Out of the approximately 20,000 genes in the human genome, a number of genes have been described to have an important effect on how individuals respond to medications. This is the focus of the field of pharmacogenomics (PGx). For example, variants in the genes VKORC1 and CYP2C9 are known to influence the required dose of warfarin, the most commonly used anticoagulant in the world. Importantly, some of the genes of PGx relevance, including the gene VKORC1, show extensive geographic differenciation, and this has implications at the population level. We have collaborated with researchers from Mexico and Brazil in the characterization of polymorphisms of PGx relevance in these two regions (Bonifaz-Peña et al. 2014. PLoS One 9: e112640; Castelan-Martinez et al. 2013. Gene 523: 167-172). In Bonifaz-Peña et al., we showed that several PGx polymoporphisms show substantial differences in allele frequencies between African, European and indigenous American populations. Admixture proportions at the population level influence the frequency of PGx alleles observed in different geographic regions. At the individual level, the odds of having a variant of PGx relevance vary depending on the relative individual admixture proportions.

   In collaboration with Dr. Guilherme Suarez-Kurtz, from the Brazilian Instituto Nacional de Cāncer (Rio de Janeiro) we recently carried out the first genome-wide association (GWA) study of stable warfarin dosing in Brazilians (Parra et al. 2015. Pharmacogenomics 16:1-11), using an Extreme Discordant Phenotype (EDP) approach (e.g. evaluating differences in allele frequency between individuals receiving low vs. high warfarin dose). We identified genome-wide signals in the known genes VKORC1 and CYP2C9. Interestingly, neither of the major functional variants described for CYP2C9 (CYP2C9*2 and CYP2C9*3) were amongst our top signals in the GWA study. When checking the pattern of Linkage Disequilibrium (LD) in this region, we observed that our top signal (rs9332238) is capturing the effects of both CYP2C9*2 and CYP2C9*3. The minor allele of rs9332238 is always associated with CYP2C9*2 or CYP2C9*3 (but never with both).

Map of Mexico showing the variation in the frequency of a CYP2C19 polymorphism that is an ultrarapid metabolizer of drugs such as amitriptyline and clopidogrel. The distribution of this allele is dependent on relative European/indigenous American admixture proportions (Modified from Bonifaz-Peña et al. 2014. PLoS One 9: e112640)

Regional plot of the CYP2C9 region in the GWA study of stable warfarin dose in a Brazilian sample. The lead SNP (rs9332238) is capturing the effects of two functional polymorphisms reported in this region, CYP2C9*2 and CYP2C9*3 (Parra et al. 2015. Pharmacogenomics 16: 1-11)