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Blood, 22 January 2009, Vol. 113, No. 4, pp. 784-792.
Prepublished online as a Blood First Edition Paper on June 23, 2008; DOI 10.1182/blood-2008-04-149070.
 Previous Article | Next Article 
Submitted April 2, 2008
Accepted June 12, 2008
The largest prospective warfarin-treated cohort supports genetic forecasting
Mia Wadelius, Leslie Y Chen, Jonatan D Lindh, Niclas Eriksson, Mohammed JR Ghori, Suzannah Bumpstead, Lennart Holm, Ralph McGinnis, Anders Rane*, and Panos Deloukas
Department of Medical Sciences, Clinical Pharmacology, Uppsala University Hospital, Uppsala, Sweden
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom
Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden
UCR - Uppsala Clinical Research Centre, Uppsala Science Park, Uppsala, Sweden
* Corresponding author; email: anders.rane{at}ki.se.
Genetic variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated. We genotyped 183 polymorphisms in 29 candidate genes in 1496 Swedish patients starting warfarin treatment, and tested for association with response. CYP2C9*2 and *3 explained 12% (p=6.63x10-34) of the variation in warfarin dose, while a single VKORC1 SNP explained 30% (p=9.82x10-100). No SNP outside the CYP2C gene cluster and VKORC1 regions was significantly associated with dose after correction for multiple testing. During initiation of therapy, homozygozity for CYP2C9 and VKORC1 variant alleles increased the risk of over-anticoagulation, hazard ratios 21.84 (95%CI 9.46;50.42) and 4.56 (95%CI 2.85;7.30), respectively. One of eight patients with CYP2C9*3/*3 (12.5%) experienced severe bleeding during the first month compared with 0.27% of other patients (p=0.066). A multiple regression model using the predictors CYP2C9, VKORC1, age, gender and drug-interactions explained 59% of the variance in warfarin dose, and 53% in an independent sample of 181 Swedish individuals. In conclusion, CYP2C9 and VKORC1 significantly influenced warfarin dose and predicted individuals predisposed to unstable anticoagulation. Our results strongly support that initiation of warfarin guided by pharmacogenetics would improve clinical outcome.
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