Pharmacogenomics: challenges and opportunities

Abstract

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.

Figure 1. The concept of pharmacogenetics

Pharmacogenetics focuses on large clinical effects of single gene variants in small numbers of patients. However, the concept of pharmacogenomics examines many genomic loci, including large biological pathways and the whole genome, to identify variants that together determine variability in response to drug therapy.

Figure 2. Two types of variability in drug action

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 antimode (arrow). Redrawn with permission from reference 10. Bottom. Change in FEV₁ in 1117 participants in 3 different trials of antiasthmatic therapy (inhaled steroids). Although the responses vary markedly, from an apparently deleterious drug effect to a highly beneficial one, there is no antimode. Redrawn with permission from reference 11.