The evolving landscape of pharmacogenomics: Current achievements and future directions
Abstract
Pharmacogenomics investigates how inherited and acquired genetic variation shapes drug efficacy, toxicity, and treatment failure. The major therapeutic areas for pharmacogenomics-assisted drug therapy include oncology, cardiology, psychiatry, neurology, infectious diseases, pain management, and metabolic disorders. Next-generation sequencing has revealed the extensive landscape of pharmacogenetic polymorphisms at the population scale. As a result, the field has evolved from early single-gene pharmacogenetics to genome-wide approaches that encompass the entirety of pharmacogenetic variability. However, much of the heritable variation in drug response remains unexplained, reflecting rare and structural variants, complex haplotypes, and the importance of polymorphisms in factors that regulate pharmacogenes in trans. A recently emphasized factor is the importance of considering differences in substrate specificities between enzymes and transporters that carry amino acid changes. Allele frequencies of actionable genetic variants are often low, requiring large, well powered studies that carefully account for key confounders, including patient adherence, placebo effects, comorbidities, hepatic and renal dysfunction, inflammation, and drug-drug and food-drug interactions. At the same time, emerging in silico variant-effect predictors, deep mutational scanning, population biobanks, and organotypic 3-dimensional human tissue models provide scalable platforms for functionally…
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