Genetic Regulation of Warfarin Metabolism and Response

Ann K. Daly; Guruprasad P. Aithal

doi:10.1055/s-2003-44458

Seminars in Vascular Medicine, Table of Contents

Semin Vasc Med 2003; 03(3): 231-238
DOI: 10.1055/s-2003-44458

Genetic Regulation of Warfarin Metabolism and Response

Ann K. Daly¹ , Guruprasad P. Aithal²

¹Department of Pharmacological Sciences, University of Newcastle, Medical School, Newcastle upon Tyne, United Kingdom
²Queen's Medical Centre University Hospital, Nottingham, United Kingdom

Abstract

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.

KEYWORDS

Warfarin metabolism - genetic factors - CYP2C9

Full Text

References

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