CYP450 Genotype/Phenotype Concordance in Mexican Amerindian Indigenous Populations-Where to from Here for Global Precision Medicine?

Global precision medicine demands characterization of drug metabolism and phenotype variation in diverse populations, including the indigenous societies. A related question is the extent to which CYP450 drug metabolizing enzyme genotype and phenotype data are concordant and whether they can be used interchangeably. These issues are increasingly debated as precision medicine continues to expand as a popular research topic worldwide. We report here the first study in clinically relevant CYP450 drug metabolism phenotypes and genotypes in Mexican Amerindian indigenous subjects. In a large sample of 450 unrelated and medication free Mexican Amerindian indigenous healthy persons from four Mexican states (Chihuahua, Durango, Nayarit, and Sonora), we performed multiplexed phenotyping for the CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 drug metabolizing enzymes using the CEIBA cocktail and genotyped the same pathways for functional polymorphic variation. Remarkable interindividual variability was found for the actual drug metabolizing capacity of all the enzymes analyzed, and, more specifically, the metabolic ratios calculated were significantly different across individuals with different number of active alleles for CYP2C9, CYP2C19, and CYP2D6. The drug metabolizing capacity "predicted" from the genotype determined was not in accordance with the actual capacity "measured" by phenotyping in several individuals for CYP2C9, CYP2C19, and CYP2D6. Consequently, a more extensive genotyping of the main CYP enzymes, including rare variants, together with the analysis of the actual drug metabolizing capacity using an appropriate phenotyping approach will add valuable information for accurate drug metabolism studies, especially useful in understudied populations such as Mexican Amerindians. In sum, this study demonstrates that current personalized medicine strategies based on "predicted" phenotype from genotyping of alleles with high frequency in European populations are not adequate for Mestizos and Native American populations.