β1‐ and β2‐Adrenoceptor polymorphisms and cardiovascular diseases
- 25 August 2009
- journal article
- research article
- Published by Wiley in British Journal of Pharmacology
- Vol. 158 (1), 61-69
- https://doi.org/10.1111/j.1476-5381.2009.00187.x
Abstract
Beta(1)- and beta(2)-adrenoceptors (AR) play a pivotal role in the regulation of cardiovascular function. Both beta-AR subtypes are polymorphic: two single nucleotide polymorphisms (SNPs) have been described for the beta(1)- (Ser49Gly, Arg389Gly) and four for the beta(2)-AR (Arg-19Cys, Arg16Gly, Gln27Glu, Thr164Ile), and they are possibly of functional relevance. In recombinant cell systems, Gly49-beta(1)-AR are more susceptible to agonist-promoted down-regulation than Ser49-beta(1)-AR, whereas Arg389-beta(1)-AR are three to four times more responsive to agonist-evoked stimulation than Gly389-beta(1)-AR. With respect to beta(2)-AR, the Cys-19 variant is associated with greater beta(2)-AR expression than the Arg-19 variant; Gly16-beta(2)-AR are more susceptible, whereas Glu27-beta(2)-AR are almost resistant to agonist-promoted down-regulation; Thr164-beta(2)-AR are three to four times more responsive to agonist-evoked stimulation than Ile164-beta(2)-AR. Several studies addressed potential phenotypic consequences of these SNPs in vivo by influencing and/or contributing to the pathophysiology of cardiovascular/pulmonary diseases such as hypertension, congestive heart failure, arrhythmias or asthma. At present, it appears that these beta-AR SNPs are very likely not disease-causing genes but possibly predictive for the responsiveness to agonists and antagonists. Patients carrying one or two alleles of the Gly389-beta(1)-AR are poor or non-responders to agonists and antagonists, whereas patients homozygous for the Arg389-beta(1)-AR are good responders. Subjects carrying the Ile164-beta(2)-AR exhibit blunted responses to beta(2)-AR stimulation. Asthma patients carrying the Arg16-Gln27-Thr164-beta(2)-AR haplotype who receive regularly short- or long-acting beta(2)-AR agonists are rather susceptible to agonist-induced desensitization and in consequence exhibit reduced bronchodilating and -protective effects and/or increased asthma exacerbations. The clinical relevance of these findings is still under debate.Keywords
This publication has 52 references indexed in Scilit:
- Thr164Ilepolymorphism of β2-adrenergic receptor negatively modulates cardiac contractility: implications for prognosis in patients with idiopathic dilated cardiomyopathyHeart, 2007
- Pharmacogenetics of β‐BlockersPharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 2007
- Real-time optical recording of β1-adrenergic receptor activation reveals supersensitivity of the Arg389 variant to carvedilolJCI Insight, 2007
- A polymorphism within a conserved β 1 -adrenergic receptor motif alters cardiac function and β-blocker response in human heart failureProceedings of the National Academy of Sciences, 2006
- ??1-Adrenergic receptor polymorphisms and left ventricular remodeling changes in response to ??-blocker therapyPharmacogenetics and Genomics, 2005
- Gly16 + Glu27 β2-adrenoceptor polymorphisms cause increased forearm blood flow responses to mental stress and handgrip in humansJournal of Applied Physiology, 2005
- The Arg389Gly ??1-adrenoceptor gene polymorphism determines contractile response to catecholaminesPharmacogenetics, 2004
- Functional responses of human ??1 adrenoceptors with defined haplotypes for the common 389R>G and 49S>G polymorphismsPharmacogenetics, 2004
- β2-adrenoceptor polymorphisms: Relation between in vitro and in vivo phenotypesLife Sciences, 2004
- The Arg 389 Gly β1-adrenergic receptor gene polymorphism and human fat cell lipolysisInternational Journal of Obesity, 2001