β-1 and β-2 adrenoceptor polymorphisms: Functional importance, impact on cardiovascular diseases and drug responses 1

β-1 and β-2 adrenoceptors (AR) play a pivotal role in regulation of the activity of the sympathetic nervous system and agonists and antagonists at both β AR subtypes are frequently used in treatment of cardiovascular diseases. Both β-1 and β-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, β-1 and β-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 β-1 AR polymorphism might predict responsiveness to β-1 AR agonist and blocker treatment: patients homozygous for the Arg389 β-1 AR polymorphism should be good responders, while patients homozygous for the Gly389 β-1 AR polymorphism should be poor or nonresponders. Furthermore, the Arg16Gln27 β-2 AR seems to have strong impact on long-term agonist-induced β-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 β-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.