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Genetic Regulation of Warfarin Metabolism and Response

Lookup NU author(s): Professor Ann Daly

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Abstract

Genetic factors make an important contribution to the wide interindividual variation in warfarin dose requirement. Several cytochromes P450, each of which shows genetic polymorphism leading to interindividual variation in levels of activity, contribute to oxidative metabolism of warfarin. The most important of these is CYP2C9, which 7-hydroxylates S-warfarin. In clinical studies, possession of the CYP2C9*2 or CYP2C9*3 variant alleles, which result in decreased enzyme activity, has been associated with a significant decrease in mean warfarin dose requirement in at least eight studies. Several studies also suggest that possession of a variant allele is associated with an increased risk of adverse events. Other genetic factors such as polymorphisms affecting CYP3A4 or CYP1A2 may also be relevant to warfarin dose requirement. The molecular basis of warfarin resistance remains unclear but could be due to unusually high CYP2C9 activity (pharmacokinetic resistance) or to abnormal vitamin K epoxide reductase (pharmacodynamic resistance). There is less information available on genetic factors affecting other anticoagulants, but the CYP2C9 genotype is also relevant to acenocoumarol dose.


Publication metadata

Author(s): Daly AK, Aithal GP

Publication type: Review

Publication status: Published

Journal: Seminars in Vascular Medicine

Year: 2003

Volume: 3

Issue: 3

Pages: 231-237

Print publication date: 01/08/2003

ISSN (print): 1528-9648

ISSN (electronic): 1529-3505

URL: http://dx.doi.org/10.1055/s-2003-44458

DOI: 10.1055/s-2003-44458

PubMed id: 15199455


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