VKORC1 Polymorphisms in Brazilians: Comparison with the Portuguese and Portuguese-Speaking Africans and Pharmacogenetic Implications

Abstract

The diversity of the Brazilian population, evident in the distribution of VKORC1 polymorphisms, must be taken into account in the design of pharmacogenetic clinical trials and dealt with as a continuous variable. Warfarin dosing algorithms that include 'race' terms defined for other populations are clearly not applicable to the heterogeneous and extensively admixed Brazilian population.

Pharmacogenomic Implications of Population Admixture: Brazil as a Model Case

“…Suarez-Kurtz and Pharmacogenomic implications of population admixture Review colleagues applied nonlinear logistic regression modeling using maximum likelihood estimation to describe the association between pharmacogenetic polymorphisms and individual biogeographical ancestry. A consistent finding in these analyses, which encompassed the GSTM1, GSTM3, CYP3A5, ABCB1, GNB3, VKORC1 genes and the CYP2C cluster is that the frequency distribution of polymorphisms among Brazilians is best fit by continuous functions of the individual proportions of African and European ancestry [10][11][12][13][14][15]. This is illustrated in Figure 2 with data pertaining to the warfarin-sensitive VKORC1 3673G>A (rs9923231) SNP [14].…”

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

“…The results of our study (Table 1) indicated that the accuracy of this 3-SNP panel to infer the NAT2 acetylator phenotype ranged from 100% in Guarani and Japanese, to 79.4% in Mozambicans. Among non-Amerindian Brazilians, accuracy declined from white (97.8%) to brown (89.7%) and then to black individuals (80.5%), a trend consistent with the increasing average proportion of African ancestry from white to brown and to black Brazilians [5,6], combined with the poor accuracy of the 3-SNP panel in Mozambicans. It is relevant, in this context, that Mozambique was a major source of enslaved Africans brought to Brazil in the 19th century [7].…”

“…The rarity of the 191A allele in white Brazilians (0.4%) [2], likely contributed to the reduced accuracy of 3-SNP panels including 191G>A to infer the NAT2 acetylator phenotype in this group. The 191G>A, 341T>C and 590G>A provided the most accurate inference of the NAT2 pheno type in brown (93.5%) and black (90.7%) Brazilians, in line with the considerable African ancestry of these two groups and the high accuracy (98%) of this panel in Mozambicans [5,6].…”

Pharmacogenetics of drug metabolizing enzymes in Brazilian populations

“…Authors in that work thus concluded that, quantifying admixture using AIMs should be used as a continuous variable, since CYP3A5*3 allele changes as a continuous function of ACA across self-declared populations. Some results from a project of PGx biomarkers that genotyped more than one thousand Brazilians from different regions led by Refargen researchers have been published [23][24][25][26][27][28][29][30]. These works have evaluated the impact that the population diversity has on the prediction of PGx biomarkers and drug-response related phenotypes.…”