Pharmacogenetic Variation in Over 100 Genes in Patients Receiving Acenocumarol

Abstract

Coumarins are widely prescribed worldwide, and in Mexico acenocumarol is the preferred form. It is well known that despite its efficacy, coumarins show a high variability for dose requirements. We investigated the pharmacogenetic variation of 110 genes in patients receiving acenocumarol using a targeted NGS approach. We report relevant population differentiation for variants on CYP2C8, CYP2C19, CYP4F11, CYP4F2, PROS, and GGCX, VKORC1, CYP2C18, NQO1. A higher proportion of novel-to-known variants for 10 genes was identified on 41 core pharmacogenomics genes related to the PK (29), PD (3), of coumarins, and coagulation proteins (9) including, CYP1A1, CYP3A4, CYP3A5, and F8, and a low proportion of novel-to-known variants on CYP2E1, VKORC1, and SULT1A1/2. Using a Bayesian approach, we identified variants influencing acenocumarol dosing on, VKORC1 (2), SULT1A1 (1), and CYP2D8P (1) explaining 40–55% of dose variability. A collection of pharmacogenetic variation on 110 genes related to the PK/PD of coumarins is also presented. Our results offer an initial insight into the use of a targeted NGS approach in the pharmacogenomics of coumarins in Mexican Mestizos.

Variation in Actionable Pharmacogenetic Markers in Natives and Mestizos From Mexico

“…Mexico is home to 68 genetically different ethnic groups which suggests urgency for an adequate collection, classification, and characterization of variants on genes that affect drug efficacy and safety. Published studies collect the identification and determination of allele frequencies of at least all PGKB level 1 variants in Mestizos (Cuautle-Rodriguez et al, 2014; Fricke-Galindo et al, 2014; Fricke-Galindo et al, 2016; Gonzalez-Covarrubias et al, 2017). Fewer studies have included Natives, NGs techniques, or genotype-phenotype assessments.…”

“…Furthermore, in vitro studies of major pharmacogenes have confirmed that many rare variants do have a functional impact confirming NGS bioinformatic predictions (Matimba et al, 2009; Han et al, 2017). More limited in scope, our own work has documented the importance of variants, derived from NGS, to increase the predictive value of genotypes on the pharmacokinetics of atorvastatin (Cruz-Correa et al, 2017) and the pharmacodynamics of cumarins (Gonzalez-Covarrubias et al, 2017). Nevertheless, the collection of a comprehensive pharmacogenetic set of variation is still underway, mostly for understudied populations.…”

Pharmacogenomics: Current Actionable Variants

“…Caucasian populations require a 30% lower dose of warfarin compared to Africans due to CYP2C9 and VKORC1 polymorphisms [28][29][30] . These variants account for 35% dose variations in Europeans, ~ 30% in Mexicans 31 , and 10% in African-Americans; . For the latter two, variants on NQO1, CALU, and GGCX may complement dose variation, highlighting the fact that certain genes distinctively impact on coumarin dosing according to population stratification.…”

Exploratory Analysis of Rare and Novel Variants in Mexican Patients Diagnosed with Schizophrenia and Dementia

“…DNA fragments were hybridized with Haloplex synthetic probes for library enrichment, and adapters were ligated by PCR. Then, library qualities for fragment size and concentration were assessed using a 2100 Bioanalyzer, as previously described 37 . Sequencing was performed using a NextSeq500 system (Illumina, USA), aiming for 200x depth coverage in paired-end reads.…”

“…A total of 1274 variants were called by both aligners, which were used for the following analyses. Variants were confirmed visually in the integrative genomic viewer IGV, and also, annotated using dbSNP version 147 37,44 .…”