Warfarin-based anticoagulant therapy is associated with large variability in 
dose response. Genetic variability in the VKORC1 and CYP2C9 genes is associated 
with increased warfarin sensitivity. In addition, rare coding region mutations 
in VKORC1 have been associated with resistance to warfarin. VKORC1 and CYP2C9 
variability associated with altered warfarin response is less well characterized 
in African and mixed-raced populations such as Brazilians. To determine genetic 
variability associated with altered warfarin response among Brazilian patients, 
sixty-two adult patients with extreme resistance or sensitivity to warfarin were 
genotyped for variants in CYP2C9 and VKORC1. Of the 51 patients on low doses of 
warfarin, the VKORC1--1639 (3673) G>A polymorphism associated with warfarin 
sensitivity was present in 48 (94.1%), including 97% of Caucasians, 82% of 
African-descent patients, and all 7 (100%) patients of Indian descent. 
Additionally, 52.9% of warfarin sensitive patients had at least one CYP2C9*2 or 
CYP2C9*3 decreased metabolism allele, 63.6% of Caucasians and 54% of 
African-descent patients. Of the 11 patients on high doses of warfarin, 
sequencing of VKORC1 revealed a nonsynonymous V66M mutation in two warfarin 
resistant patients, both of African-descent. Brazilian patients requiring low 
doses of warfarin have a high frequency of VKORC1 and CYP2C9 variants associated 
with warfarin sensitivity. The presence of the rare VKORC1 V66M in two warfarin 
high dose outlier patients implies that this variant may be more frequent among 
African Brazilians and has implications for future warfarin studies in other 
populations of African descent.