Alpha 2- and B-adrenergic Receptor Polymorphisms in Heart Failure

肾上腺素能受体（AR）功能对心力衰竭的稳态至关重要。突触前α-2-AR控制交感神经释放去甲肾上腺素，而心肌细胞上表达的β-1-和β-2-AR增加变力性和变时性。然而，AR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中高度可变，并且这种个体间变异性的基础仍然未知。常见遗传变异在易感性、进展和治疗反应中的作用通过表型的家族聚集、家族性心肌病中的低发病率以及三种α 2 AR和两种β AR亚型的功能显著多态性的存在而被提出。 该项目的总体目标是定义关系 AR多态性和心力衰竭表型之间的关系，并确定它们影响完整人类心力衰竭的机制，这将导致基于受体基因型的个性化预后和治疗。 在目标1中，我们将完成这些无内含子基因的多态性发现，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。在目标2中，我们将对α 2c和β 1AR的2个基因单倍型进行关联和同胞研究，以确定心力衰竭风险。在对个体α 2c和β 1AR的初步研究中， 多态性，我们发现非裔美国人心力衰竭的风险增加了10倍。扩展单倍型的使用将潜在地提供更大的区分力，并精确地定义基因-基因和基因-环境相互作用。在目标3中，将确定在没有β受体阻滞剂治疗的情况下，根据纯合β 1 AR单倍型分层的早期和晚期衰竭患者的心脏β 1 AR功能状态。从转基因小鼠中，我们发现多态性β 1 AR在失败过程中经历表型转换，这意味着存在治疗干预的机会“窗口”。研究将涉及对β 1 AR激动剂多巴酚丁胺、非受体正性肌力药米力农和运动反应的心脏功能的侵入性血流动力学测试。在回顾性研究中，我们发现β 1 AR多态性可能与β受体阻滞剂的治疗反应有关。 为了进一步研究这一点，在目标4中，我们将进行一项前瞻性、双盲、 对纯合β 1 AR单倍型患者进行长期研究，以确定β 1 AR遗传变异性对卡维地洛反应的影响。如果这种关系成立，这将是第一个药物遗传学测试，以预测谁将最有可能响应，而不是响应，这类疗法。

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.