Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

182 Applying Pharmacogenomics in Therapeutics
KEY CONCEPTS
• Recommendations for genetic testing prior to prescribing certain drugs in
product labeling including warfarin, whose metabolism is affected by a
patient’s CYP2C9 and VKORC1 genotypes.
• The genetic polymorphisms of a drug transporter have been strongly implicated
in statin-induced myopathy. Although this may not be predictive
enough to use clinically, it has enhanced our understanding of this potentially
serious adverse drug event.
• β-Blocker pharmacogenomic research in heart failure has noticeably associated
with various components of the adrenergic signaling pathway, and
these data have the potential to influence future drug development in heart
failure.
• The clinical utilization of pharmacogenomics in cardiovascular disease is
promising, and clinical implementation has begun in certain centers, and
the findings will provide important insight into the challenges and future
directions for cardiovascular pharmacogenomics.
• Evaluation of the ultimate effects of a combination of polymorphisms in
drug-metabolizing enzymes, drug transporters, drug targets, and/or disease
progression genes on cardiovascular drug response.
• The potential for improvement in cardiovascular disease management may
arise from the applications of pharmacogenomics.
INTRODUCTION
Cardiovascular diseases remain the number one cause of death in the United States
and will likely soon become the number one cause of death globally. At the same
time, new understandings of individual characteristics including genetic variations
are reforming our ability to treat various aspects of cardiovascular disorders.
Although large randomized clinical trials clearly demonstrate population benefits
with many cardiovascular drugs, individual patients exhibit remarkable variability in
efficacy and adverse effects. There are many sources of variability in response to drug
therapy, such as noncompliance and unknown drug interactions. This chapter focuses
on genetic mechanisms contributing to variability in response to cardiovascular drugs
used to treat hypertension, hyperlipidemia, arrhythmia, and heart failure (Figure 7.1).
Since its inception, the field of pharmacogenetics has extended to study a wide range
of cardiovascular drugs and has become a typical research discipline. Cardiovascular
pharmacogenomics offers improved prevention of adverse drug events and treatment
outcomes. Variants common in the population have been shown to modify targets,
metabolism, and transport of drugs and could be utilized to predict an individual’s
treatment response. Evidence suggests that the common polymorphic variants of modifier
genes could influence drug response in cardiovascular disease (CVD) in a variety
of areas, including heart failure, arrhythmias, dyslipidemia, and hypertension. 1
In the realm of cardiovascular pharmacogenetics, major advances have identified
markers in each class for a variety of therapeutics, some with a potential to refining
patient outcomes. Included in this chapter are the major pharmacogenetic variants