Received November 18, 2004
Revised December 7, 2004
Accepted after revision February 1, 2005

¹ University of Florida
² University of Illinois at Chicago

^* To whom correspondence should be addressed. E-mail: johnson{at}cop.ufl.edu.

	Abstract

There is large inter-patient variability in the response to drugs, including cardiovascular drugs. Thus, while some patients achieved the desired therapeutic response from their drug therapy, others do not. There is also a subset of patients who will experience adverse effects, which can range from bothersome to life-threatening. Research in recent years has provided compelling evidence that in many cases, genetics contributes importantly to this variable drug response. Thus, pharmacogenomics is a field focused on unraveling the genetic determinants of variable drug response. Examples from the literature of genetic associations with drug efficacy and toxicity are described to provide insight into the field, including the roles of genetic variability in drug metabolizing enzymes and drug targets. There is also a detailed discussion of the experimental approaches used in cardiovascular pharmacogenomics. Current research is largely focused on a limited candidate gene approach, which allows for description of significant genetic associations with variable response, but often does not sufficiently explain the genetic basis of variable drug response to be useful clinically. As such, there is a move toward genome-wide approaches, and the various technologies available to obtain genomic data are discussed. Cardiovascular pharmacogenomics has the potential for leading to improvements in the use of cardiovascular drug therapy, through selection of the most appropriate drug therapy in an individual based on their genetic information. It will likely be a decade or more before genetic information is widely used in drug therapy decisions, but it seems clear that important findings in the area will continue to expand and the experimental approaches will continue to evolve. There is great inter-patient variability in response to drugs, including drugs used to treat cardiovascular disease. While some patients may attain the desired therapeutic response from a given drug, others may have no therapeutic benefit, while others may experience toxicities. There is increasing evidence that for a number of drugs, genetic variability plays an important (and sometimes central) role in variable response to drugs. Thus the field of pharmacogenomics is focused on providing an understanding of the genetic contribution to variable drug response. There are two broad manners in which pharmacogenomics can add to our knowledge of pharmacological agents for cardiovascular disease. The first is to use genomic information to help identify potential new drug targets. The concept is that if the genetic or genomic basis of a disease is understood, then it might be possible to develop highly targeted therapies. Currently, all drugs used today represent only about 500 different drug targets, although it is estimated that there are probably 5,000 to 10,000 potential drug targets in the body. Thus, such an approach clearly has the potential to increase the number of novel drug targets. While there are certain examples in the area of cancer of marketed drugs that have been developed through such an approach, no marketed cardiovascular drugs have been discovered by this strategy. While this is a promising strategy for development of cardiovascular drugs, it will not be the focus of this review, although it will be addressed in other reviews in this series. The other manner in which pharmacogenomics can provide important insights into cardiovascular drug therapy is through elucidation of the genetic (or genomic) contribution to variable response for existing drugs, either ones on the market or currently under development in man. Herein, we will focus on recent findings in this area, and the experimental approaches and laboratory techniques commonly used.

Key Words: Cardiovascular, Metabolism, Pharmacology