Beta 1- and beta 2-adrenoceptor polymorphisms and cardiovascular diseases.

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.