Cardiovascular pharmacogenetics

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Abstract

Human genetic variation in the form of single nucleotide polymorphisms as well as more complex structural variations such as insertions, deletions and copy number variants, is partially responsible for the clinical variation seen in response to pharmacotherapeutic drugs. This affects the likelihood of experiencing adverse drug reactions and also of achieving therapeutic success. In this paper, we review key studies in cardiovascular pharmacogenetics that reveal genetic variations underlying the outcomes of drug treatment in cardiovascular disease. Examples of genetic associations with drug efficacy and toxicity are described, including the roles of genetic variability in pharmacokinetics (e.g. drug metabolizing enzymes) and pharmacodynamics (e.g. drug targets). These findings have functional implications that could lead to the development of genetic tests aimed at minimizing drug toxicity and optimizing drug efficacy in cardiovascular medicine.

Introduction

Pharmacogenetics is the determination of the genetic contribution to individual variations in response to pharmacotherapy, and is central to the concept of personalized medicine. Developments in genome-based technology, including the availability of whole genome single nucleotide polymorphism (SNP) arrays, have provided researchers with an opportunity to assess variability in human reactions to pharmacotherapeutics and other exogenous substances as a function of intrinsic human genetic variability (Caulfield et al., 2003). It has become a common practice in pre-clinical and clinical drug testing to include a pharmacogenetic component, in order to select for drugs that have greater efficacy with fewer side effects, as well as fewer variations in individual response.

Pharmacogenetics underlies several observations dating back more than half a century that suggested the existence of genetic variation in drug metabolism pathways. Two examples include the enzyme butyrylcholinesterase that metabolizes suxamethonium chloride (scoline), used to induce muscle paralysis in anesthesia, and N-acetyltransferase that metabolizes isoniazid which is used in the treatment of tuberculosis. Reduced or absent enzyme activity in either case leads to toxicity, which manifests as prolonged muscle relaxation (scoline apnoea) in the case of the former, and as hepatotoxicity and neurotoxicity in the latter. Another example is glucose-6-phosphate dehydrogenase deficiency which is the most common disease-producing enzymopathy in humans, affecting nearly 400 million people worldwide (Frank, 2005). This enzyme, which is absent in 5–14% of Black individuals, is associated with the risk of developing drug-induced hemolytic anemia in response to a large number of currently employed drugs (Kaplan et al., 2004).

Optimal drug type and dose depend on many factors including age, organ function, concomitant therapy, lifestyle, ethnicity, drug interactions, gender, the nature of the disease and pharmacogenetics. Despite this multitude of factors, plasma drug concentrations, which in many but not all cases mirror drug concentrations at target sites, frequently reflect genetic variations in molecules involved in drug metabolism. It is estimated that more than 50% of adverse drug reactions are in fact dose-related and that in some drug classes, up to 50% of individuals do not respond to a “standard” dose of the drug.

The potential consequences of genetic polymorphisms on drug metabolism include the following:

  • Drug toxicity and adverse drug reactions

  • Reduced compliance

  • Decreased effective dose

  • Requirement for higher doses in order to be efficacious

  • Extended pharmacological effects

  • Lack of drug efficacy

  • Exacerbation of drug–drug interactions

  • Metabolism by alternative pathways leading to the generation of metabolites with deleterious effects

  • Lack of prodrug activation

From a functional perspective, when considering the underlying genetic contribution to adverse drug reactions and therapeutic efficacy, two broad categories can be delineated. These include pharmacokinetics and pharmacodynamics. Pharmacokinetics describes the fate of drugs following administration to patients. It includes the extent and rate of absorption (drug entry into the circulation), distribution (drug dispersion or dissemination in body fluids and tissues), metabolism (transformation into water-soluble metabolites) and excretion (elimination from the body). Recently, the term “liberation” has also been included, which describes the process of drug release from the initial formulation.

Pharmacodynamics describes the study of the physiological effects of drugs on the body and the mechanisms of drug action including the relationship between drug concentration and effect. An important example includes drug–receptor interactions. Pharmacodynamics is often summarized as the study of what a drug does to the body, whereas pharmacokinetics is the study of what the body does to a drug.

To date, the large majority of pharmacokinetic studies have focused on genetic polymorphisms of the cytochrome P450 (CYP450) family of enzymes as well as a growing list of transporter proteins that influence drug absorption, distribution, and excretion. CYP450 enzymes are responsible for the biotransformation of xenobiotic compounds and the metabolism of most commonly prescribed medications. The most intensely studied have been CYP2D6, CYP2C9, and CYP2C19, for which polymorphic forms have been implicated in a significant number of adverse drug reactions as well as lack of response/efficacy. However, developments in the field have also extended to pharmacodynamic determinants of drug response which include cellular receptors.

In this review, we have highlighted areas that are currently topical in both pharmacodynamic and pharmacokinetic aspects of cardiovascular drug pharmacogenetics. However, it is not our intention to provide an exhaustive overview of either pharmacodynamics or pharmacokinetics, and as will become apparent, data is lacking in either one of these areas for several classes of cardiovascular drugs which has affected the symmetry of the review. As a result we have had to limit our discussion to one of the two areas (i.e. either pharmacodynamics or pharmacokinetics) for certain drug classes.

Section snippets

Cardiovascular drug classes and pharmacogenetics

Cardiovascular risk factors are highly prevalent, remain under diagnosed and inadequately treated (Hunt et al., 2009). For example, hypertension, a major cardiovascular risk factor, is a common disorder that affects approximately 950 million adults worldwide (Kearney et al., 2005). Most drugs are approved and developed on the basis of their performance in large population groups, and although guided by evidence from well controlled clinical trials, they are less informative when treating

Conclusions and future prospects

In this review, we have discussed the potential application of pharmacogenetics to personalized cardiovascular pharmacotherapy by highlighting selected examples of well-characterized genetic loci that affect response to therapy.

In summary, the response to beta-blockers is mediated primarily by an effect on the beta-1 adrenergic receptor encoded by ADRB1. The data on the beta-1 AR G389R locus appears to have functional implications that affect outcome after beta-blocker therapy, and if shown to

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