Dan Roden
Faculty Member
Last active: 3/24/2020

Predicting warfarin dosage in European-Americans and African-Americans using DNA samples linked to an electronic health record.

Ramirez AH, Shi Y, Schildcrout JS, Delaney JT, Xu H, Oetjens MT, Zuvich RL, Basford MA, Bowton E, Jiang M, Speltz P, Zink R, Cowan J, Pulley JM, Ritchie MD, Masys DR, Roden DM, Crawford DC, Denny JC
Pharmacogenomics. 2012 13 (4): 407-18

PMID: 22329724 · PMCID: PMC3361510 · DOI:10.2217/pgs.11.164

AIM - 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.

PATIENTS & METHODS - 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.

RESULTS - 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.

CONCLUSION - These results validate EHR-linked DNA biorepositories as real-world resources for pharmacogenomic validation and discovery.

MeSH Terms (23)

Adult African Americans Aged Aged, 80 and over Anticoagulants Aryl Hydrocarbon Hydroxylases Calcium-Binding Proteins Cytochrome P-450 CYP2C9 Cytochrome P-450 Enzyme System Cytochrome P450 Family 4 Dose-Response Relationship, Drug Drug Administration Schedule Electronic Health Records European Continental Ancestry Group Female Humans Male Middle Aged Mixed Function Oxygenases Polymorphism, Single Nucleotide Substance-Related Disorders Vitamin K Epoxide Reductases Warfarin

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