Interethnic Variability inCYP2D6,CYP2C9, andCYP2C19Genes and Predicted Drug Metabolism Phenotypes Among 6060 Ibero- and Native Americans: RIBEF-CEIBA Consortium Report on Population Pharmacogenomics

Abstract

Pharmacogenetic variation in Latin Americans is understudied, which sets a barrier for the goal of global precision medicine. The RIBEF-CEIBA Network Consortium was established to characterize interindividual and between population variations in CYP2D6, CYP2C9, and CYP2C19 drug metabolizing enzyme genotypes, which were subsequently utilized to catalog their "predicted drug metabolism phenotypes" across Native American and Ibero American populations. Importantly, we report in this study, a total of 6060 healthy individuals from Ibero-America who were classified according to their self-reported ancestry: 1395 Native Americans, 2571 Admixed Latin Americans, 96 Afro-Latin Americans, 287 white Latin Americans (from Cuba), 1537 Iberians, and 174 Argentinean Ashkenazi Jews. Moreover, Native Americans were grouped into North-, Central-, and South Amerindians (from Mexico, Costa Rica, and Peru, respectively). All subjects were studied for the most common and functional CYP2D6, CYP2C9, and CYP2C19 allelic variants, and grouped as genotype-predicted poor or ultrarapid metabolizer phenotypes (gPMs and gUMs, respectively). Native Americans showed differences from each ethnic group in at least two alleles of CYP2D6, CYP2C9, and CYP2C19. Native Americans had higher frequencies of wild-type alleles for all genes, and lower frequency of CYP2D6*41, CYP2C9*2, and CYP2C19*17 (p < 0.05). Native Americans also showed less CYP2C19 gUMs than the rest of the population sample. In addition, differences within Native Americans (mostly North vs. South) were also found. The interethnic differences described supports the need for population-specific personalized and precision medicine programs for Native Americans. To the best of our knowledge, this is the largest study carried out in Native Americans and other Ibero-American populations analyzing CYP2D6, CYP2C9, and CYP2C19 genetic polymorphisms. Population pharmacogenomics is a nascent field of global health and warrants further research and education.

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 EM profile was the most common in all countries (Figure 2), and the Amerindian populations from different countries present relatively homogeneous frequencies of this profile. 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).…”

“…The poor metabolizer (PM) profile is the result of the combination of two alleles that have a complete loss of function (no enzymatic activity), that is, null alleles due to mutations or the deletion of the gene [8,41]. The highest frequency of PM (30%) was recorded in Costa Rica [30,31], followed by Argentina/Paraguay, with 13% [34], and Venezuela [33] and the US [32], each with 6% ( Figure 2). The PM profile typically results in low levels of active metabolites of some medications, such as opioid analgesics, resulting in the reduced effectiveness of pain relief [42,43].…”