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Molecular Pharmacology

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Mechanisms of Pharmacogenomic Effects of Genetic Variation within the Cardiac Adrenergic Network in Heart Failure

Gerald W. Dorn II and Stephen B. Liggett
Molecular Pharmacology September 2009, 76 (3) 466-480; DOI: https://doi.org/10.1124/mol.109.056572
Gerald W. Dorn II
Center for Pharmacogenomics, Department of Internal Medicine, Washington University, St. Louis, Missouri (G.W.D.); and Cardiopulmonary Genomics Program, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland (S.B.L.)
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Stephen B. Liggett
Center for Pharmacogenomics, Department of Internal Medicine, Washington University, St. Louis, Missouri (G.W.D.); and Cardiopulmonary Genomics Program, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland (S.B.L.)
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Abstract

One of the goals of pharmacogenomics is the use of genetic variants to predict an individual's response to treatment. Although numerous candidate and genome-wide associations have been made for cardiovascular response-outcomes, little is known about how a given polymorphism imposes the phenotype. Such mechanisms are important, because they tie the observed human response to specific signaling alterations and thus provide cause-and-effect relationships, aid in the design of hypothesis-based clinical studies, can help to devise workaround drugs, and can reveal new aspects of the pathophysiology of the disease. Here we discuss polymorphisms within the adrenergic receptor network in the context of heart failure and β-adrenergic receptor blocker therapy, where multiple approaches to understand the mechanism have been undertaken. We propose a comprehensive series of studies, ranging from transfected cells, transgenic mice, and ex vivo and in vitro human studies as a model approach to explore mechanisms of action of pharmacogenomic effects and extend the field beyond observational associations.

Footnotes

    • Received March 26, 2009.
    • Accepted June 2, 2009.
  • This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants HL045967, HL077101, HL052318].

  • ABBREVIATIONS: βAR, β-adrenergic receptor; β-blockers, β-adrenergic receptor blockers; GRK, G-protein coupled receptor kinase; NE, norepinephrine; AR, adrenergic receptor; CHW, Chinese hamster fibroblast; PKA, protein kinase A; VO2, oxygen consumption; ACV, adenylyl cyclase type V; LVEF, left ventricular ejection fraction; UTR, untranslated region; SNP, single nucleotide polymorphism.

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Molecular Pharmacology: 76 (3)
Molecular Pharmacology
Vol. 76, Issue 3
1 Sep 2009
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Mechanisms of Pharmacogenomic Effects of Genetic Variation within the Cardiac Adrenergic Network in Heart Failure

Gerald W. Dorn and Stephen B. Liggett
Molecular Pharmacology September 1, 2009, 76 (3) 466-480; DOI: https://doi.org/10.1124/mol.109.056572

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OtherMINIREVIEWS

Mechanisms of Pharmacogenomic Effects of Genetic Variation within the Cardiac Adrenergic Network in Heart Failure

Gerald W. Dorn and Stephen B. Liggett
Molecular Pharmacology September 1, 2009, 76 (3) 466-480; DOI: https://doi.org/10.1124/mol.109.056572
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  • Article
    • Abstract
    • A Mechanistic Approach for Pharmacogenomic Studies
    • Variations in the β1AR Gene
    • Human Studies
    • A βAR-Desensitizing GRK5 Polymorphism Is Protective in Experimental and Clinical Heart Failure and Mimics β-Blockers
    • Beyond Individual Polymorphisms—The Challenge of Haplotypes
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