Identification and functional validation of novel pharmacogenomic variants using a next-generation sequencing-based approach for clinical pharmacogenomics.
Pharmacol Res
; 176: 106087, 2022 02.
Article
em En
| MEDLINE
| ID: mdl-35033648
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Citocromo P-450 CYP2D6
/
Sequenciamento de Nucleotídeos em Larga Escala
/
Citocromo P-450 CYP2C19
/
Variantes Farmacogenômicos
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Pharmacol Res
Assunto da revista:
FARMACOLOGIA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Grécia