β 1- and β 2-Adrenoceptor polymorphisms and cardiovascular diseases

Abstract

β 1- and β 2-Adrenoceptors (AR) play a pivotal role in the regulation of cardiovascular function. Both β-AR subtypes are polymorphic: two single nucleotide polymorphisms (SNPs) have been described for the β 1- (Ser49Gly, Arg389Gly) and four for the β 2-AR (Arg-19Cys, Arg16Gly, Gln27Glu, Thr164Ile), and they are possibly of functional relevance. In recombinant cell systems, Gly49-β 1-AR are more susceptible to agonist-promoted down-regulation than Ser49-β 1-AR, whereas Arg389- β 1-AR are three to four times more responsive to agonist-evoked stimulation than Gly389-β 1-AR. With respect to β 2-AR, the Cys-19 variant is associated with greater β 2-AR expression than the Arg-19 variant; Gly16- β 2-AR are more susceptible, whereas Glu27-β 2-AR are almost resistant to agonist-promoted down-regulation; Thr164- β 2-AR are three to four times more responsive to agonist-evoked stimulation than Ile164-β 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 β-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-β 1-AR are poor or non-responders to agonists and antagonists, whereas patients homozygous for the Arg389-β 1-AR are good responders. Subjects carrying the Ile164-β 2-AR exhibit blunted responses to β 2-AR stimulation. Asthma patients carrying the Arg16-Gln27-Thr164-β 2- AR haplotype who receive regularly short- or long-acting β 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. © 2009 The British Pharmacological Society.