Preemptive Pharmacogenomic Testing for Precision Medicine: A Comprehensive Analysis of Five Actionable Pharmacogenomic Genes Using Next-Generation DNA Sequencing and a Customized CYP2D6 Genotyping Cascade

Abstract

Significant barriers, such as lack of professional guidelines, specialized training for interpretation of pharmacogenomics (PGx) data, and insufficient evidence to support clinical utility, prevent preemptive PGx testing from being widely clinically implemented. The current study, as a pilot project for the Right Drug, Right Dose, Right Time-Using Genomic Data to Individualize Treatment Protocol, was designed to evaluate the impact of preemptive PGx and to optimize the workflow in the clinic setting. We used an 84-gene next-generation sequencing panel that included SLCO1B1, CYP2C19, CYP2C9, and VKORC1 together with a custom-designed CYP2D6 testing cascade to genotype the 1013 subjects in laboratories approved by the Clinical Laboratory Improvement Act. Actionable PGx variants were placed in patient's electronic medical records where integrated clinical decision support rules alert providers when a relevant medication is ordered. The fraction of this cohort carrying actionable PGx variant(s) in individual genes ranged from 30% (SLCO1B1) to 79% (CYP2D6). When considering all five genes together, 99% of the subjects carried an actionable PGx variant(s) in at least one gene. Our study provides evidence in favor of preemptive PGx testing by identifying the risk of a variant being present in the population we studied.

Figure 1

The RIGHT Protocol study design with a focus on five PGx genes. CDS, clinical decision support; EMR, electronic medical record; NGS, next-generation sequencing; PGx, pharmacogenomics; QC, quality control; RIGHT, Right Drug, Right Dose, Right Time–Using Genomic Data to Individualize Treatment.

Figure 2

Distributions of RIGHT subjects in CYP2D6, CYP2C9, CYP2C19, SLCO1B1*5, and VKORC1 categories. Percentage of subjects among the total RIGHT cohort for each of the predicted CYP2D6 (A), CYP2C9 (B), and CYP2C19 (C) metabolizer groups; percentage of subjects among the total RIGHT cohort carrying various genotypes for SLCO1B1*5 (TT, TC, or TT) and VKORC1 SNP rs9923231 (GG, GA, and AA) (D). EM, extensive metabolizer; IM, intermediate metabolizer; PM, poor metabolizer; RIGHT, Right Drug, Right Dose, Right Time–Using Genomic Data to Individualize Treatment; UM, ultrarapid metabolizer.

Figure 3

Percentage of RIGHT subjects among groups carrying actionable PGx variants in zero to five of the PGx genes. PGx, pharmacogenomics; RIGHT, Right Drug, Right Dose, Right Time–Using Genomic Data to Individualize Treatment.

Figure 4

Examples of CYP2C19 CDS alerts triggered for the RIGHT subjects at the point of care. A: Patient predicted to carry one single actionable PGx variant-triggered alert for one medication, clopidogrel. B: Patient predicted to carry one single actionable PGx variant-triggered alerts for two medications, codeine and tramadol. C: Patient predicted to carry actionable PGx variants in two genes that triggered alerts for several relevant drugs. CDS, clinical decision support; MICS, Mayo Integrated Clinical Systems; PGx, pharmacogenomics; RIGHT, Right Drug, Right Dose, Right Time–Using Genomic Data to Individualize Treatment.