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Ramirez, Andrea H; Shi, Yaping; Schildcrout, Jonathan S; Delaney, Jessica T; Xu, Hua; Oetjens, Matthew T; Zuvich, Rebecca L; Basford, Melissa A; Bowton, Erica; Jiang, Min; Speltz, Peter; Zink, Raquel; Cowan, James; Pulley, Jill M; Ritchie, Marylyn D; Masys, Daniel R; Roden, Dan M; Crawford, Dana C; Denny, Joshua C
Pharmacogenomics, 03/2012, Letnik: 13, Številka: 4Journal Article
Warfarin pharmacogenomic algorithms reduce dosing error, but perform poorly in non-European-Americans. Electronic health record (EHR) systems linked to biobanks may allow for pharmacogenomic analysis, but they have not yet been used for this purpose. We used BioVU, the Vanderbilt EHR-linked DNA repository, to identify European-Americans (n = 1022) and African-Americans (n = 145) on stable warfarin therapy and evaluated the effect of 15 pharmacogenetic variants on stable warfarin dose. Associations between variants in VKORC1, CYP2C9 and CYP4F2 with weekly dose were observed in European-Americans as well as additional variants in CYP2C9 and CALU in African-Americans. Compared with traditional 5 mg/day dosing, implementing the US FDA recommendations or the International Warfarin Pharmacogenomics Consortium (IWPC) algorithm reduced error in weekly dose in European-Americans (13.5-12.4 and 9.5 mg/week, respectively) but less so in African-Americans (15.2-15.0 and 13.8 mg/week, respectively). By further incorporating associated variants specific for European-Americans and African-Americans in an expanded algorithm, dose-prediction error reduced to 9.1 mg/week (95% CI: 8.4-9.6) in European-Americans and 12.4 mg/week (95% CI: 10.0-13.2) in African-Americans. The expanded algorithm explained 41 and 53% of dose variation in African-Americans and European-Americans, respectively, compared with 29 and 50%, respectively, for the IWPC algorithm. Implementing these predictions via dispensable pill regimens similarly reduced dosing error. These results validate EHR-linked DNA biorepositories as real-world resources for pharmacogenomic validation and discovery.
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in: SICRIS
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