Personalized medicine: Genetic risk prediction of drug response

I just came across this FANTASTIC article on the topic of “genetic risk prediction of drug response.” The article is lucid, very well written; just appeared this week. Pharmacogenomics (PGx) comprises a substantial component of “personalized medicine”. PGx seeks to understand each individual’s genetic composition to optimize drug therapy –– maximizing a 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 the (very complicated) 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 the rarity of these events and incomplete penetrance, however, prospective tests based on genotype will exhibit 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 virtually 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.

Pharmacol Ther 2o17; 175: 75–90

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