AUTHOR=Gonzalez-Covarrubias Vanessa , Morales-Franco Marlet , Cruz-Correa Omar F. , Martínez-Hernández Angélica , García-Ortíz Humberto , Barajas-Olmos Francisco , Genis-Mendoza Alma Delia , Martínez-Magaña José Jaime , Nicolini Humberto , Orozco Lorena , Soberón Xavier 

TITLE=Variation in Actionable Pharmacogenetic Markers in Natives and Mestizos From Mexico

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.01169

DOI=10.3389/fphar.2019.01169

ISSN=1663-9812

ABSTRACT=<p>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, <italic>in silico</italic>, 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 <italic>UGT1A &gt; ACE &gt; COMT &gt; ABCB1</italic> and the lowest on <italic>APOE</italic> and <italic>NAT2</italic>. 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 <italic>CYP2B6</italic>, <italic>CYP2D6</italic>, and <italic>CYP3A4</italic> in Natives; and <italic>APOE</italic>, <italic>UGT1A</italic>, and <italic>VKORC1</italic> in Mestizos. Similarities in allele frequency, comparing major continental groups for VIP pharmacogenes, hint towards a comparable PGx for drugs metabolized by <italic>UGT1A1</italic>, <italic>DPYD</italic>, <italic>ABCB1</italic>, <italic>CBR3</italic>, <italic>COMT</italic>, and <italic>TPMT</italic>; in contrast to variants on <italic>CYP3A5</italic> and <italic>CYP2B6</italic> 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.</p>