Pharmacogenomics: a systems approach.
Pharmacogenetics and pharmacogenomics involve the study of the role of inheritance in individual variation in drug response, a phenotype that varies from potentially life-threatening adverse drug reactions to equally serious lack of therapeutic efficacy. Pharmacogenetics-pharmacogenomics represents a major component of the movement to 'individualized medicine'. Pharmacogenetic studies originally focused on monogenic traits, often involving genetic variation in drug metabolism. However, contemporary studies increasingly involve entire 'pathways' that include both pharmacokinetics (PKs)--factors that influence the concentration of a drug reaching its target(s)--and pharmacodynamics (PDs), factors associated with the drug target(s), as well as genome-wide approaches. The convergence of advances in pharmacogenetics with rapid developments in human genomics has resulted in the evolution of pharmacogenetics into pharmacogenomics. At the same time, studies of drug response are expanding beyond genomics to encompass pharmacotranscriptomics and pharmacometabolomics to become a systems-based discipline. This discipline is also increasingly moving across the 'translational interface' into the clinic and is being incorporated into the drug development process and governmental regulation of that process. The article will provide an overview of the development of pharmacogenetics-pharmacogenomics, the scientific advances that have contributed to the continuing evolution of this discipline, the incorporation of transcriptomic and metabolomic data into attempts to understand and predict variation in drug response phenotypes as well as challenges associated with the 'translation' of this important aspect of biomedical science into the clinic.
Wang
Liewei
L
Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D014644:Genetic Variation; D015894:Genome, Human / Q000502:physiology; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D055432:Metabolomics / Q000379:methods; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D010597:Pharmacogenetics / Q000379:methods* / Q000639:trends*; D015398:Signal Transduction / Q000235:genetics; D049490:Systems Biology / Q000379:methods / Q000639:trends
D019389:Cytochrome P-450 CYP2D6; D008780:Methyltransferases; C022745:thiopurine methyltransferase