Pharmacogenetics in the brazilian population.

Guilherme Suarez-Kurtz

doi:10.3389/fphar.2010.00118

Abstract

Brazil is the fifth largest country in the world and its present population, in excess of 190;million, is highly heterogeneous, as a result of centuries of admixture between Amerindians, Europeans, and Sub-Saharan Africans. The estimated individual proportions of biogeographical ancestry vary widely and continuously among Brazilians: most individuals, irrespective of self-identification as White, Brown or Black – the major categories of the Brazilian Census “race/color” system – have significant degrees of European and African ancestry, while a sizeable number display also Amerindian ancestry. These features have important pharmacogenetic (PGx) implications: first, extrapolation of PGx data from relatively well-defined ethnic groups is clearly not applicable to the majority of Brazilians; second, the frequency distribution of polymorphisms in pharmacogenes (e.g., CYP3A5, CYP2C9, GSTM1, ABCB1, GSTM3, VKORC, etc) varies continuously among Brazilians and is not captured by race/color self-identification; third, the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of PGx studies in order to avoid spurious conclusions based on improper matching of study cohorts. The peculiarities of PGx in Brazilians are illustrated with data for different therapeutic groups, such as anticoagulants, HIV protease inhibitors and non-steroidal antinflammatory drugs, and the challenges and advantages created by population admixture for the study and implementation of PGx are discussed. PGx data for Amerindian groups and Brazilian-born, first-generation Japanese are presented to illustrate the rich diversity of the Brazilian population. Finally, I introduce the reader to the Brazilian Pharmacogenetic Network or Refargen1, a nation-wide consortium of research groups, with the mission to provide leadership in PGx research and education in Brazil, with a population health impact.

Highlights

We studied the impact of polymorphisms in the ABCB1, CYP3A5, and SLCO1B1 genes on the pharmacokinetics of lopinavir and ritonavir in HIV-infected men under stable treatment
We extended our studies on the Instituto Nacional de Cardiologia Laranjeiras (INCL) cohort to explore the association of other variables with warfarin dose requirements (SuarezKurtz et al, 2009), and reported that the inclusion of international normalized ratio (INR)/dose as a covariate in regression modeling of the stable warfarin dose leads to a novel algorithm with greater predictive power (R2 = 60%; Figure 5)
A distinct message that emerges from these studies is that race/color categorization does not capture the distribution of PGx polymorphisms among Brazilians, which is best modeled by continuous functions of the individual proportions of European and African ancestry, irrespective of self-identified Color

Summary

Pharmacogenetics in the Brazilian population

Divisão de Farmacologia, Coordenação de Pesquisa, Instituto Nacional de Câncer, Rio de Janeiro, Brazil. Admixture gains relevance as an additional challenge to the successful worldwide implementation of PGx in clinical practice From this perspective, the Brazilian population, with tri-hybrid ancestral roots in Amerindian, European and African groups, and five centuries of extensive interethnic mating, provides a valuable model for studying the impact of admixture on the conceptual development and clinical implementation of PGxinformed prescription. I will initially offer a brief overview of the genetic diversity of present-day Brazilians and move to the PGx arena to discuss data from our laboratory for different therapeutic groups and the PGx implications of the Brazilian population heterogeneity and admixture

Pharmacogenetics in Brazilians

Findings

ANOVA P valuea