Clinical Implications of Combinatorial Pharmacogenomic Tests Based on Cytochrome P450 Variant Selection.

Michael Sayer,Ashley Duche,Richard Beuttler,Kunj Patel,Danny Pham,Jacqueline Vu,Brianne Vernick,Don Roosan,Moom R Roosan,Michelle Le,Trang Jenny Tran Nguyen

doi:10.3389/fgene.2021.719671

Abstract

Despite the potential to improve patient outcomes, the application of pharmacogenomics (PGx) is yet to be routine. A growing number of PGx implementers are leaning toward using combinatorial PGx (CPGx) tests (i.e., multigene tests) that are reusable over patients’ lifetimes. However, selecting a single best available CPGx test is challenging owing to many patient- and population-specific factors, including variant frequency differences across ethnic groups. The primary objective of this study was to evaluate the detection rate of currently available CPGx tests based on the cytochrome P450 (CYP) gene variants they target. The detection rate was defined as the percentage of a given population with an “altered metabolizer” genotype predicted phenotype, where a CPGx test targeted both gene variants a prospective diplotypes. A potential genotype predicted phenotype was considered an altered metabolizer when it resulted in medication therapy modification based on Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Targeted variant CPGx tests found in the Genetic Testing Registry (GTR), gene selection information, and diplotype frequency data from the Pharmacogenomics Knowledge Base (PharmGKB) were used to determine the detection rate of each CPGx test. Our results indicated that the detection rate of CPGx tests covering CYP2C19, CYP2C9, CYP2D6, and CYP2B6 show significant variation across ethnic groups. Specifically, the Sub-Saharan Africans have 63.9% and 77.9% average detection rates for CYP2B6 and CYP2C19 assays analyzed, respectively. In addition, East Asians (EAs) have an average detection rate of 55.1% for CYP2C9 assays. Therefore, the patient’s ethnic background should be carefully considered in selecting CPGx tests.

Highlights

Drug-related morbidity and mortality owing to unoptimized medication therapy are estimated to cost $528.4 billion annually in the United States alone (Watanabe et al, 2018)
CYP2C9, CYP2C19, and CYP2D6 were selected by 11 Combinatorial PGx tests (CPGx) tests; only six CPGx tests covered CYP2B6
The most commonly selected gene targets in CPGx tests were cytochrome P450 (CYP) enzymes, with CYP2D6 and CYP2C19 being selected by 50 different tests (Figure 1B; Diagnostics R, 2021; Genetics C, 2021; Genetics H, 2021; Genomics A, 2021; Health A, 2021a,b; Incorporated CH, 2021; Indiana University School of Medicine DoDG-PL, 2021; Invitae, 2021; Laboratories KD, 2021; Lineagen, 2021; OneOme, 2021; Services PML, 2021)

Summary

Introduction

Drug-related morbidity and mortality owing to unoptimized medication therapy are estimated to cost $528.4 billion annually in the United States alone (Watanabe et al, 2018). Clinical PGx practice has the potential to be relevant to a large patient population, bring cost savings, and improve therapy outcomes. Critical to PGx implementation is the availability of genetic test results having relevant genes to guide therapy decisions. As clinical decision support systems grow, preemptive PGx testing approaches are being utilized, allowing genotyping results to be available prior to prescribing decisions and in the planning of therapy (Dunnenberger et al, 2015). Combinatorial PGx tests (CPGx) are critical to the development of these programs because they offer genotyping results of several different genes simultaneously. While utilizing CPGx tests preemptively helps overcome barriers to PGx implementation, it is important to ensure the genotyping results they provide are reliable. If CPGx tests utilized preemptively have limitations, they can cause sub-optimal outcomes for subsequent therapeutic decisions

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Conclusion