Abstract
The identification and characterization of pharmacogenetic variants in Latin American populations is still an ongoing endeavor. Here, we investigated SNVs on genes listed by the Pharmacogenomics Knowledge Base in 1284 Mestizos and 94 Natives from Mexico. Five institutional cohorts with NGS data were retrieved from different research projects at INMEGEN, sequencing files were filtered for 55 pharmacogenes present in all cohorts to identify novel and known variation. Bioinformatic tools VEP, PROVEAN, and FATHMM were used to assess, in silico, the functional impact of this variation. Next, we focused on 17 genes with actionable variants that have been clinically implemented. Allele frequencies were compared with major continental groups and differences discussed in the scope of a pharmacogenomic impact. We observed a wide genetic variability for known and novel SNVs, the largest variation was on UGT1A > ACE > COMT > ABCB1 and the lowest on APOE and NAT2. Although with allele frequencies around 1%, novel variation was observed in 16 of 17 PGKB genes. In Natives we identified 59 variants and 58 in Mestizos. Several genes did not show novel variation, on CYP2B6, CYP2D6, and CYP3A4 in Natives; and APOE, UGT1A, and VKORC1 in Mestizos. Similarities in allele frequency, comparing major continental groups for VIP pharmacogenes, hint towards a comparable PGx for drugs metabolized by UGT1A1, DPYD, ABCB1, CBR3, COMT, and TPMT; in contrast to variants on CYP3A5 and CYP2B6 for which significant MAF differences were identified. Our observations offer some discernment into the extent of pharmacogenetic variation registered up-to-date in Mexicans and contribute to quantitatively dissect actionable pharmacogenetic variants in Natives and Mestizos.
Highlights
Pharmacogenetic studies in Mexican populations have been directed towards the identification of markers previously reported with functional consequences for drug safety and efficacy (Contreras et al, 2011; Bonifaz-Pena et al, 2014; Marsh et al, 2015; Fricke-Galindo et al, 2016)
TNGS showed a range of depth and coverage of 40×–600× and 80–100% for the selected genes, but after quality control some pharmacogenetic relevant regions including that of VKORC1 rs9323231 and CYP2C19*17 rs12248560 were not covered
Non-synonymous single nucleotide variant (SNVs) were five times more abundant in Natives, suggesting a genetic diversity uncovered by next generation sequencing (NGS), but these 436 genes were not identified in all individuals
Summary
Pharmacogenetic studies in Mexican populations have been directed towards the identification of markers previously reported with functional consequences for drug safety and efficacy (Contreras et al, 2011; Bonifaz-Pena et al, 2014; Marsh et al, 2015; Fricke-Galindo et al, 2016). In most of the developed world pharmacogenetic testing is being implemented with the aid of consortia and institutions such as the PGRN, the PGKB, CPIC, and the FDA These offer a list of genetic variants to guide drug selection, dose optimization, and to reduce the risk of adverse drug reactions. Implementation programs such as The electronic Medical Records and Genomics (eMERGE) initiative have started preemptive pharmacogenomics testing in over 10,000 patients, on the basis of the benefits of pharmacogenetic information, despite the so-called lack of cost–benefit evidence (van Driest et al, 2014 ). In Mexicans higher allele frequencies have been reported for CYP3A4 rs2750574 and NQO1 rs1800566, which may be differentially affecting the efficacy of tacrolimus, fluorouracil, and anthracyclines, when compared to Europeans
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