Common Treatment, Common Variant: Evolutionary Prediction of Functional Pharmacogenomic Variants

Abstract

Pharmacogenomics holds the promise of personalized drug efficacy optimization and drug toxicity minimization. Much of the research conducted to date, however, suffers from an ascertainment bias towards European participants. Here, we leverage publicly available, whole genome sequencing data collected from global populations, evolutionary characteristics, and annotated protein features to construct a new in silico machine learning pharmacogenetic identification method called XGB-PGX. When applied to pharmacogenetic data, XGB-PGX outperformed all existing prediction methods and identified over 2000 new pharmacogenetic variants. While there are modest pharmacogenetic allele frequency distribution differences across global population samples, the most striking distinction is between the relatively rare putatively neutral pharmacogene variants and the relatively common established and newly predicted functional pharamacogenetic variants. Our findings therefore support a focus on individual patient pharmacogenetic testing rather than on clinical presumptions about patient race, ethnicity, or ancestral geographic residence. We further encourage more attention be given to the impact of common variation on drug response and propose a new ‘common treatment, common variant’ perspective for pharmacogenetic prediction that is distinct from the types of variation that underlie complex and Mendelian disease. XGB-PGX has identified many new pharmacovariants that are present across all global communities; however, communities that have been underrepresented in genomic research are likely to benefit the most from XGB-PGX’s in silico predictions.

Patient Perceptions and Potential Utility of Pharmacogenetic Testing in Chronic Pain Management and Opioid Use Disorder in the Camden Opioid Research Initiative

“…While pharmacogenetics has the potential to improve medication management [2][3][4][5][6][7][8], the potential clinical utility should be considered within the context of each specific drug/gene/indication. Here, we investigated the potential clinical utility of pharmacogenetic information in opioid management for chronic pain and for the treatment of opioid use disorder.…”

“…In theory, pharmacogenetics has the potential to improve medication management by increasing medication efficacy and decreasing adverse drug reactions [2][3][4][5][6][7][8][9]. There are, however, several important considerations for the translation of pharmacogenetics into clinical care [10], including whether there is clear, clinically interpretable evidence for a PGx role in medication management that is potentially useful in the relevant clinical care setting, and whether the relevant patients are willing to consent to PGx testing as part of their clinical care.…”

Pharmacogenomics: From Basic Research to Clinical Implementation

“…The established contribution of genetic variation to drug response has the potential to improve drug efficacy and reduce drug toxicity [ 1 ]. The uptake of pharmacogenomics (PGx) in clinical care, however, has been relatively slow despite the documentation and validation of many known genetic determinants of drug response.…”

“…Four of the special issue articles, Han et al [ 2 ], Lee et al [ 3 ], Scheinfeldt et al [ 1 ], and Kim et al [ 4 ] focus on the identification, characterization, and documentation of functionally important PGx variation. Kim et al [ 4 ] conducted a longitudinal review of FDA-approved PGx drugs and FDA PGx drug labels.…”

“…This example demonstrates that PGx variation may impact disease treatment through drug response as well as through physiological effects in kidney that may exacerbate kidney disease. Scheinfeldt et al [ 1 ] took a complementary in silico approach that leveraged the evolutionary history of the genes involved in drug response to predict functionally important pharmacovariants. Not only did they identify over 2000 new putative pharmacovariants, but they demonstrated that these pharmacovariants are common across worldwide communities.…”