Adrenergic Receptor Polymorphisms and Cardiac Function (and Dysfunction)
A Failure to Communicate?
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For a number of cardiovascular diseases, it has been proposed that both the susceptibility to disease and the interindividual variability in response to treatment relates in part to genetic polymorphisms, particularly those polymorphisms for neurotransmitter and drug receptors. Perhaps the most intensively studied family of receptors are the G-protein–coupled receptors, of which the β-adrenergic receptor is the prototype.
The β-adrenergic receptor family members (β1, β2, and β3) are highly polymorphic. Further, specific single-nucleotide polymorphisms have been associated with a range of cardiovascular diseases and cardiovascular risk factors, including obesity, hypertension, diabetes, and congestive heart failure.1 However, although a number of genetic polymorphisms of the β-adrenergic receptor have been linked to an increased risk of cardiovascular and respiratory diseases, ultimately the proof of the importance of these polymorphisms beyond that of a risk marker is dependant on the characterization of an intermediate phenotype that could be linked to the presentation of the disease or a response to therapy. This is the importance of the current findings from Brodde and colleagues2 in this issue of Circulation.
In patients with congestive heart failure, polymorphisms of both β1- and β2-adrenergic receptors have been linked with disease expression. N-terminal polymorphisms of the β1-adrenoceptor have been associated with an increased risk of developing idiopathic dilated cardiomyopathy.3 However, most attention has been focused on single-nucleotide polymorphisms of the β2-adrenergic receptor. Specifically, a relatively rare polymorphism at amino acid 164 of the β2- adrenergic receptor (Ile164, occurring in <5% of the general population) has been associated with worse outcomes in patients with congestive heart failure4 and greater impairment in exercise capacity in these patients.5 However, the pathobiological mechanism …