Pharmacogenetics in the Brazilian Population

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 Refargen 1 , 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.Keywords: biogeographical ancestry, Brazilian pharmacogenetic network, population admixture, warfarin, HIV protease inhibitors, non-steroidal anti-inflammatory drugs databases, in consonance with either the first or the second models described by Pena (2007). However, both models are poor descriptors of admixed populations, since genetic admixture is best modeled as a continuous variable, consistent with the VMG paradigm Pena, 2006, 2007;Pena, 2007). The individual uniqueness that is central to this paradigm implies that "each person must be treated as an individual… rather than as an exemplar of a race" (Patrinos, 2004) or in the words of McLeod (2007) "data from ethnic groups will not be as useful as analysis of individuals patients. While knowledge of ethnic differences may be relevant to much of the world's population, its usefulness is significantly limited in situations of extensive genetic mixing". With increasing global migration, admixture gains relevance as an additional challenge to the successful worldwide implementation of PGx in clinical practice. From this perspective, the Brazilian population, ...

Global Pharmacogenomics: Distribution of CYP3A5 Polymorphisms and Phenotypes in the Brazilian Population

“…Regarding CYP3A5 phenotypes, the best fitting models show increasing odds of having the poor metabolizer phenotype as European ancestry increases and African ancestry decreases, whereas the opposite trend prevails for the extensive and intermediate phenotypes. No significant effect of Amerindian ancestry on the distribution of CYP3A5 alleles or phenotypes was observed, which may be explained by the relatively small average proportion (<10%) of Amerindian ancestry in the overall Brazilian population, compared to European and African ancestry [22] , [23] .…”

Pharmacogenetics of Calcineurin Inhibitors in Brazilian Renal Transplant Patients

“…Since most Brazilians have significant proportions of African ancestry [19], we genotyped our patients for the CYP3A5*6 and CYP3A5*7, in addition to the CYP3A5*3 allele. Longitudinal mixed-effects modeling revealed CYP3A5 polymorphisms as the only variable significantly associated with TAC C 0 /dose throughout the observation period: TAC C 0 /dose decreased progressively as the number of CYP3A5-defective alleles decreased from two (default) to one and then to zero.…”

“…Conclusion: Individual adjustment of the initial TAC dose according to the CYP3A5 haplotypes comprising the CYP3A5*3, *6 and *7 defective alleles might prove beneficial to Brazilian renal transplant recipients and should be further investigated in prospective trials. extrapolation of pharmacogenetic data derived from well-defined ethnic groups to the majority of Brazilians, especially when the frequency of the relevant polymorphisms differs markedly between Europeans and sub-Saharan Africans, the two major ancestral roots of the present-day Brazilians [17][18][19]. This is the case of the ABCB1 (1236C>T rs1128503, 2677G>T/A rs2032582 and 3435C>T rs1045462) and CYP3A5*3 polymorphisms [101], which have been extensively investigated as modulators of CSA and TAC pharmacokinetics in renal transplant patients of European and Asian descent.…”

Accuracy of NAT2 SNP Genotyping Panels to Infer Acetylator Phenotypes in African, Asian, Amerindian and Admixed Populations

“…Of note, the high accuracy (98%) provided by the 191G>A, 341T>C and 590G>A 3-SNP panel in Mozambicans may prove sufficient for specific clinical or research applications in this, and possibly, other African groups. Finally, the fact that no 3-SNP panel inferred with >91% accuracy the NAT2 acetylator phenotypes in brown and black Brazilians, highlights the implications of population admixture, heterogeneity and diversity in pharmacogenomics investigation and adoption of pharmacogenomics-informed drug prescription in clinical practice [9]. …”