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Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications

Lookup NU author(s): Professor Chris Day, Dr Patrick Kesteven, Professor Ann Daly

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Abstract

Background. The cytochrome P450 CYP2C9 is responsible for the metabolism of S-warfarin. Two known allelic variants CYP2C9*2 and CYP2C9*3 differ from the wild type CYP2C9*1 by a single aminoacid substitution in each case. The allelic variants are associated with impaired hydroxylation of S-warfarin in in-vitro expression systems. We have studied the effect of CYP2C9 polymorphism on the in-vivo warfarin dose requirement. Methods. Patients with a daily warfarin dose requirement of 1.5 mg or less (low-dose group, n = 36), randomly selected patients with a wide range of dose requirements from an anticoagulant clinic in north-east England (clinic control group, n = 52), and 100 healthy controls from the community in the same region were studied. Genotyping for the CYP2C9*2 and CYP2C9*3 alleles was done by PCR analysis. Case notes were reviewed to assess the difficulties encountered during the induction of warfarin therapy and bleeding complications in the low-dose and clinic control groups. Findings. The odds ratio for individuals with a low warfarin dose requirement having one or more CYP2C9 variant alleles compared with the normal population was 6.21 (95% CI 2.48-15.6). Patients in the low-dose group were more likely to have difficulties at the time of induction of warfarin therapy (5.97 [2.26-15.82]) and have increased risk of major bleeding complications (rate ratio 3.68 [1.43-9.50]) when compared with randomly selected clinic controls. Interpretation. We have shown that there is a strong association between CYP2C9 variant alleles and low warfarin dose requirement. CYP2C9 genotyping may identify a subgroup of patients who have difficulty at induction of warfarin therapy and are potentially at a higher risk of bleeding complications.


Publication metadata

Author(s): Daly AK; Day CP; Kesteven PJL; Aithal GP

Publication type: Article

Publication status: Published

Journal: Lancet

Year: 1999

Volume: 353

Issue: 9154

Pages: 717-719

Print publication date: 27/02/1999

ISSN (print): 0140-6736

ISSN (electronic): 1474-547X

Publisher: The Lancet Publishing Group

URL: http://dx.doi.org/10.1016/S0140-6736(98)04474-2

DOI: 10.1016/S0140-6736(98)04474-2

PubMed id: 10073515


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