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

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.

Keywords: cytochrome P450 enzymes; detection rate; pharmacogenomic tests; pharmacogenomics; variant selection.

Figure 1

(A) The total number of genes selected by pharmacogenomics (PGx) tests as detailed by the test information included in the Genetic Testing Registry (GTR). (B) Most commonly selected genes by PGx tests based on gene selection information included in GTR.

Figure 2

The prevalence of altered metabolizing phenotypes of cytochrome P450 (CYP) enzymes across various ethnic groups. Abbreviations for ethnic groups are as follows: AAAC, African American/Afro-Caribbean; Amer, American; CSA, Central/South Asian; EA, East Asian; Eur, European; Lat, Latino; NE, Near Eastern; Oc, Oceanian; and SSA, Sub-Saharan African. ^*Values of 0 are due to the lack of variant frequencies documented in the Pharmacogenomics Knowledge Base (PharmGKB) database for a specific ethnic group.

Figure 3

Heatmaps displaying detection rate values and coverage percentage of PGx tests covering (A) CYP2C9, (B) CYP2D6, (C) CYP2C19, and (D) CYP2B6. The brighter the red, the higher the detection rate. On the contrary, the darker blue, the lower the detection rate. In addition to the PGx tests, detection rate was calculated for selected Tier 1 and Tier 2 alleles of Association for Molecular Pathology (AMP) recommendations for CYP2C9 and CYP2C19. PGx test coverage percentage is included with each heatmap as a bar chart on the right side of each heatmap. Abbreviations for ethnic groups listed on the bottom of the figure are as follows: Amer, American; CSA, Central/South Asian; EA, East Asian; Eur, European; Lat, Latino; NE, Near Eastern; Oc, Oceanian; and SSA, Sub-Saharan African.