Evaluation of genetic factors for warfarin dose prediction.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
Caldwell
Michael D
MD
Center for Human Genetics, Marshfield Clinic Research Foundation, 1000 North Oak Avenue, Marshfield, WI 54449, USA.
Berg
Richard L
RL
Zhang
Kai Qi
KQ
Glurich
Ingrid
I
Schmelzer
John R
JR
Yale
Steven H
SH
Vidaillet
Humberto J
HJ
Burmester
James K
JK
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002264:Carboxylic Acids / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000188:drug therapy*; D065729:Cytochrome P-450 CYP2C9; D004334:Drug Administration Schedule; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods*; D011110:Polymorphism, Genetic; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage*
D000925:Anticoagulants; D002264:Carboxylic Acids; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases