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 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.

Adverse Drug Reactions Across the Age Continuum: Epidemiology, Diagnostic Challenges, Prevention, and Treatments

“…8,77 An approach that is becoming more widely used, notably for adults, is the use of genetically directed prescribing. [78][79][80] Although there are increasing numbers of drugs for which this approach is not only demonstrably useful but is also mandated by drug regulatory agencies, there has been much less progress implementing the approach in children. 8 There are a number of research initiatives under way to address this issue.…”

Primary Care Physician Experiences with Integrated Pharmacogenomic Testing in a Community Health System

“…More than 160 medications currently have PGx labeling from the US FDA, ranging from heart disease medications to psychiatric drugs [2]. Identifying genetic variants associated with response to medication may benefit patients for more accurate drug dosing and selection in order to optimize responses and/or to avoid unwanted side effects [3,4].…”

Pharmacogenetics of asparaginase in acute lymphoblastic leukemia

“…Relapse is a major cause of treatment failure in pediatric ALL as it was reported to arise in 11%-36% of patients with high-risk B-precursor ALL [42][43][44][45][46][47][48][49] . The risk of relapse and treatment toxicity can be modulated by multiple factors, and differences in genetic composition among patients have recently driven considerable attention [5,16] . Several PGx studies reported that genomic variation was associated with higher risk of relapse in ALL patients [42,50,51] .…”