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Evaluation of Genetic Factors for Warfarin Dose Prediction

Michael D. Caldwell, MD, PhD, Department of Surgery, Marshfield Clinic, 1000 North Oak Avenue, Marshfield, Wisconsin 54449
Richard L. Berg, MS, Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, 1000 North Oak Avenue, Marshfield, Wisconsin 54449
Kai Qi Zhang, BS, Center for Human Genetics, Marshfield Clinic Research Foundation 1000 North Oak Avenue Marshfield, Wisconsin 54449
Ingrid Glurich, PhD, Office of Research Facilitation, Marshfield Clinic Research Foundation, 1000 North Oak Avenue, Marshfield, Wisconsin 54449
John R. Schmelzer, PhD, Health Services Research Center, Marshfield Clinic Research Foundation, 1000 North Oak Avenue, Marshfield, Wisconsin 54449
Steven H. Yale, MD, Department of Internal Medicine, Marshfield Clinic and Clinical Research Center, Marshfield Clinic Research Foundation, 1000 North Oak Avenue, Marshfield, Wisconsin 54449
Humberto J. Vidaillet, MD, Department of Cardiology, Marshfield Clinic and Administration, Marshfield Clinic Research Foundation, 1000 North Oak Avenue, Marshfield, Wisconsin 54449
James K. Burmester, PhD, Center for Human Genetics, Marshfield Clinic Research Foundation, 1000 North Oak Avenue, Marshfield, Wisconsin 54449

Reprint Requests: James K. Burmester, PhD, Center for Human Genetics, Marshfield Clinic Research Foundation, 1000 North Oak Avenue, Marshfield, WI 54449, Telephone: 715-389-4368, Fax: 715-389-3808, Email: burmester.jim{at}mcrf.mfldclin.edu

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.

Key Words: Bleeding • Coagulation • Vitamin K

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