Pharmacogenetics of Warfarin: Development of a Dosing Algorithm for Brazilian Patients

Abstract

A dosing algorithm including genetic (VKORC1 and CYP2C9 genotypes) and nongenetic factors (age, weight, therapeutic indication, and cotreatment with amiodarone or simvastatin) explained 51% of the variance in stable weekly warfarin doses in 390 patients attending an anticoagulant clinic in a Brazilian public hospital. The VKORC1 3673G>A genotype was the most important predictor of warfarin dose, with a partial R(2) value of 23.9%. Replacing the VKORC1 3673G>A genotype with VKORC1 diplotype did not increase the algorithm's predictive power. We suggest that three other single-nucleotide polymorphisms (SNPs) (5808T>G, 6853G>C, and 9041G>A) that are in strong linkage disequilibrium (LD) with 3673G>A would be equally good predictors of the warfarin dose requirement. The algorithm's predictive power was similar across the self-identified "race/color" subsets. "Race/color" was not associated with stable warfarin dose in the multiple regression model, although the required warfarin dose was significantly lower (P = 0.006) in white (29 +/- 13 mg/week, n = 196) than in black patients (35 +/- 15 mg/week, n = 76).

Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements

“…29 Together with our findings, this suggests that a high percentage of individuals of Native American ancestry may require reduced warfarin doses. 29 Our hierarchical analysis of molecular variance indicates that the VKORC1 rs9923231 SNP shows an extremely high differentiation between geographic groups, with more than 31% of the total variation due to differences between the seven groups included in the analysis. This geographic differentiation is much more pronounced than that observed for the other three SNPs analyzed in this study (Table 3).…”

“…When applied to Brazilian patients of self-identified 'race/color' , researchers observed that it explained 51% of the total variance in warfarin dose. 29 This compares well with the power of other dosing algorithms developed for European and Asian populations, and works equally well among white and black Brazilians. 29 The development of a universally useful algorithm will, however, rely on further research into the frequency of VKORC1, CYP2C9 and CYP4F2 variants in a greater number of populations and characterization of other genetic variants associated with warfarin dosing.…”

“…The ultimate goal was to improve our understanding of the worldwide allele frequency distribution of these polymorphisms and to discuss the results in light of the known effect of these markers on warfarin dosing and the differences in average warfarin dosing that have been reported The VKORC1 gene is believed to be the most important individual predictor of warfarin dose. 29,38 Previous research has shown that the derived T allele of the rs9923231 polymorphism, which is located in the promoter region of the gene, is associated with lower warfarin dose requirements. Moreover, there is evidence indicating that the rs9923231 T allele is associated with a reduction of VKORC1 mRNA levels of up to 70%, in comparison to the wild-type allele.…”

“…Finally, it is important to mention that the frequency of the derived T allele in Native American populations shows considerable variation (14-75%). Perini et al 29 recently analyzed two Amerindian populations, the Guarani and Kaingang from Brazil, and they estimated that 60% of Guarani and 40% of Kaingang individuals have the variant T allele. 29 Together with our findings, this suggests that a high percentage of individuals of Native American ancestry may require reduced warfarin doses.…”

“…Perini et al 29 recently analyzed two Amerindian populations, the Guarani and Kaingang from Brazil, and they estimated that 60% of Guarani and 40% of Kaingang individuals have the variant T allele. 29 Together with our findings, this suggests that a high percentage of individuals of Native American ancestry may require reduced warfarin doses. 29 Our hierarchical analysis of molecular variance indicates that the VKORC1 rs9923231 SNP shows an extremely high differentiation between geographic groups, with more than 31% of the total variation due to differences between the seven groups included in the analysis.…”