Mechanisms of pharmacogenomic effects of genetic variation within the cardiac adrenergic network in heart failure.
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 beta-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.
Dorn
Gerald W
GW
Center for Pharmacogenomics, Department of Internal Medicine, Washington University, St. Louis, Missouri, USA.
Liggett
Stephen B
SB
D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000595:Amino Acid Sequence; D000818:Animals; D002908:Chronic Disease; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics; D014644:Genetic Variation; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics*
D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D018342:Receptors, Adrenergic, beta-1; D054774:G-Protein-Coupled Receptor Kinase 5