Predicting Warfarin Dosage in European–Americans and African–Americans using DNA Samples Linked to an Electronic Health Record

Abstract

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.

Does CALU SNP rs1043550 Contribute Variability to Therapeutic Warfarin Dosing Requirements?

“…Inclusion of these SNPs in dosing models explained 41% of warfarin dose variation in African Americans, compared to only 29% explained in African Americans applying the algorithms of the International Warfarin Consortium, which was modeled in populations wherein the Black race was under-represented. 16 These data validated an earlier study by Voora et al 9 who also reported higher warfarin dose requirements in African American patients (P = 0.01) using two separate replication cohorts: one with subjects of mixed ethnicity and one consisting of African American subjects. However, while this SNP is rare in Caucasians of European descent, (allele frequency=0.002), it exhibits comparatively higher allele frequency among individuals of sub-saharan African and African American racial origin (allele frequency=0.14.)…”

“…The allele frequency was A (49%) and G (51%). This differed from frequencies reported in the HapMap CEU population, 10 (table 1, P <0.0001) but resembled other subpopulations of subjects from other studies with underlying cardiovascular disease conditions, 16,17 although ethnicity differed in these studies compared to the study cohort. The study cohort showed deviation from Hardy-Weinberg equilibrium (P = 0.035), while the HapMap CEU does not (P = 0.49, see table 2).…”

“…A recent study by Ramirez et al, 16 that linked the electronic medical record to biorepositories storing genetic data, similarly validated the contribution of CALU SNP rs339097 and other CYP2C9 SNPs to therapeutic dose requirement prediction in African Americans. Inclusion of these SNPs in dosing models explained 41% of warfarin dose variation in African Americans, compared to only 29% explained in African Americans applying the algorithms of the International Warfarin Consortium, which was modeled in populations wherein the Black race was under-represented.…”

The curious tale of perioperative precision medicine: a story of hydroxocobalamin and cardiac surgery-associated vasoplegia

“…1 In several areas of medicine, examples of the role of precision medicine in day-to-day clinical care are emerging. These include targeted approaches to treating the underlying causes of specific genetic variants in cystic fibrosis, 2 pharmacogenomic-guided methods of warfarin dosing, 3 prediction of response to clopidogrel, 4 and molecular testing of cancer patients for selection of a more targeted chemotherapy approach. 5 In contrast, the role of precision medicine in the perioperative setting (perhaps for the prevention or treatment of perioperative adverse events) has not been as widely explored.…”

“…Ce sont notamment des approches ciblées du traitement des causes sous-jacentes de différentes variantes génétiques spécifiques de la fibrose kystique, 2 des méthodes de dosage de la warfarine guidées par la pharmacogénomique, 3 de prédiction de la réponse au clopidogrel, 4 et des tests moléculaires pour la sélection d'une chimiothérapie ciblée chez des patients cancéreux. 5 En revanche, la place de la médecine de précision dans un contexte périopératoire (pour la prévention ou le traitement d'événements indésirables périopératoires, par exemple) n'a pas été largement explorée.…”