Evaluation of genetic factors for warfarin dose prediction

Abstract

Objectives: Warfarin is a commonly prescribed anticoagulant drug used to prevent thromboses that may arise as a consequence of orthopedic and vascular surgery or underlying cardiovascular disease. Warfarin is associated with a notoriously narrow therapeutic window where small variations in dosing may result in hemorrhagic or thrombotic complications. To ultimately improve dosing of warfarin, we evaluated models for stable maintenance dose that incorporated both clinical and genetic factors.

Method: A model was constructed by evaluating the contribution to dosing variability of the following clinical factors: age, gender, body surface area, and presence or absence of prosthetic heart valves or diabetes. The model was then sequentially expanded by incorporating polymorphisms of cytochrome P450 (CYP) 2C9; vitamin K 2,3 epoxide reductase complex, subunit 1 (VKORC1); gamma carboxylase; factor VII; and apolipoprotein (Apo) E genes.

Results: Of genetic factors evaluated in the model, CYP2C9 and VKORC1 each contributed substantially to dose variability, and together with clinical factors explained 56% of the individual variability in stable warfarin dose. In contrast, gamma carboxylase, factor VII and Apo E polymorphisms contributed little to dose variability.

Conclusion: The importance of CYP2C9 and VKORC1 to patient-specific dose of warfarin has been confirmed, while polymorphisms of gamma carboxylase, factor VII and Apo E genes did not substantially contribute to predictive models for stable warfarin dose.

Figure 1.

Stable coumadin dose by genotype. Distribution of weekly stabilizing warfarin dose in relation to (A) CYP2C9 and (B) CYP2C9 and VKORC1 genotypes. For (B) CYP2C9 genotype is labeled as *1/*1, *1/*2, *1/*3, *2/*2, *2/*3 and *3/*3. Within each CYP2C9 genotype, the VKORC1 genotype is shown as GG, GC or CC.

Figure 2.

Paired scatter plots of predicted versus observed weekly stable dose. Models involving different genetic variables were compared for the study cohort with complete data. Each pair incorporates another gene: CYP2C9 (A, B), VKORC1 (C, D), Apo E (E, F), gamma carboxylase (G, H) and factor VII (I, J). Note: panels A–F appear on page 12.

Figure 2.

Paired scatter plots of predicted versus observed weekly stable dose. Models involving different genetic variables were compared for the study cohort with complete data. Each pair incorporates another gene: CYP2C9 (A, B), VKORC1 (C, D), Apo E (E, F), gamma carboxylase (G, H) and factor VII (I, J). Note: panels A–F appear on page 12.

Figure 3.

Nomograms based on CYP2C9 and VKORC1 genotype, age and gender. These nomograms indicate daily dose when the patient’s CYP2C9 and VKORC1 genotype, age and gender are known. Nomograms are provided for (A) CYP2C9 *1/*1, (B) CYP2C9 *1/*2, and (C) CYP2C9 *1/*3. Patient age is specified on the horizontal axis and predicted dose is specified on the vertical axis. Dose is calculated by selecting the correct nomogram based on CYP2C9 genotype, locating the patient age across the bottom, identifying the correct predictive line based on VKORC1 genotype and gender, and reading the predicted dose from the left axis.