Race influences warfarin dose changes associated with genetic factors

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Abstract

Warfarin dosing algorithms adjust for race, assigning a fixed effect size to each predictor, thereby attenuating the differential effect by race. Attenuation likely occurs in both race groups but may be more pronounced in the less-represented race group. Therefore, we evaluated whether the effect of clinical (age, body surface area [BSA], chronic kidney disease [CKD], and amiodarone use) and genetic factors (CYP2C9*2,*3,*5,*6,*11, rs12777823, VKORC1, and CYP4F2) on warfarin dose differs by race using regression analyses among 1357 patients enrolled in a prospective cohort study and compared predictive ability of race-combined vs race-stratified models. Differential effect of predictors by race was assessed using predictor-race interactions in race-combined analyses. Warfarin dose was influenced by age, BSA, CKD, amiodarone use, and CYP2C9*3 and VKORC1 variants in both races, by CYP2C9*2 and CYP4F2 variants in European Americans, and by rs12777823 in African Americans. CYP2C9*2 was associated with a lower dose only among European Americans (20.6% vs 3.0%, P < .001) and rs12777823 only among African Americans (12.3% vs 2.3%, P = .006). Although VKORC1 was associated with dose decrease in both races, the proportional decrease was higher among European Americans (28.9% vs 19.9%, P = .003) compared with African Americans. Race-stratified analysis improved dose prediction in both race groups compared with race-combined analysis. We demonstrate that the effect of predictors on warfarin dose differs by race, which may explain divergent findings reported by recent warfarin pharmacogenetic trials. We recommend that warfarin dosing algorithms should be stratified by race rather than adjusted for race.

Figures

  • Table 1. Clinical, genetic, and sociodemographic characteristics of participants by race
  • Table 3). Possession of variant VKORC1 was associated with a significant dose decrease in both race groups; however, the dose reduction per variant allele was higher among European Americans (28.9% vs 19.9%, interaction P value 5 .003) compared with African Americans. Possession of CYP2C9*2 was associated with lower doses amongEuropeanAmericans, but not AfricanAmericans (20.6% vs 3.0% per variant allele, interaction P value, .001). Possession of variant rs12777823 was associated significantly lower dose among African Americans, but not in European Americans (12.3% vs 2.3%, interaction P value5 .006). Possession ofCYP4F2 variant resulted in 5.9% higher dose (per allele) in European Americans, but not in African Americans; however, the parameter estimates were not significantly different.
  • Table 4. Proportion of dose variability uniquely explained by clinical and genetic in race combined and race-stratified analysis using dosing algorithms shown in Tables 2 and 3

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APA

Limdi, N. A., Brown, T. M., Yan, Q., Thigpen, J. L., Shendre, A., Liu, N., … Beasley, T. M. (2015). Race influences warfarin dose changes associated with genetic factors. Blood, 126(4), 539–545. https://doi.org/10.1182/blood-2015-02-627042

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