Journal article
Clinical Importance of β-Adrenoceptor Polymorphisms in Cardiovascular Disease
American journal of pharmacogenomics, Vol.2(2), pp.73-78
06/2002
DOI: 10.2165/00129785-200202020-00001
PMID: 12083943
Abstract
β-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 β-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, β1 and β2. 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 β1- and β2-adrenoceptors.Initial research in adrenoceptor variation focused on the β2-adrenoceptor. Three common polymorphisms appear to influence receptor function: Arg16→Gly, Glu27→Gln, and Thr164→Ile. In in vitro studies of agonist stimulation, Gly16 receptors demonstrate enhanced downregulation, while Glu27 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 Ile164 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 β1-adrenoceptor: Ser49→Gly, and Arg389→Gly. In vitro studies of Arg389 receptors demonstrate a gain of function, as agonist stimulation results in significantly higher intracellular levels of cyclic adenosine monophosphate when compared with the Gly389 variant. Consistent with the in vitro data, clinical studies demonstrate increased responsiveness to β-agonist stimulation, and an increased risk of hypertension among Arg389 homozygotes.Further investigation of the clinical implications of these common variants of β1- and β2-adrenoceptors are needed. Importantly, the pharmacogenetic impact of these variants on the effectiveness of β-adrenergic blockade remains unknown.
Details
- Title: Subtitle
- Clinical Importance of β-Adrenoceptor Polymorphisms in Cardiovascular Disease
- Creators
- Dennis McNamara - Department of Medicine, Heart Failure Section University of Pittsburgh S-558 Scaife Hall, 200 Lothrop Street Pittsburgh Pennsylvania 15213-2582 USAGuy MacGowan - Department of Medicine, Heart Failure Section University of Pittsburgh S-558 Scaife Hall, 200 Lothrop Street Pittsburgh Pennsylvania 15213-2582 USABarry London - Department of Medicine, Heart Failure Section University of Pittsburgh S-558 Scaife Hall, 200 Lothrop Street Pittsburgh Pennsylvania 15213-2582 USA
- Resource Type
- Journal article
- Publication Details
- American journal of pharmacogenomics, Vol.2(2), pp.73-78
- Publisher
- Springer International Publishing; Cham
- DOI
- 10.2165/00129785-200202020-00001
- PMID
- 12083943
- ISSN
- 1175-2203
- Language
- English
- Date published
- 06/2002
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984025567202771
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