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

肾上腺素能受体(AR)功能对心力衰竭的动态平衡至关重要。突触前α-2-AR控制交感神经去甲肾上腺素的释放，而心肌细胞表达的β-1和β-2-AR增加变力和变时性。然而，ARs的表达和功能、临床进展以及对β-受体阻滞剂的反应在心力衰竭中是高度可变的，这种个体间差异的基础仍然未知。通过表型的家族聚集性，家族性心肌病的外显性降低，以及三个α2AR和两个βAR亚型功能上显著的多态性的存在，表明了常见的遗传变异在易感性、进展和治疗反应中的作用。本项目的总体目标是定义 目的：研究AR基因多态性与心力衰竭表型之间的关系，并确定其影响正常人心力衰竭的机制，从而根据受体基因型别制定个性化的预后和治疗方案。在目标1中，我们将完成这些无内含子基因的多态发现，组装单倍型，并进行体外研究，以评估遗传变异对受体表达、功能或调节的影响。在目标2中，我们将对α2c和β1AR的2个基因单倍型进行关联和同胞研究，以确定心力衰竭的风险。在个体α2c和β1AR的初步研究中 我们发现，在非裔美国人中，心力衰竭的风险是后者的10倍。扩展单倍型的使用可能会提供更大的鉴别力，并精确地定义基因-基因和基因-环境的相互作用。在目标3中，将确定在没有β-受体阻滞剂治疗的早期和晚期衰竭患者中心脏β1AR的功能状态，按纯合子β1AR单倍型进行分层。从转基因小鼠中，我们发现在失败的过程中，多态的Beta1AR经历了表型转换，这意味着有机会进行治疗干预。研究将涉及对β1AR激动剂多巴酚丁胺、非受体促肌力米力农和运动的心功能进行有创性血流动力学测试。在回溯性研究中，我们已经表明，β-受体基因的多态性可能与对β-受体阻滞剂的治疗反应有关。为了进一步检验这一点，在目标4中，我们将进行前瞻性、双盲、 长期对纯合子β-1AR单倍型患者的研究，以确定β-1AR遗传变异对卡维地洛反应的影响。如果这种关系保持不变，这将是第一个预测谁最有可能对这类疗法有反应而不是有反应的药物遗传学测试。

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.