title: Beta1- and beta2-adrenoceptor polymorphisms and cardiovascular diseases.
abstract: Beta(1)- and beta(2)-adrenoceptors (AR) play a pivotal role in regulation of the cardiovascular system. Both beta-AR subtypes are polymorphic. There are two major single nucleotide polymorphisms (SNPs) in the beta(1)-AR gene: the Ser49Gly and Arg389Gly beta(1)-AR polymorphisms. In vitro, in recombinant cell systems Gly49 beta(1)-AR is much more susceptible to agonist-promoted downregulation than Ser49 beta(1)-AR, while Arg389 beta(1)-AR is three to four times more responsive to agonist-evoked stimulation than Gly389 beta(1)-AR. There are three major SNPs in the beta(2)-AR gene: the Arg16Gly, Gln27Glu and Thr164Ile beta(2)-AR polymorphisms (occur in humans only in the heterozygous form). In recombinant cell systems Gly16 beta(2)-AR is much more susceptible to agonist-promoted downregulation while Glu27 beta(2)-AR is rather resistant to agonist-induced downregulation but only in combination with Arg16, that occurs naturally extremely rare. Thr164 beta(2)-AR is three to four times more responsive to agonist-evoked stimulation than Ile164 beta(2)-AR. This review summarizes results from various studies on the possible relationship of these polymorphisms to cardiovascular diseases. At present it appears to be clear that, for cardiovascular diseases such as hypertension, coronary artery disease and chronic heart failure, beta(1)- and beta(2)-AR polymorphisms do not play a role as disease-causing genes; however, they might affect drug responses. Thus, it might be possible, by assessing the beta(1)-AR genotype, to predict responsiveness to beta(1)-AR agonist and -blocker treatment: patients homozygous for the Arg389 beta(1)-AR polymorphism should be good responders while patients homozygous for the Gly389 beta(1)-AR polymorphism should be poor responders or non-responders. Furthermore, subjects heterozygous for the Thr164Ile beta(2)-AR polymorphism exhibit blunted responses to beta(2)-AR stimulation. Finally, the Arg16Gln27 beta(2)-AR haplotype appears to be - at least in human vascular and bronchial smooth muscles - rather susceptible to agonist-induced desensitization (in contrast to the recombinant cell system findings), and might have some predictive value for poor outcome of heart failure. However, future large prospective studies have to replicate these findings in order to substantiate their clinical relevance.
authors: Department of Pathophysiology, University of Essen School of Medicine, D-45147 Essen, Germany.
authors: Otto-Erich
authors: OE
authors: Brodde
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000818:Animals; D002318:Cardiovascular Diseases / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2