VKORC1 polymorphisms explained 18% of warfarin dose variability in European-Americans and 5% in African-Americans, with haplotypes offering similar predictive value to single polymorphisms.
Observational (n=575)
Does the assessment of VKORC1 haplotypes explain a higher variability in warfarin dose compared to single polymorphisms in African-Americans and European-Americans?
VKORC1 haplotypes do not explain more variability in warfarin dose than single informative polymorphisms, supporting the use of specific polymorphisms and clinical covariates for dose prediction across diverse populations.
Absolute Event Rate: 18% vs 5%
BACKGROUND: Although the influence of VKORC1 and CYP2C9 polymorphisms on warfarin response has been studied, variability in dose explained by CYP2C9 and VKORC1 is lower among African-Americans compared with European-Americans. This has lead investigators to hypothesize that assessment of VKORC1 haplotypes may help capture a greater proportion of the variability in dose for this under-represented group. However, the inadequate representation of African-Americans and the assessment of a few VKORC1 polymorphisms have hindered this effort. METHODS: To determine if VKORC1 haplotypes or haplotype groups explain a higher variability in warfarin dose, we comprehensively assessed VKORC1 polymorphisms in 273 African-Americans and 302 European-Americans. The influence of VKORC1 polymorphisms, race-specific haplotypes and haplotype groups on warfarin dose was evaluated in race-stratified multivariable analyses after accounting for CYP2C9 (*2, *3, *5, *6 and *11) and clinical covariates. RESULTS: VKORC1 explained 18% (30% with CYP2C9) variability in warfarin dose among European-Americans and 5% (8% with CYP2C9) among African-Americans. Four common haplotypes in European-Americans and twelve in African-Americans were identified. In each race VKORC1 haplotypes emerged into two groups: low-dose (Group A) and high-dose (Group B). African-Americans had a lower frequency of Group A haplotype (10.6%) compared with European-Americans (35%, p < 0.0001).The variability in dose explained by VKORC1 haplotype or haplotype groups was similar to that of a single informative polymorphism. CONCLUSIONS: Our findings support the use of CYP2C9, VKORC1 polymorphisms (rs9934438 or rs9923231) and clinical covariates to predict warfarin dose in both African- and European-Americans. A uniform set of common polymorphisms in CYP2C9 and VKORC1, and limited clinical covariates can be used to improve warfarin dose prediction for a racially diverse population.
Limdi et al. (Wed,) conducted a observational in Warfarin dose variability (n=575). VKORC1 and CYP2C9 genotyping was evaluated on Variability in warfarin dose explained by VKORC1. VKORC1 polymorphisms explained 18% of warfarin dose variability in European-Americans and 5% in African-Americans, with haplotypes offering similar predictive value to single polymorphisms.