Beta-1 and beta-2 adrenoceptor polymorphisms: functional importance, impact on cardiovascular diseases and drug responses.

Beta-1 and beta-2 adrenoceptors (AR) play a pivotal role in regulation of the activity of the sympathetic nervous system and agonists and antagonists at both beta AR subtypes are frequently used in treatment of cardiovascular diseases. Both beta-1 and beta-2 AR genes have several polymorphisms that encode different amino acids. This review summarizes new insights into the functional importance of these polymorphisms, as well as their relationship to cardiovascular diseases and their impact on responses to adrenergic drug treatment. At present, it seems that, for cardiovascular diseases, beta-1 and beta-2 AR polymorphisms do not play a role as disease-causing genes; they might, however, be associated with disease-related phenotypes. In addition they could influence adrenergic drug responses. Thus, the Arg389Gly beta-1 AR polymorphism might 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 or nonresponders. Furthermore, the Arg16Gln27 beta-2 AR seems to have strong impact on long-term agonist-induced beta-2 AR desensitization. Thus, patients carrying this haplotype appear to suffer from rapid loss of therapeutic efficacy of chronic agonist treatment, as has been demonstrated in asthma patients. Moreover, the Arg16Gln27 beta-2 AR haplotype might have some predictive value for poor outcome of heart failure. Future large prospective studies have to replicate these findings in order to reach the final goal of pharmacogenomic research: to optimize and individualize drug therapy based on the patient's genetic determinants of drug efficacy.