title: Personalized medicine: Genetic risk prediction of drug response.
abstract: Pharmacogenomics (PGx), a substantial component of "personalized medicine", seeks to understand each individual's genetic composition to optimize drug therapy -- maximizing beneficial drug response, while minimizing adverse drug reactions (ADRs). Drug responses are highly variable because innumerable factors contribute to ultimate phenotypic outcomes. Recent genome-wide PGx studies have provided some insight into genetic basis of variability in drug response. These can be grouped into three categories. [a] Monogenic (Mendelian) traits include early examples mostly of inherited disorders, and some severe (idiosyncratic) ADRs typically influenced by single rare coding variants. [b] Predominantly oligogenic traits represent variation largely influenced by a small number of major pharmacokinetic or pharmacodynamic genes. [c] Complex PGx traits resemble most multifactorial quantitative traits -- influenced by numerous small-effect variants, together with epigenetic effects and environmental factors. Prediction of monogenic drug responses is relatively simple, involving detection of underlying mutations; due to rarity of these events and incomplete penetrance, however, prospective tests based on genotype will have high false-positive rates, plus pharmacoeconomics will require justification. Prediction of predominantly oligogenic traits is slowly improving. Although a substantial fraction of variation can be explained by limited numbers of large-effect genetic variants, uncertainty in successful predictions and overall cost-benefit ratios will make such tests elusive for everyday clinical use. Prediction of complex PGx traits is almost impossible in the foreseeable future. Genome-wide association studies of large cohorts will continue to discover relevant genetic variants; however, these small-effect variants, combined, explain only a small fraction of phenotypic variance -- thus having limited predictive power and clinical utility.
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, United States. Electronic address: ge.zhang@cchmc.org.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, United States; Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati School of Medicine, Cincinnati, OH 45267-0056, United States. Electronic address: dan.nebert@uc.edu.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nebert
mesh_terms: D004348:Drug Labeling; D005838:Genotype; D006801:Humans; D010597:Pharmacogenetics; D057285:Precision Medicine; D016896:Treatment Outcome
keywords: Complex PGx traits; Genetic architecture; Genetic risk prediction; Monogenic (Mendelian) PGx traits; Pharmacogenetics; Pharmacogenomics (PGx); Predominantly oligogenetic PGx traits