, clinical progression, and response to beta-blockers is highly variable in heart failure, and the basis of this interindividual variability remains unknown. A role for common genetic variants in susceptibility, progression and therapeutic response is suggested by familial clustering of phenotypes, reduced penetrance in familial cardiomyopathies, and the existence of functionally significant polymorphisms of the three alpha2AR and two betaAR subtypes. The overall goal of this project is to define the relationships between AR polymorphisms and heart failure phenotypes, and to determine the mechanism by which they affect heart failure in the intact human, which will lead to personalized prognosis and treatment, based on receptor genotype. In Aim 1 we will complete polymorphism discovery in these intronless genes, assemble haplotypes and carry out in vitro studies to assess the consequences of genetic variation on receptor expression, function or regulation. In Aim 2, we will carry out an association and sibling study of 2-gene haplotypes of the alpha2c and beta1AR to ascertain heart failure risk. In an initial study of individual alpha2c and beta1AR polymorphisms, we found a 10-fold risk for heart failure in African-Americans. The use of extended haplotypes will potentially provide greater discrimination and precisely define the gene-gene and gene-environment interactions. In Aim 3 the functional status of cardiac beta1AR in patients with early and late failure in the absence of beta-blocker treatment, stratified by homozygous beta1AR haplotypes, will be ascertained. From transgenic mice, we have found that polymorphic beta1AR undergo phenotypic switching during the course of failure, which implies that there are "windows" of opportunity for therapeutic intervention. Studies will involve invasive hemodynamic testing of cardiac function in response to the beta1AR agonist dobutamine, the nonreceptor inotrope milrinone, and exercise. In retrospective studies we have shown that a beta1AR polymorphism may be associated with treatment response to beta-blocker. To further examine this, in Aim 4 we will carry out a prospective, double-blind, long-term, study of patients with homozygous beta1AR haplotypes to ascertain the effect of beta1AR genetic variability on carvedilol response. If the relationship holds, this would be the first pharmacogenetic test to predict who will be most likely to respond, and not respond, to this class of therapeutics.

肾上腺素能受体（AR）功能对于心力衰竭中的稳态至关重要。突触前的α-2-AR对照从交感神经中释放出去甲肾上腺素，而在心肌细胞上表达的β-1和β-2-AR会增加肌瘤和成年疗法。但是，ARS的表达和功能，临床进展和对β受体阻滞剂的反应在心力衰竭上是高度变化，并且这种个体差异的基础尚不清楚。共同遗传变异在易感性，进展和治疗反应中的作用是由家族性的表型聚类，家族性心肌病的渗透率降低以及三种α2AR和两个βAR亚型的功能显着多态性的存在。 该项目的总体目标是定义关系 在AR多态性和心力衰竭表型之间，并确定它们影响完整人心力衰竭的机制，这将基于受体基因型导致个性化的预后和治疗。 在AIM 1中，我们将在这些内固有基因中完成多态性发现，组装单倍型并进行体外研究，以评估遗传变异对受体表达，功能或调节的后果。在AIM 2中，我们将对α2C和Beta1AR的2基因单倍型进行关联和兄弟姐妹研究，以确定心力衰竭的风险。在对单个alpha2c和beta1ar的初步研究中 多态性，我们发现非裔美国人心力衰竭有10倍的风险。扩展单倍型的使用将有可能提供更大的歧视，并精确定义基因基因和基因环境相互作用。在AIM 3中，将确定在缺乏β受体阻滞剂治疗的情况下，通过纯合β1AR单倍型分层的患者心脏β1AR的功能状态。从转基因小鼠中，我们发现多态性β1AR在失败过程中会经历表型转换，这意味着治疗干预的机会“窗口”。研究将涉及对心脏功能的侵入性血液动力学测试，以响应β1AR激动剂多巴达胺，非受体肌电肌电肌和运动。在回顾性研究中，我们表明β1AR多态性可能与对β受体阻滞剂的治疗反应有关。 为了进一步研究这一点，在AIM 4中，我们将执行一个预期的双盲 长期的，对纯合β1AR单倍型患者的研究，以确定β1AR遗传变异性对卡维地（Carvedilol）反应的影响。如果这种关系成立，这将是第一个预测谁最有可能反应而不反应的药物遗传学测试。