Editorial [Hot topic: Novel Approaches to Pharmacogenomic Investigations (Executive Editor: Kelan G. Tantisira)]

The complementary fields of pharmacogenetics and pharmacogenomics have been widely espoused as promising methods both in achieving the goal of tailored drug therapy at an individual level and in the formulation of methods to for the development of novel drug compounds at a global level. By definition, pharmacogenetics is the study of variability in drug response due to heredity. That is, pharmacogenetics seeks to determine the role of genetic determinants in an individual's response to therapy. The related term, pharmacogenomics, refers to the development of novel drugs based upon the evolving knowledge of the genome. The two terms, however, are frequently used interchangeably. Ideally, pharmacogenetics will allow for “individualized therapy” based upon an individual's genetic make-up that will maximize the potential for therapeutic benefit, while minimizing the risk of adverse effects to any given medication. The potential for cost savings (via increased drug efficacy) and for decreasing morbidity and mortality (via increasing drug safety) is immense. Indeed, the formative basis for everyday clinical use of pharmacogenetic testing has been laid out, with two tests now approved by the United States Food and Drug Administration (FDA). These include the Invader® UGTlAl Molecular Assay (for the UGT1A1*28 allele) and the Roche AmpliChip Cytochrome P450 Genotyping test (for variants in CYP2D6 and CYP2C19). The UGT1A1*28 allele has been consistently associated with toxicity related to irinotecan administration [1-3], while CYP2D6 and CYP2C19 variants alter the metabolism of a wide number of medications [4, 5]. In addition to these tests, pharmacogenomic information is present in about 10% of labels for drugs approved by the FDA. A list of valid genomic biomarkers in the context of drug labels is available (www.fda.gov/cder/genomics/genomic_biomarkers_table.htm). Despite the successful translation of pharmacogenetics to the clinical realm for several compounds, as a field, pharmacogenetics has not yet lived up to the widely espoused “promise of personalized medicine” in that tailored treatment is not even conceptually in the guidelines for the vast majority of diseases nor have novel therapeutic compounds been commonly developed using genomic information. From a predictive testing perspective, initial pharmacogenetic studies have often been limited by the lack of reproducibility of results, small sample size, or lack of a significant proportion of the variability of the drug-response phenotype explained by a given genetic variant. Implicit in these limitations is the fact that for complex diseases, drug treatment response is not likely to be explained by simple Mendelian inheritance, in a fashion consistent with the epistatic nature of the underlying disease biology. Techniques that will efficiently identify additional genetic variants that focus on maximizing the sensitivity for detecting true variants or maximizing specificity of the variants as contributing biologically to the drug response phenotype of interest are clearly needed. The focus of this series of articles is on novel ways of investigating or analyzing data that may have pharmacogenetic or pharmacogenomic relevance. We begin with an overview of the pharmacogenetics of two complex diseases -- arrythmias, presented by Dr. Roden and colleagues and asthma, written by Dr. Duan and myself. Each of these overview reviews reinforce the promise of pharmacogenetics, citing several genes implicated in variation in drug-target response. These manuscripts also both highlight the problems with prior association work and the need for better ways to interrogate data related to drug response in these complex diseases. Dr. Akkari and colleagues provide a detailed overview of “Pipeline Pharmacogenetics”, which is the integration of pharmacogenomics into and across the development process, with each successive phase being informed by PGx science performed in the previous phases. This differs in context from the traditional use of pharmacogenetics in drug development, which focuses on genetic variation related to a compounds initial development and safety profile. This approach can increase the rate of success in ushering a promising compound through the pipeline, since companion diagnostic testing accompanies drug development.