Pharmacogenomics of β-Adrenergic Receptors and Their Accessory Signaling Proteins in Heart Failure
Pharmacogenomics of β-Adrenergic Receptors and Their Accessory Signaling Proteins in Heart Failure
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DOI：
10.1111/j.1752-8062.2008.00059.x
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发表时间：
2008-12-01
影响因子：
3.9
通讯作者：
Liggett, Stephen B.
中科院分区：
文献类型：
--
作者：
Dorn, Gerald W., II;Liggett, Stephen B.
β-肾上腺素能受体（β AR）在心血管细胞上广泛表达。β AR信号传导的药理学刺激或阻断是心源性休克、高血压、缺血、心律失常和心力衰竭的主要治疗手段。对β AR激动剂和拮抗剂反应的个体间变异性促使对编码β AR信号传导途径成员的基因的变异性进行检查。到目前为止，在心力衰竭中已经检测到的主要基因是β（1）AR、β（2）AR和G蛋白偶联受体激酶5（GRK 5）。每一种都具有非同义的多态性，这些多态性改变了基于细胞的系统、遗传改变的小鼠模型或人类心脏中的氨基酸序列和蛋白质功能和调节。在这里，我们回顾了这些表型和已发表的临床研究结果，重点是心力衰竭药物基因组学。到目前为止，很少有研究使用类似的协议或药物，在临床研究中的差异是显而易见的。一种令人信服的方法是使用多种方法来了解变异的分子，细胞和器官表型，并将这些与旨在专门解决这些表型在人类中的相关性的临床研究相结合。毫无疑问，其他基因座将被确定，并将共同为心力衰竭提供遗传驱动的个体化治疗。
beta-adrenergic receptors (beta AR) are widely expressed on cardiovascular cells. Pharmacological stimulation or blockade of beta AR signaling is the therapeutic mainstay in cardiogenic shock, hypertension, ischemia, arrhythmias, and heart failure. Interindividual variability in the response to beta AR agonists and antagonists has prompted examination of variability in the genes encoding beta AR signaling pathway members. Prominent among the genes that have been examined so far in heart failure are the beta(1)AR,beta(2)AR, and G-protein-coupled receptor kinase 5 (GRK5). Each has nonsynonymous polymorphisms that alter amino acid sequence and protein function and regulation in cell-based systems, genetically altered mouse models, or human hearts. Here, we review these phenotypes and results from published clinical studies, with a focus on heart failure pharmacogenomics. Thus far, very few studies have utilized analogous protocols or drugs, and discrepancies in the clinical studies are apparent. A compelling approach is the use of multiple methods to understand the molecular, cellular, and organ phenotypes of a variant and couple these with clinical studies designed to specifically address the relevance of those phenotypes in humans. Undoubtedly, additional loci will be identified, and together, will provide for genetically driven, individualized treatments for heart failure.