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Published online before print December 12, 2008

0031-6997/08/6004-513-535$7.00
Pharmacol Rev 60:513-535, 2008

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Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine

Dieter Rosskopf and Martin C. Michel

Department of Pharmacology, Ernst-Moritz-Arndt University, Greifswald, Germany (D.R.); and Department of Pharmacology & Pharmacotherapy, Academic Medical Center, University of Amsterdam, the Netherlands (M.C.M.)

Abstract
I. Introduction
II. Adrenergic Receptor Ligands
    A. alpha1-Adrenergic Receptor Ligands
    B. alpha2-Adrenergic Receptor Ligands
    C. β-Adrenergic Receptor Ligands
        1. β-Agonist Responses.
        2. β-Antagonist Responses.
III. Angiotensin II Receptor Ligands and Inhibitors of Angiotensin-Converting Enzyme
    A. Angiotensin-Converting Enzyme Inhibitors and Genetic Variants in the Angiotensin-Converting Enzyme Gene
    B. Variants in the AT1 Receptor Gene and Responses to AT1 Blockers
IV. Ligands at Other G Protein-Coupled Receptors
    A. Muscarinic Acetylcholine Receptors
    B. Vasopressin Receptors
    C. Endothelin Receptors
V. Conclusions and Prospects
Agonists and antagonists of G protein-coupled receptors are important drugs for the treatment of cardiovascular disease, but the therapeutic response of any given patient remains difficult to predict because of large interindividual variability. Among the factors potentially contributing to such variability, we have reviewed the evidence for a role of pharmacodynamic pharmacogenetics (i.e., polymorphisms in the cognate receptors for such drugs as well as other proteins potentially modifying their action). Based upon the availability of data and the prevalence of use, we have focused on ligands at adrenergic and angiotensin II receptors (including the indirectly acting angiotensin-converting enzyme inhibitors). The vast majority of gene polymorphisms reviewed here have shown only inconsistent effects on drug action, which does not make these polymorphisms useful genetic markers to predict treatment responses. We conclude that considerable additional research, partly involving other types of study than those available now, will be necessary to allow a definitive judgment whether pharmacodynamic pharmacogenetic markers are useful in an individualized approach to cardiovascular therapy. Moreover, we predict that even such additional research will result in only few cases where the promise of tailored treatment can be fulfilled; however, some of these few cases may be of major clinical relevance.

Address correspondence to: Martin C. Michel, Dept. Pharmacology & Pharmacotherapy, AMC, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, Netherlands. E-mail: m.c.michel{at}amc.uva.nl






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