Associate editor: H. Bönisch
β-1 and β-2 adrenoceptor polymorphisms: Functional importance, impact on cardiovascular diseases and drug responses1

https://doi.org/10.1016/j.pharmthera.2007.07.002Get rights and content

Abstract

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.

Introduction

β-1 and β-2 adrenoceptors (AR), targets of the endogenous catecholamines noradrenaline and adrenaline, play a pivotal role in regulation of the activity of the sympathetic nervous system. β-1 AR are expressed in the heart where they mediate increases in heart rate and contractility, in the kidney where they mediate release of renin and, by this, activation of the renin–angiotensin–aldosterone system and in adipocytes where they mediate lipolysis (Brodde & Michel, 1999). β-2 AR are abundantly expressed on bronchial and vascular smooth muscle cells where they mediate bronchodilation and vasodilation (Guimaraes & Moura, 2001). They are also expressed in the heart and can mediate positive inotropic and chronotropic effects, but to a lesser extent than do β-1 AR, and are found on glands, lymphocytes and hepatocytes.

Thus, β-1 and β-2 AR are involved in manifold effects of the sympathetic nervous system and might be, therefore, involved pathophysiologically in cardiovascular diseases; moreover, they are often used as targets for drug treatment of cardiovascular diseases. In fact, β-1 AR agonists, such as dobutamine, are often used to acutely give the failing heart inotropic support, and β-2 AR agonists are frequently used in therapy of asthma. In addition, β-1 and β-1 and β-2 AR antagonists (β AR blocker) are first line drugs in treatment of hypertension, stable and unstable angina, acute and post myocardial infarction, ventricular and supraventricular arrhythmias and chronic heart failure (CHF).

It has been known for a very long time that β-1 and β-2 AR responses to drug treatment exhibit marked interindividual variability within the human population. Since the discovery that β-1 AR (Maqbool et al., 1999, Mason et al., 1999, Tesson et al., 1999, Börjesson et al., 2000) and β-2 AR (Green et al., 1993, Reihsaus et al., 1993, Green et al., 1994) are polymorphic, numerous attempts have been made to find out whether these polymorphisms might be, at least partly, responsible for the marked interpatient variability in the cause of cardiovascular diseases and in responses to β AR drug treatment. The aim of this review is therefore to discuss the possible pathophysiological importance of β-1 and β-2 AR polymorphisms for cardiovascular diseases and their impact on responses to β AR drug treatment.

Section snippets

Functional properties of β-1 adrenoceptor polymorphisms

The β-1 AR is encoded by an intronless gene located on chromosome 10q24–26, consisting of a short 5′ untranslated region (UTR) of 86 bp, an open reading frame that encodes a protein of 477 amino acid residues and 3′ UTR of about 900 bp (Frielle et al., 1987). There are 2 major single nucleotide polymorphisms (SNP) in the human β-1 AR coding region: at position 49 in the amino-terminus of the receptor, a serine (Ser) is substituted by a glycine (Gly; Maqbool et al., 1999, Börjesson et al., 2000)

Functional properties of β-2 adrenoceptor polymorphisms

The human β-2 AR, encoded by an intronless gene, is located on chromosome 5q31–32 (Kobilka et al., 1987). In the β-2 AR coding region, 12 single base substitutions have been identified; 5 of these are nonsynonymous (Arg16Gly, Gln27Glu, Val34Met, Thr164Ile and Ser220Cys; for allele frequencies among different racial/ethnic groups, see Table 6) whereas 7 are synonymous and are unlikely to be functionally significant (Table 6) although Silverman et al. (2003) could show that the SNP +523 might

Summary and conclusion

The data published so far clearly indicate that β-1 AR polymorphisms appear not to be disease-causing genes, neither in hypertension or coronary artery disease nor in heart failure. This appears to be also true for the combination of the α-2CDel AR polymorphism (which can be associated with enhanced release of noradrenaline) and the Arg389 β-1 AR polymorphism: the original finding of Small et al. (2002) that this combination significantly increases the risk of heart failure in African Americans

Acknowledgments

Part of the authors work cited in this review was supported by the Deutsche Forschungsgemeinschaft (Bonn/Germany: grant DFG BR 526/8-1; SFB 598-02, BR526/8-3, BR526/10-1; BR526/12-1), the Deutsche Herzstiftung und the Nationales Genomforschungsnetz (Förderzeichen 01GS0107 to O.-E.B.).

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    The editors note that after completion of this manuscript Dr. Brodde passed away on October 13th, 2007. His contribution to science, in general, and β-adrenoceptor research, in particular, will be sorely missed.

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