Identification and functional validation of novel pharmacogenomic variants using a next-generation sequencing-based approach for clinical pharmacogenomics
Issued Date
2022-02-01
Resource Type
ISSN
10436618
eISSN
10961186
Scopus ID
2-s2.0-85122823184
Pubmed ID
35033648
Journal Title
Pharmacological Research
Volume
176
Rights Holder(s)
SCOPUS
Bibliographic Citation
Pharmacological Research Vol.176 (2022)
Suggested Citation
Siamoglou S., Koromina M., Hishinuma E., Yamazaki S., Tsermpini E.E., Kordou Z., Fukunaga K., Chantratita W., Zhou Y., Lauschke V., Mushiroda T., Hiratsuka M., Patrinos G.P. Identification and functional validation of novel pharmacogenomic variants using a next-generation sequencing-based approach for clinical pharmacogenomics. Pharmacological Research Vol.176 (2022). doi:10.1016/j.phrs.2022.106087 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/87580
Title
Identification and functional validation of novel pharmacogenomic variants using a next-generation sequencing-based approach for clinical pharmacogenomics
Author's Affiliation
RIKEN Center for Integrative Medical Sciences
Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie
College of Medicine and Health Sciences United Arab Emirates University
School of Health Sciences
Eberhard Karls Universität Tübingen
Faculty of Medicine Ramathibodi Hospital, Mahidol University
Karolinska Institutet
Tohoku University Hospital
United Arab Emirates University
Tohoku University
Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie
College of Medicine and Health Sciences United Arab Emirates University
School of Health Sciences
Eberhard Karls Universität Tübingen
Faculty of Medicine Ramathibodi Hospital, Mahidol University
Karolinska Institutet
Tohoku University Hospital
United Arab Emirates University
Tohoku University
Other Contributor(s)
Abstract
Inter-individual variability in pharmacokinetics and drug response is heavily influenced by single-nucleotide variants (SNVs) and copy-number variations (CNVs) in genes with importance for drug disposition. Nowadays, a plethora of studies implement next generation sequencing to capture rare and novel pharmacogenomic (PGx) variants that influence drug response. To address these issues, we present a comprehensive end-to-end analysis workflow, beginning from targeted PGx panel re-sequencing to in silico analysis pipelines and in vitro validation assays. Specifically, we show that novel pharmacogenetic missense variants that are predicted or putatively predicted to be functionally deleterious, significantly alter protein activity levels of CYP2D6 and CYP2C19 proteins. We further demonstrate that variant priorization pipelines tailored with functional in vitro validation assays provide supporting evidence for the deleterious effect of novel PGx variants. The proposed workflow could provide the basis for integrating next-generation sequencing for PGx testing into routine clinical practice.