Pharmacogenomics of beta-adrenergic receptors and their accessory signaling proteins in heart failure.
beta-Adrenergic receptors (betaAR) are widely expressed on cardiovascular cells. Pharmacological stimulation or blockade of betaAR signaling is the therapeutic mainstay in cardiogenic shock, hypertension, ischemia, arrhythmias, and heart failure. Interindividual variability in the response to betaAR agonists and antagonists has prompted examination of variability in the genes encoding betaAR 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.
Dorn
Gerald W
GW
Center for Pharmacogenomics, Department of Internal Medicine, Washington University, St. Louis, Missouri, USA. gdorn@dom.wustl
Liggett
Stephen B
SB
D000818:Animals; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011943:Receptors, Adrenergic, beta / Q000235:genetics*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D015398:Signal Transduction; D057170:Translational Research, Biomedical
D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human