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

Abstract

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.

The Metabolization Profile of the CYP2D6 Gene in Amerindian Populations: A Review

“…The ultrarapid metabolization (UM) profile has a relatively low frequency in the general Amerindian population (7%), although it is slightly higher in Mexican populations (9%) than in the other countries [24][25][26][27][28][29][30], probably due to the isolation of Mexican mestizos [24,30]. The UM profile was also substantial (7%) in Costa Rica [30,31].…”

“…The highest frequency (90%) was recorded in the populations from the US [32], followed by Peru (87%) [30], Argentina/Paraguay (86%) [34], Chile (85%) [35], and Venezuela (80%) [33]. However, much lower frequencies were recorded in Mexico (69%) and Costa Rica (45%) [24][25][26][27][28][29][30][31].…”

“…This profile was recorded in the Amerindian populations from three countries, Mexico, with a frequency of 9%, Costa Rica (7%), and the US, with 1% [24][25][26][27][28][29][30][31]. The highest frequency of this type of metabolizer has been recorded in an Ethiopian study (28.7%) [49].…”

“…The IM profile is the second most frequent (19%) in the Amerindian populations included in the present review. The highest frequency of the IM profile was recorded in Mexico (22%) [23][24][25][26][27][28][29][30], followed by Costa Rica (18%) [30,31], Chile (15%) [35], Venezuela (14%) [33], Peru (13%) [30], the US (3%) [32], and Argentina/Paraguay (1%) [34] (see Figure 2).…”

Essential Characteristics of Pharmacogenomics Study Publications

“…For example, in a study that compared CYP450 drug metabolism phenotypes in a Mexican Amerindian indigenous population and their predicted phenotypes based on genotypes, there was not good concordance. 25 The authors proposed this was likely due to inadequate inclusion of variants that were more common in this population and rare in European populations. Similarly, the IWPC dosing algorithm for warfarin has been shown to be less accurate in predicting dose for African Americans compared with white or Asian individuals, and additional variants that were more frequent in this population were needed to improve utility.…”