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Emerging clinical applications in cardiovascular pharmacogenomics

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Abstract Over one‐fourth of the 36 million annual outpatient prescriptions filled in the United States are known to have human genomic biomarker information available that predicts drug safety and efficacy, or both. However, to date, we have not systematically implemented strategies to effectively use this data in clinical practice to improve patient outcomes. Part of the difficulty has stemmed from the only modest predictive capacity of previously identified gene variants, lack of replication of data in multiple studies, and the hesitancy of the clinical community to translate data gleaned from basic and translational research to routine clinical practice. Now, additional key variants that strongly impact drug absorption, metabolism, and excretion are rapidly surfacing through the use of genome‐wide association technology. Most importantly, these variants are being validated in independent cohorts of thousands of cases and controls. In the near future, the dramatic reduction in the cost of DNA sequencing will lead to further insight into the common and rare genetic variants that strongly predict our individual response to commonly used medications. The clinical community will need to be prepared to utilize this vital data in aiding their selection of the right drug for the right patient if we expect to significantly reduce the ever increasing burden of societies' most common diseases. Herein, we detail the most clinically compelling and robust examples of pharmacogenomics emerging in the field of cardiovascular disease and hopefully foretell how cardiovascular disease might be treated in the era of genomic medicine. WIREs Syst Biol Med 2011 3 206–215 DOI: 10.1002/wsbm.113 This article is categorized under: Physiology > Mammalian Physiology in Health and Disease Translational, Genomic, and Systems Medicine > Therapeutic Methods

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Vitamin K (vit K) epoxide reductase (VKOR) regenerates the reduced form of vit K, which is necessary for the carboxylation and activation of vit K dependent clotting factors II, VII, IX, and X. Warfarin inhibits VKOR thereby exerting its anticoagulant effect. Genetic polymorphisms in VKOR result in significant variability to warfarin response and a requirement for upward or downward dosage adjustment.

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Norepinephrine (NE) and Epinephrine (Epi) binding to the β‐AR results in recruitment of heterotrimeric G proteins, G∝ and Gγ. This stimulates adenylyl cyclase activity, which results in downstream increases in myocardial contractility. G‐protein coupled receptors kinases (GRK) uncouple the heterotrimeric proteins and limit persistent myocardial stimulation present in hyperadrenergic states. A gene variant in GRK 5 results in enhanced β‐AR uncoupling and diminished response to adrenergic stimulation thereby conferring a ‘genetic β‐blockade.’

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The β1‐AR 389 polymorphism is within a highly conserved intracellular region. Amino acid sequences from diverse species are shown aligned with human residues 379–397, with differences indicated in red. The human polymorphism is located at position 389 (yellow) in patients treated with bucindolol. (Adapted with permission from Ref 39. Copyright 2003 the Proceeding of the National Academy of Sciences).

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Translational, Genomic, and Systems Medicine > Therapeutic Methods

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