Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans

Abstract

Both VKORC1 and CYP2C9 polymorphisms contribute to inter-population difference in warfarin doses among the three populations, but their contribution to intra-population variability may differ within each population.

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

“…These findings are also in agreement with studies indicating that, on average, warfarin dose requirements among East Asian individuals are lower than in African and European subjects. 3,37 The average frequency of the derived T allele in European populations was 51% in the HGDP-CEPH samples and 38% in the sample of Canadians of European ancestry. These values are in the middle of those observed among the African and East Asian populations and also reflect current population-based trends in warfarin dosing.…”

“…The low frequency of the derived T allele observed among African populations (o10% with the exception of the San who had a frequency of 33%) is consistent with previous research indicating that individuals of African ancestry require a higher average warfarin dose than those of European or Asian descent. 3,26 In contrast, the East Asian populations included in the HGDP-CEPH panel had very high frequencies for the derived T allele, ranging from 75 (among the She) to 100% (Han and Oroqen). Canadians of East Asian ancestry showed a similar frequency for the T allele (86%).…”

“…These statistics can be attributed to the high interindividual variability in warfarin dosing requirements and the combination of genetic and non-genetic factors that contribute to an individual's sensitivity to the medication. 3 Dosing of warfarin attempts to maintain the international normalized ratio of prothrombin time between 2.0 and 3.0, in between which there is minimal risk of over or under anticoagulation. 4,5 With a narrow therapeutic window and large interindividual variability, clinical factors, such as age, height, sex, diet and drug-drug interactions 6-8 explain 12 6 to 15% 9 of the observed variability in warfarin dosing.…”

“…Genetic factors have also been shown to affect warfarin maintenance. 3,10 Previous studies have demonstrated that two genes, VKORC1 and CYP2C9, which are involved in the vitamin K-dependent clotting pathway, explain an additional 30-54% of variance observed in warfarin dosing. 6,9,11 Warfarin exists as a mixture of two stereoisomers, R and S. 8,12 S-warfarin is approximately three times as active as the R-enantiomer 12 and works by antagonizing the vitamin K-dependent clotting pathway.…”

“…25 Typically, in individuals of Asian ancestry the initial dose is 3.5 mg and in individuals of European ancestry is 5 mg or 10 mg. 25,26 In this respect, it is important to mention that several studies have characterized individuals of African ancestry as requiring higher average warfarin doses and Asians as requiring lower doses than Europeans. 3,26 Research has recognized the influence that genetics has on the metabolism of warfarin and led to a revision of warfarin labels by the US Food and Drug Administration in 2007. New package inserts have been designed to include information on the effects of VKORC1 and CYP2C9 polymorphisms.…”