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The largest prospective warfarin-treated cohort supports genetic forecasting
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.ORCID iD: 0000-0002-6368-2622
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
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2009 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 113, no 4, 784-792 p.Article in journal (Refereed) Published
Abstract [en]

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 = 6.63 x 10(-34)) of the variation in warfarin dose, while a single VKORC1 SNP explained 30% (P = 9.82 x 10(-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, homozygosity 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 8 patients with CYP2C9*3/*3 (12.5%) experienced severe bleeding during the first month compared with 0.27% of other patients (P = .066). A multiple regression model using the predictors CYP2C9, VKORC1, age, sex, and druginteractions 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.

Place, publisher, year, edition, pages
2009. Vol. 113, no 4, 784-792 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-98487DOI: 10.1182/blood-2008-04-149070ISI: 000262646200006PubMedID: 18574025OAI: oai:DiVA.org:uu-98487DiVA: diva2:174703
Available from: 2009-02-24 Created: 2009-02-24 Last updated: 2016-02-19
In thesis
1. On the Prediction of Warfarin Dose
Open this publication in new window or tab >>On the Prediction of Warfarin Dose
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Warfarin is one of the most widely used anticoagulants in the world. Treatment is complicated by a large inter-individual variation in the dose needed to reach adequate levels of anticoagulation i.e. INR 2.0 – 3.0. The objective of this thesis was to evaluate which factors, mainly genetic but also non-genetic, that affect the response to warfarin in terms of required maintenance dose, efficacy and safety with special focus on warfarin dose prediction.

Through candidate gene and genome-wide studies, we have shown that the genes CYP2C9 and VKORC1 are the major determinants of warfarin maintenance dose. By combining the SNPs CYP2C9 *2, CYP2C9 *3 and VKORC1 rs9923231 with the clinical factors age, height, weight, ethnicity, amiodarone and use of inducers (carbamazepine, phenytoin or rifampicin) into a prediction model (the IWPC model) we can explain 43 % to 51 % of the variation in warfarin maintenance dose. Patients requiring doses < 29 mg/week and doses ≥ 49 mg/week benefitted the most from pharmacogenetic dosing. Further, we have shown that the difference across ethnicities in percent variance explained by VKORC1 was largely accounted for by the allele frequency of rs9923231. Other novel genes affecting maintenance dose (NEDD4 and DDHD1), as well as the replicated CYP4F2 gene, have small effects on dose predictions and are not likely to be cost-effective, unless inexpensive genotyping is available.

Three types of prediction models for warfarin dosing exist: maintenance dose models, loading dose models and dose revision models. The combination of these three models is currently being used in the warfarin treatment arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) study. Other clinical trials aiming to prove the clinical validity and utility of pharmacogenetic dosing are also underway.

The future of pharmacogenetic warfarin dosing relies on results from these ongoing studies, the availability of inexpensive genotyping and the cost-effectiveness of pharmacogenetic driven warfarin dosing compared with new oral anticoagulant drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 79 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 773
Warfarin, pharmacogenetics, prediction models, Dosing algorithm, GWAS, VKORC1, CYP2C9
National Category
Pharmacology and Toxicology
Research subject
Clinical Pharmacology
urn:nbn:se:uu:diva-172864 (URN)978-91-554-8359-3 (ISBN)
Public defence
2012-06-05, Enghoffsalen, Akademiska sjukhuset, ingång 50, bv, Uppsala, 09:00 (Swedish)
Available from: 2012-05-14 Created: 2012-04-16 Last updated: 2012-08-01Bibliographically approved

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