title: First report of warfarin dose requirements in patients possessing the CYP2C9*12 allele.
abstract: 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.
  
  
  METHODS
  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.
authors.affiliation: The George Washington University, Department of Pharmacology and Physiology, Washington, DC, United States.
authors.forename: Travis J
authors.initials: TJ
authors.lastname: O'Brien
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kidd
authors.forename: Craig A H
authors.initials: CA
authors.lastname: Richard
authors.forename: Ngoc-Han
authors.initials: NH
authors.lastname: Ha
authors.forename: Preston
authors.initials: P
authors.lastname: Witcher
authors.forename: Linda V
authors.initials: LV
authors.lastname: Tran
authors.forename: April
authors.initials: A
authors.lastname: Barbour
authors.forename: Matthew
authors.initials: M
authors.lastname: Tuck
authors.forename: Samantha D
authors.initials: SD
authors.lastname: McIntosh
authors.forename: Jacqueline N
authors.initials: JN
authors.lastname: Douglas
authors.forename: Arthur F
authors.initials: AF
authors.lastname: Harralson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D019943:Amino Acid Substitution; D000925:Anticoagulants / Q000378:metabolism* / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000235:genetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D001711:Biotransformation; D065729:Cytochrome P-450 CYP2C9; D054796:Drug Dosage Calculations; D005260:Female; D005838:Genotype; D060005:Genotyping Techniques; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D013923:Thromboembolism / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D001057:Apolipoproteins E; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
keywords: CYP2C9; CYP2C9*12; Warfarin; rs9332239