Prediction of drug response and adverse drug reactions: From twin studies to Next Generation Sequencing

Understanding and predicting inter-individual differences related to the success of drug therapy is of tremendous importance, both during drug development and for clinical applications. Importantly, while seminal twin studies indicate that the majority of inter-individual differences in drug disposition are driven by hereditary factors, common genetic polymorphisms explain only less than half of this genetically encoded variability. Recent progress in Next Generation Sequencing (NGS) technologies has for the first time allowed to comprehensively map the genetic landscape of human pharmacogenes. Importantly, these projects have unveiled vast numbers of rare genetic variants, which are estimated to contribute substantially to the missing heritability of drug metabolism phenotypes. However, functional interpretation of these rare variants remains challenging and constitutes one of the important frontiers of contemporary pharmacogenomics. Furthermore, NGS technologies face challenges in the interrogation of genes residing in complex genomic regions, such as CYP2D6 and HLA genes. We here provide an update of the implementation of pharmacogenomic variations in the clinical setting and present emerging strategies that facilitate the translation of NGS data into clinically useful information. Importantly, we anticipate that these developments will soon result in a paradigm shift of pre-emptive genotyping away from the interrogation to candidate variants and towards the comprehensive profiling of an individuals genotype, thus allowing for a true individualization of patient drug treatment regimens.