Abstract
We live in an amazing era of clinical medicine. There are an abundance of medications, devices, and procedures for the treatment of most common maladies. This includes the therapies for heart failure, where the level of sophistication has gone from digitalis leaves to a synergy of medications and implantable devices in just a few decades. Indeed, improvements in both patient symptoms and mortality have been achieved. However, we still must put patients through a series of ‘trial-and-error’ episodes in our quest for therapeutic perfection. One of the many reasons that medicine remains as much art as science is the extraordinary variation in the response to medications. Therapeutic success, adverse drug reactions (ADR), and refractory disease are often apparent among a group of patients with seemingly identical diagnoses. This is compounded in the context of primary care physicians who are often managing the treatment of a wide array of acute and chronic illness. Such differences are often greater across a population than within the same person (or between monozygotic twins) [1]. It is estimated that genetics can account for 20–95% of variability in drug disposition and effects [2]. There are now numerous examples where inter-individual differences in drug response have been attributed to polymorphisms in genes encoding drug metabolizing enzymes, drug transporters, or drug targets [3–5]. It is clear that many non-genetic factors such as age, organ function, concomitant pharmacotherapy, and severity of the disease, can influence the effects of medication. However, inherited determinants of drug response remain stable for an individual’s lifetime, and the effects can be profound, making them potentially very useful for rational drug prescription strategies, especially given the current environment in which there are usually many available medicines for a given condition but no single best therapeutic strategy. Inherited differences in drug effects were first documented in terms of drug metabolism in the 1950s [6, 7], giving rise to ‘‘pharmacogenetics’’. The field has now extended to all aspects of drug disposition (absorption, distribution, and excretion) [8] as well as drug targets and downstream effect mediators. It has also been rediscovered by a broader spectrum of academia and industry, giving birth to ‘‘pharmacogenomics’’. This latter term would apply when genome-wide approaches are used to identify genetic polymorphisms that govern response to specific medications, though in practice the terms are often used interchangeably. The genetic sequence variants of interest come in many forms such as variable repeats (where short sequences are repeated a number of times that differs between individuals), insertion/deletions (I/D; where some number of bases are either present or absent from the sequence; e.g., the Angiotensin Converting Enzyme I/D polymorphism), and Single Nucleotide Polymorphisms (SNP). SNPs are the most common with more than 1.4 million identified in the initial sequencing of the human genome [9], and estimations that there could be up to 15 million. The ongoing International HapMap project (www.hapmap.org) plans to culminate with nearly 6 million SNPs (or one every 600 bp) characterized in multiple world populations [10]. The recent advancements in H. L. McLeod (&) UNC Institute for Pharmacogenomics and Individualized Therapy, Division of Pharmacotherapy and Experimental Therapeutics, Division of Hematology and Oncology, and the Lineberger Comprehensive Cancer Center, University of North Carolina, Campus Box 7360, Chapel Hill, NC 27599, USA e-mail: hmcleod@unc.edu
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