The derived -1639T or A allele (referred to differently depending on the publication) is associated with lower required warfarin dosing and higher risks of bleeding (Ross et al., 2010).
In a study to determine DNA sequence variants in 16 Chinese patients with warfarin sensitivity or resistance (122700), 104 randomly selected Chinese patients receiving warfarin, 95 normal Chinese controls, and 92 normal Caucasians, Yuan et al. (2005) identified homozygosity for a VKORC1 promoter polymorphism, -1639G-A (rs9923231), in genomic DNA of all 11 warfarin-sensitive patients. Among the 104 randomly selected Chinese patients receiving warfarin, those with the AA genotype required a lower dose than those with the AG or GG genotype (P less than 0.0001). Frequencies of AA, AG, and GG genotypes were comparable in Chinese patients receiving warfarin (79.7%, 17.6%, and 2.7%) and normal Chinese controls (82%, 18%, and 0%), but differed significantly from Caucasians (14%, 47%, and 39%) (P less than 0.0001). The promoter polymorphism abolished the E-box consensus sequences, and dual luciferase assay revealed that VKORC1 promoter with the G allele had a 44% increase of activity when compared with the A allele.
The VKORC1 promoter polymorphism -1639G-A occurs frequently in patients who are warfarin-sensitive and require lower doses, whereas patients with VKORC1 missense mutations are warfarin-resistant and require higher doses. Scott et al. (2008) studied this and other polymorphisms of CYP2C9 (601130) and VKORC1 in Ashkenazi and Sephardi Jewish individuals. Unlike African Americans and similar to other individuals of European descent, the -1639A allele was present at high frequencies in both Ashkenazi (0.467) and Sephardi (0.500) cohorts.
Ross et al. (2010), who referred to the VKORC1 rs9923231 polymorphism as a C-to-T change, genotyped 963 individuals from 7 geographic regions. Very low frequencies for the T allele were found in African populations (less than 10%), with the exception of the San (33%). The frequencies of the T allele were intermediate in Europe (30 to 65%), the Middle East (41 to 51%), Central/South Asia (17 to 61%), Oceania (23 to 39%), and the Americas (14 to 75%). The frequencies of the T allele were very high in East Asian populations, with frequencies ranging from 75% (She) to 100% (Han and Oroqen). Similar frequencies were found in a Canadian cohort of 316 individuals of European, East Asian, and South Asian ancestry. The findings indicated a high overall percentage (about 32%) of total variation of this allele due to genetic differences in various geographic regions.
