First report of warfarin dose requirements in patients possessing the CYP2C912 allele

• Published in: Clinica chimica acta 2013-09, Vol.424, p.73-75
• Main Authors: O'Brien, Travis J., Kidd, Robert S., Richard, Craig A.H., Ha, Ngoc-Han, Witcher, Preston, Tran, Linda V., Barbour, April, Tuck, Matthew, McIntosh, Samantha D., Douglas, Jacqueline N., Harralson, Arthur F.
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Alleles; Amino Acid Substitution; Anticoagulants - metabolism; Anticoagulants - therapeutic use; Apolipoproteins E - genetics; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; Base Sequence; Biotransformation; CYP2C9; CYP2C912; Cytochrome P-450 CYP2C9; Drug Dosage Calculations; Female; Genotype; Genotyping Techniques; Heterozygote; Humans; Male; Middle Aged; Molecular Sequence Data; Mutation; rs9332239; Thromboembolism - enzymology; Thromboembolism - genetics; Thromboembolism - pathology; Thromboembolism - prevention & control; Vitamin K Epoxide Reductases - genetics; Warfarin; Warfarin - metabolism; Warfarin - therapeutic use
• ISSN: 0009-8981; 1873-3492
• DOI: 10.1016/j.cca.2013.05.008

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. 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±7.94mg) compared to 208 patients carrying the CYP29C9*1 genotype (32.2±12.65mg). 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. 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.