Population Diversity in Pharmacogenetics: A Latin American Perspective.

Abstract

Pharmacogenetics/pharmacogenomics (PGx) relies on human genetic diversity. In this review we initially examine the PGx implications of human demographic history and genetic diversity, and highlight results from recent studies on the worldwide distribution of common and rare variants in pharmacogenes. The abundance of rare variants implies that a substantial effort will be required to identify their putative functional effects and to develop reliable algorithms for PGx-guided prescription. Furthermore, variants in all pharmacogenes relevant to a drug treatment must be considered. This implies a shift of the current paradigm of PGx-informed prescription based on genotyping a few common variants in selected genes toward comprehensive sequencing approaches. The following sections deal with the impact of population admixture on PGx diversity focusing on Latin America, where a kaleidoscopic combination of individual proportions of Native American, European, and sub-Saharan African ancestries prevails. We illustrate this diversity by contrasting Brazil and Mexico, the two most populous countries in Latin America, and show that population average admixture proportions are not predictive of the corresponding proportions at the individual level. As a consequence of admixture, the genetic differentiation of common pharmacogenetic variants in Latin Americans is much attenuated in comparison to their most relevant ancestral populations. Finally, we review data for tacrolimus and warfarin to illustrate the opportunities and challenges presented by Latin American populations for PGx studies and clinical implementation.