First report of warfarin dose requirements in patients possessing the CYP2C9*12 allele.

Document Type

Journal Article

Publication Date



Clinica Chimica Acta


Volume 424 Issue C

Inclusive Pages



Anticoagulants--metabolism; Aryl Hydrocarbon Hydroxylases--genetics; Mutation; Thromboembolism--genetics; Warfarin--metabolism; Aged, Aged, 80 and over, Alleles, Amino Acid Substitution, Anticoagulants, Apolipoproteins E, Aryl Hydrocarbon Hydroxylases, Base Sequence, Biotransformation, Drug Dosage Calculations, Female, Genotype, Genotyping Techniques, Heterozygote, Humans, Male, Middle Aged, Molecular Sequence Data, Mutation, Thromboembolism, Vitamin K Epoxide Reductases, Warfarin


BACKGROUND: Warfarin is the most frequently prescribed anticoagulant in North America and Europe. It is administered as a racemate, but S-warfarin is principally responsible for its anticoagulant activity. Cytochrome P450 (CYP) 2C9 is the enzyme primarily responsible for the metabolism of S-warfarin. Numerous variant alleles of CYP2C9 have been identified. The CYP2C9*12 (rs9332239) allele harbors a P489S substitution in CYP2C9 which has been shown to result in a 40% decline in catalytic activity in vitro.

CASES: Four Caucasian patients with a low mean weekly warfarin dose (MWWD) were genotyped for CYP2C9, VKORC1 and APOE variant alleles. None of the four patients carried the common CYP2C9 variant alleles (*2, *3, *5, *6, *7, *8, *9, *11, *13) despite a relatively low MWWD (23.4±7.94 mg) compared to 208 patients carrying the CYP29C9*1 genotype (32.2±12.65 mg). Given that CYP2C9*12 confers decreased in vitro activity to the enzyme, we investigated whether these patients carried this allele. All four patients were CYP2C9*12 CT heterozygotes. Individual comparisons with patients possessing the same VKORC1 and APOE genotypes also demonstrated lower dose requirements in the patients that possessed CYP2C9*12 allele.

CONCLUSIONS: There are no reports of the clinical impact of rs9332239 on CYP2C9 substrates. This is the first report of patients with the rare CYP2C9*12 genotype and lower warfarin dose requirements.

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