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Cardiovascular Pharmacogenomics of Adrenergic Receptor Signaling: Clinical Implications and Future Directions
Author(s) -
Johnson JA,
Liggett SB
Publication year - 2011
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2010.315
Subject(s) - pharmacogenomics , crosstalk , receptor , pharmacogenetics , g protein coupled receptor , clinical pharmacology , biology , pharmacology , bioinformatics , computational biology , single nucleotide polymorphism , signal transduction , gene , genetics , medicine , genotype , physics , optics
G‐protein‐coupled receptors (GPCRs) are the targets for many drugs, and genetic variation in coding and noncoding regions is apparent in many such receptors. In this superfamily, adrenergic receptors (ARs) were among the first in which single‐nucleotide polymorphisms (SNPs) were discovered, and studies including in vitro mutagenesis, genetically modified mouse models, human ex vivo and in vitro studies and pharmacogenetic association studies were conducted. The signal transduction in these receptors includes amplification steps, desensitization, crosstalk, and redundancies, enabling potential mitigation of the size of the clinical effect for a single variant in a single gene. Nevertheless, convincing evidence has emerged that several variants have an impact on therapy, with certain caveats as to how the results are to be interpreted. Here we review these results for selected ARs and associated regulatory kinases relative to the pharmacogenomics of β‐blocker treatment for hypertension and heart failure. We emphasize the linking of clinical results to molecular mechanisms, discuss study design limitations, and offer some recommendations for future directions. Clinical Pharmacology & Therapeutics (2011) 89 3, 366–378. doi: 10.1038/clpt.2010.315