Clinical importance of beta-adrenoceptor polymorphisms in cardiovascular disease.
beta-Adrenoceptor antagonists play an important role in the treatment of cardiovascular disease and have been used for three decades in the treatment of hypertension and ischemic heart disease. More recently they have been demonstrated to improve survival in patients with mild to moderate congestive heart failure. The beneficial effects of beta-adrenoceptor antagonists stems from their ability to limit the deleterious effects of adrenergic stimulation, which in the cardiovascular system is primarily transmitted through two subclasses of receptor, beta(1) and beta(2). The advances of the Human Genome Project have led to an increased appreciation that variations in genetic background may underlie a substantial portion of the clinical heterogeneity apparent in cardiovascular disease. This review examines the molecular, functional, and clinical significance of the most common polymorphisms of the beta(1 and beta(2)-adrenoceptors. Initial research in adrenoceptor variation focused on the beta(2)-adrenoceptor. Three common polymorphisms appear to influence receptor function: Arg16-->Gly, Glu(27)-->Gln, and Thr(164)-->Ile. In in vitro studies of agonist stimulation, Gly(16) receptors demonstrate enhanced downregulation, while Glu(27) variants are resistant to downregulation. There is much controversy and conflict among various clinical studies regarding the effect of these variants on vasoreactivity and hypertensive risk. The Ile(164) variant demonstrates decreased responsiveness to agonist activity both in vitro and in animal models. In studies of patients with congestive heart failure, this variant has been associated with poor functional capacity and decreased survival. More recent investigations have focused on the two common polymorphisms of the beta(1)-adrenoceptor: Ser(49)-->Gly, and Arg(389)-->Gly. In vitro studies of Arg(389) receptors demonstrate a gain of function, as agonist stimulation results in significantly higher intracellular levels of cyclic adenosine monophosphate when compared with the Gly(389) variant. Consistent with the in vitro data, clinical studies demonstrate increased responsiveness to beta-agonist stimulation, and an increased risk of hypertension among Arg(389) homozygotes. Further investigation of the clinical implications of these common variants of beta(1)- and beta2)-adrenoceptors are needed. Importantly, the pharmacogenetic impact of these variants on the effectiveness of beta-adrenergic blockade remains unknown.
McNamara
Dennis M
DM
Department of Medicine, Heart Failure Section, University of Pittsburgh, Pittsburgh, Pennsylvania 15213-2582, USA. mcnamaradm@msx.upm.edu
MacGowan
Guy A
GA
London
Barry
B
D000818:Animals; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D011110:Polymorphism, Genetic / Q000235:genetics*; D011943:Receptors, Adrenergic, beta / Q000737:chemistry / Q000235:genetics*
D011943:Receptors, Adrenergic, beta