AUTHOR=Parada-Márquez Juan Fernando , Maldonado-Rodriguez Nicolás David , Triana-Fonseca Paula , Contreras-Bravo Nora Constanza , Calderón-Ospina Carlos Alberto , Restrepo Carlos M. , Morel Adrien , Ortega-Recalde Oscar Javier , Silgado-Guzmán Daniel Felipe , Angulo-Aguado Mariana , Fonseca-Mendoza Dora Janeth
TITLE=Pharmacogenomic profile of actionable molecular variants related to drugs commonly used in anesthesia: WES analysis reveals new mutations
JOURNAL=Frontiers in Pharmacology
VOLUME=14
YEAR=2023
URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1047854
DOI=10.3389/fphar.2023.1047854
ISSN=1663-9812
ABSTRACT=Background: Genetic interindividual variability is associated with adverse drug reactions (ADRs) and affects the response to common drugs used in anesthesia. Despite their importance, these variants remain largely underexplored in Latin-American countries. This study describes rare and common variants found in genes related to metabolism of analgesic and anaesthetic drug in the Colombian population.
Methods: We conducted a study that included 625 Colombian healthy individuals. We generated a subset of 14 genes implicated in metabolic pathways of common medications used in anesthesia and assessed them by whole-exome sequencing (WES). Variants were filtered using two pipelines: A) novel or rare (minor allele frequency—MAF <1%) variants including missense, loss-of-function (LoF, e.g., frameshift, nonsense), and splice site variants with potential deleterious effect and B) clinically validated variants described in the PharmGKB (categories 1, 2 and 3) and/or ClinVar databases. For rare and novel missense variants, we applied an optimized prediction framework (OPF) to assess the functional impact of pharmacogenetic variants. Allelic, genotypic frequencies and Hardy-Weinberg equilibrium were calculated. We compare our allelic frequencies with these from populations described in the gnomAD database.
Results: Our study identified 148 molecular variants potentially related to variability in the therapeutic response to 14 drugs commonly used in anesthesiology. 83.1% of them correspond to rare and novel missense variants classified as pathogenic according to the pharmacogenetic optimized prediction framework, 5.4% were loss-of-function (LoF), 2.7% led to potential splicing alterations and 8.8% were assigned as actionable or informative pharmacogenetic variants. Novel variants were confirmed by Sanger sequencing. Allelic frequency comparison showed that the Colombian population has a unique pharmacogenomic profile for anesthesia drugs with some allele frequencies different from other populations.
Conclusion: Our results demonstrated high allelic heterogeneity among the analyzed sampled, enriched by rare (91.2%) variants in pharmacogenes related to common drugs used in anesthesia. The clinical implications of these results highlight the importance of implementation of next-generation sequencing data into pharmacogenomic approaches and personalized medicine.