VKORC1 polymorphisms in Amerindian populations of Brazil

Noncoding polymorphisms in the VKORC1 gene associate with variation of interindividual dosing requirements of warfarin and other coumarin anticoagulants. The frequency of VKORC1 polymorphisms displays distinct interpopulation differences. Here, we report the distribution of the VKORC1 3673G>A, 5808T>G, 6853G>C and 9041G>A SNPs in three endogamous Amerindian (Native American) populations, namely, Guarani-Kaiowá, Guarani-Nandeva and Kaingang. Individual DNA from 180 healthy adults was genotyped for the VKORC1 polymorphisms using TaqMan Detection System assays. The ARLEQUIN 3.1 software package was used to estimate haplotype frequency and linkage disequilibrium. The VKORC1 3673G>A, 5808T>G, 6853G>C and 9041G>A polymorphisms were in Hardy-Weinberg equilibrium in each population. The 5808G allele was absent or rare (<3%), whereas 3673A, 6853C and 9041A were frequent (34-63%) in the three Amerindian populations. No difference was detected in allele or genotype frequency bewteen the two Guarani populations, whereas significant differences were observed between Kaingang and Guarani. Polymorphisms 3673G>A, 6853G>C and 9041G>A were in significant linkage disequilibrium in both Guarani and Kaingang (pairwise r2 values: 0.77-1.0). Haplotypes ATCG and GTGA accounted for more than 94% of the haplotypes in both populations, ATCG being the most common in Guarani (49.5%) and GTGA in Kaingang (54%). These data disclose the uniqueness of the frequency distribution of the VKORC1 SNPs in the Amerindians, compared with Asian, African and European populations. In view of the vast interpopulational diversity among Amerindians, the present data should not be interpreted as representative of other extant Amerindian peoples. Our estimates that 40% of Kaingang and 60% of Guarani have haplotypes including the variant 3673A allele suggest that these two Amerindian populations comprise high proportions of individuals requiring reduced warfarin doses.