A paradigm shift in pharmacogenomics: From candidate polymorphisms to comprehensive sequencing

Abstract

Genetic factors have long been recognized as important determinants of interindividual variability in drug efficacy and toxicity. However, despite the increasing number of established gene-drug associations, candidate polymorphisms can only explain a fraction of the genetically encoded functional variability in drug disposition. Advancements in genetic profiling methods now allow to analyse the landscape of human pharmacogenetic variations comprehensively, which opens new opportunities to identify novel factors that could explain the "missing heritability." Here, we provide an updated overview of the landscape of pharmacogenomic variability based on recent analyses of population-scale sequencing projects. We then summarize the current state-of-the-art how the functional consequences of variants with unknown effects can be quantitatively estimated while discussing challenges and peculiarities that are specific to pharmacogenes. In the last sections, we discuss the importance of considering ethnogeographic diversity to provide equitable benefits of pharmacogenomics and summarize current roadblocks for the implementation of sequencing-based guidance of clinical decision-making.Based on the current state of the field, we conclude that testing is likely to gradually shift from the interrogation of selected candidate polymorphisms to comprehensive sequencing, which allows to consider the full spectrum of pharmacogenomic variations for a true personalization of genomic prescribing.

Implementation of pharmacogenetic testing in medication reviews in a hospital setting

“…One step in the process that should be straightforward to conduct more effectively is time from hospitalization to blood sampling and further shipment to the laboratory for pharmacogenetic analysis. This is in line with previous studies pointing to the importance of a short pharmacogenetic turnaround time to facilitate the implementation of pharmacogenetic testing 45–48 …”

“…This is in line with previous studies pointing to the importance of a short pharmacogenetic turnaround time to facilitate the implementation of pharmacogenetic testing. [45][46][47][48] Considering that there are some obstacles to implementing pharmacogenetic testing in the medication review while the patient is hospitalized, such as a short hospital stay, it is relevant to discuss whether pharmacogenetic testing to a greater extent could be implemented in primary care. Thereby, more patients could have pharmacogenetic test results available for inclusion in the medication review when admitted to hospital, given that the test results are accessible across different levels of care.…”

Frequencies of Combined Dysfunction of Cytochromes P450 2C9, 2C19, and 2D6 in an Italian Cohort: Suggestions for a More Appropriate Medication Prescribing Process

“…The low frequency of subjects with a fully functional set of cytochrome P450 enzymes claims a paradigm shift in the approach to PGX test prescription, also considering the increasing sustainability and availability of next-generation sequencing, allowing the assessment of many pharmacogenes in the same test [ 53 ]. Since the additional healthcare expenditure associated with increased rates of ADRs, hospitalization, and death in polytreated patients is well documented, it is expected that the cost of preemptive and comprehensive PGX testing is fully affordable when considering the benefits, at least in such patient groups.…”

CYP2D6 and CYP2C19 Variant Coverage of Commercial Antidepressant Pharmacogenomic Testing Panels Available in Victoria, Australia

“…Furthermore, it should be noted that interindividual differences in drug response are a mix of genetic as well as environmental and pathophysiological factors, including age, sex, hormonal status, dietary intake, alcohol, and other illicit and prescription drug use [35][36][37]. Improvements in technological capability, including nextgeneration sequencing and computational prediction, may allow for the discovery of rare or novel variants and the integration of non-genetic factors that can enhance individualized drug prescription [38].…”