The emerging pharmacogenomics of the beta-adrenergic receptors.

Beta-adrenergic signaling mechanisms are of central importance to cardiovascular health and disease. Modulation of these pathways represents an important pharmacologic approach to the treatment of heart failure and hypertension. Advances in molecular genetics have identified genetic polymorphisms in the human beta-adrenergic receptor genes; some of this variation predicts changes in protein sequence/structure, and potentially changes in function, of the b-adrenergic receptors. This article reviews the current state of knowledge and understanding of the genetic variation present in the three human beta-adrenergic receptor genes. Already, variation in these genes has been associated with observed differences in several cardiovascular phenotypes. This work has led to the demonstration of functional differences in activity between receptors with certain known polymorphisms and "wild-type" receptors. An understanding of these polymorphisms is key to the development of studies of how differences in drug response/effects may be mediated by these polymorphisms. Such studies are anticipated to provide a foundation for the development of novel pharmacologic approaches where selection of and dosing of cardiovascular therapy is tailored to individuals on the basis of each patient's specific genetic makeup.