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The outcome of drug therapy is often unpredictable, ranging from beneficial effects to lack of efficacy to serious adverse effects. Variations in single genes are 1 well-recognized cause of such unpredictability, defining the field of pharmacogenetics (see Glossary). Such variations may involve genes controlling drug metabolism, drug transport, disease susceptibility, or drug targets. The sequencing of the human genome and the cataloguing of variants across human genomes are the enabling resources for the nascent field of pharmacogenomics (see Glossary), which tests the idea that genomic variability underlies variability in drug responses. However, there are many challenges that must be overcome to apply rapidly accumulating genomic information to understand variable drug responses, including defining candidate genes and pathways; relating disease genes to drug response genes; precisely defining drug response phenotypes; and addressing analytic, ethical, and technological issues involved in generation and management of large drug response data sets. Overcoming these challenges holds the promise of improving new drug development and ultimately individualizing the selection of appropriate drugs and dosages for individual patients. The concept that genetic variation contributes to variability in disease phenotypes and in drug responses is widely accepted and validated in many research settings. For some drugs, there are clear implications of genetic information for drug therapy to avoid toxicity and to optimize response (1, 2). In addition, understanding genetic contributors to variability in drug response provides a new tool in drug development that carries the hope of decreasing the risk for unexpected toxicities, identifying patients most likely to respond, and streamlining drug development (3). The English physiologist Archibald Garrod (4) proposed that similar genetic factors might underlie inborn errors of metabolism and variable responses to drugs. The field of pharmacogenetics developed after variant drug responses due to large single gene effects were described (1, 5–8), as Garrod suggested. Genetic science is now increasingly turning its attention to how variation in large gene sets, in complex biological pathways (see Glossary), or in the whole genome, contributes to variable phenotypes, such as disease susceptibility (9). This evolution from genetics to genomics is paralleled by progress in understanding the genetic contribution to variable drug responses, from pharmacogenetics to pharmacogenomics This review will outline progress in the field by describing mechanisms underlying variable drug responses, the potential role of genetic factors in their causes, and contemporary and evolving approaches to identifying these genetic factors. Examples are presented throughout, although it is not our goal to review these in a comprehensive fashion; rather it is our intent to identify the challenges that must be overcome and their potential solutions if genetic and genomic information is to be integrated into drug prescribing. Mechanisms Underlying Variable Drug Responses Clinicians and the lay public accept the notion that not all patients respond to drug therapy in the same fashion. An overarching challenge in contemporary therapeutics is to define the mechanisms underlying such variability. Occasionally, the distribution of drug responses across a population is clearly bimodal, suggesting a predominant role for a single variable that is often genetic top). More commonly, drug responses in patient populations show a broad distribution, Studies with twins done as early as the 1960s support the idea that this pattern of responses may also include a prominent genetic component (12–14). Top. Volunteers received 10 mg of the CYP2D6 substrate debrisoquine, and the ratio of urinary concentrations of the parent drug and its 4-hydroxy metabolite in urine were determined. This experiment identifies at least 2 distinct populations, extensive and poor metabolizers, separated at the
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