Variation in Actionable Pharmacogenetic Markers in Natives and Mestizos From Mexico

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.

Variation in 100 relevant pharmacogenes among emiratis with insights from understudied populations

“…Our results suggested that a significant number of the detected variants were rare, which is in concordance with findings from different population studies of pharmacogenes using NGS 34,35 . A high percentage of these rare variants were novel.…”

Prevalence of pharmacogenomic variants in 100 pharmacogenes among Southeast Asian populations under the collaboration of the Southeast Asian Pharmacogenomics Research Network (SEAPharm)

“…The investigation of variants in 12 CYP genes revealed that the majority of variants are remarkably rare in both African-American and European-American ancestries 25 . Additionally, a large proportion of rare alleles with the potential to impact drug metabolism has been documented in Slovenian and Latino populations 26 , 27 . This is also supported by the investigation of individual variants by sequencing drug target genes, which demonstrated that rare variants are abundant in humans, and many have potentially relevant effects on drug metabolism 25 , 28 , 29 .…”

The Identification of Admixture Patterns Could Refine Pharmacogenetic Counseling: Analysis of a Population-Based Sample in Mexico

“…Microarray genotyping technology eliminates the possibility of finding new variants in these pharmacogenes, but this could be accomplished with other techniques, such as next-generation technologies (NGS). An analysis of the Mexican population recently performed utilizing NGS found novel variation for some pharmacogenes between NA and MM populations (Gonzalez-Covarrubias et al, 2019). However, that analysis considered the MM population as a single group: an analysis of admixture patterns within the MM population, as performed in the present study, could be applied using NGS to refine the analysis of the Mexican population, and genomic guided some public health decisions in Mexico.…”

“…The admixture of the Mexican population has been divided into two populations: Native Americans (NA) and Mexican Mestizos (MM) (Wang et al, 2008;Moreno-Estrada et al, 2014). There have been some attempts to identify how variants in the NA population affect pharmacology (Gonzalez-Covarrubias et al, 2016;Romero-Hidalgo et al, 2017;Gonzalez-Covarrubias et al, 2019), but in many analyses the entire MM population is grouped together, with no estimation of how admixture patterns within that group could affect the frequency of actionable pharmacogenetic variants or clinical counseling.…”

“…Its genomic ancestry has been divided into Native American (NA) and Mexican Mestizo (MM) classifications (Silva-Zolezzi et al, 2009). Differences have been reported between these two groups in actionable PGx variants, including greater allele frequency of VKORC1 (rs8050894), CYP2B6 (rs2279343), and CYP3A5 (rs776746) in the NA population, and of CYP2C19 (rs4244285), CYP2C9 (rs1799853, rs1057910), NAT2 (rs179930), SLCO1B1 (rs4149015), and APOE (rs7412) in the MM population (Gonzalez-Covarrubias et al, 2019). The MM population is the largest in Mexico, and the prevalence of admixture patterns in this population is high.…”