Pharmacogenetic Testing in Admixed Populations: Frequency of the AMR PGx Working Group Tier 1 Variant Alleles in Brazilians.

Abstract

This article examines the frequency distribution of Tier 1 pharmacogenetic variants of the Association for Molecular Pathology Pharmacogenomics Working Group Recommendations in two large (>1.000 individuals) cohorts of the admixed Brazilian population, and in patients from the Brazilian Public Health System enrolled in pharmacogenetic trials. Three Tier 1 variants, all in DPYD, were consistently absent, which may justify their non-inclusion in genotyping panels for Brazilians; 13 variants had frequency < 1.0% and the remaining 21 variants ranged in frequency from 1.2% (NUDT15*3) to 76.4% (CYP3A5*3). The frequency of some CYP2C9, CYP2D6, CYP3A4 and VKORC1 variants differed significantly across the three major "race/Color" categories of the Brazilian Census (White, Brown and Black), as a consequence of different proportions of individual European and African ancestry. However, it is recommended that selection of variants for inclusion in pharmacogenetic testing panels and implementation of pharmacogenetic-informed dosing guidelines for Brazilians should not be determined by race/Color categories. Native Americans (0.4% of the Brazilian population), virtually absent from the study cohorts, display wide inter-ethnic diversity in frequency of some Tier 1 variants (e.g. NUDT15*3 and TPMT*3A) and/or differ markedly from non-Indigenous people in frequency of some variant alleles (e.g. CYP2C19*17). Collectively, the data support the notion that population diversity must be taken into account on the design and implementation of pharmacogenetic testing panels.