title: Targeted Next-Generation Sequencing for Comprehensive Genetic Profiling of Pharmacogenes.
abstract: Phenotypic differences in drug responses have been associated with known pharmacogenomic loci, but many remain to be characterized. Therefore, we developed next-generation sequencing (NGS) panels to enable broad and unbiased inspection of genes that are involved in pharmacokinetics (PKs) and pharmacodynamics (PDs). These panels feature repetitively optimized probes to capture up to 114 PK/PD-related genes with high coverage (99.6%) and accuracy (99.9%). Sequencing of a Korean cohort (n = 376) with the panels enabled profiling of actionable variants as well as rare variants of unknown functional consequences. Notably, variants that occurred at low frequency were enriched with likely protein-damaging variants and previously unreported variants. Furthermore, in vitro evaluation of four pharmacogenes, including cytochrome P450 2C19 (CYP2C19), confirmed that many of these rare variants have considerable functional impact. The present study suggests that targeted NGS panels are readily applicable platforms to facilitate comprehensive profiling of pharmacogenes, including common but also rare variants that warrant screening for personalized medicine.
authors.affiliation: Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: S M
authors.initials: SM
authors.lastname: Han
authors.affiliation: Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: J
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, College of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan, Korea.
authors.forename: S S
authors.initials: SS
authors.lastname: Lee
authors.affiliation: Celemics Inc, Seoul, Korea.
authors.forename: H
authors.initials: H
authors.lastname: Kim
authors.affiliation: Celemics Inc, Seoul, Korea.
authors.forename: H
authors.initials: H
authors.lastname: Han
authors.affiliation: Celemics Inc, Seoul, Korea.
authors.forename: Y
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea.
authors.forename: S
authors.initials: S
authors.lastname: Yi
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Cho
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea.
authors.forename: I-J
authors.initials: IJ
authors.lastname: Jang
authors.affiliation: Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: M G
authors.initials: MG
authors.lastname: Lee
mesh_terms: D003198:Computer Simulation; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics / Q000378:metabolism; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D010597:Pharmacogenetics / Q000379:methods*; D000071185:Pharmacogenomic Testing / Q000379:methods*; D057285:Precision Medicine / Q000379:methods; D015203:Reproducibility of Results; D056910:Republic of Korea
chemical_list: D065731:Cytochrome P-450 CYP2C19