title: Warfarin dosing and cytochrome P450 2C9 polymorphisms.
abstract: Two cytochrome P450 2C9 (CYP2C9) polymorphisms, CYP2C9*2 and *3, metabolize warfarin inefficiently. We assessed the extent to which these polymorphisms explain very low warfarin dose requirements and hemorrhagic complications after excluding non-genetic determinants of warfarin dosing. In this retrospective observational study, 73 patients with stable warfarin doses for > or =1 month and International Normalized Ratios (INR) of 2.0-3.0 were enrolled from our Anticoagulation Clinic. Seventeen patients required < or =2 mg (low-dose), 41 required 4-6 mg (moderate-dose), and 15 required > or =10 mg (high-dose) of daily warfarin. CYP2C9 genotyping was assessed by PCR amplification and restriction enzyme digestion analysis of DNA isolated from circulating leukocytes. The CYP2C9 polymorphisms independently predicted low warfarin requirements after adjusting for Body Mass Index, age, acetaminophen use, and race (OR 24.80; 95% CI 3.83-160.78). At least one polymorphism was present in every patient requiring < or =1.5 mg of daily warfarin, and 88%, 37%, and 7% of the low-, moderate-, and high-dose groups, respectively. All homozygotes and compound-heterozygotes for the variant alleles were in the low-dose group. Rates of excessive (INR>6.0) anticoagulation (and bleeding) were 4.5 (6.0), 7.9 (7.9), and 14.7 (0) per 100 patient-years in the wild-types, heterozygotes, and compound heterozygotes/homozygotes, respectively. In conclusion, CYP2C9*2 or *3 compound heterozygotes and homozygotes have low warfarin requirements even after excluding liver disease, excessive alcohol or acetaminophen consumption, low body weight, advancing age, and drug interactions. These polymorphisms increase the rate of excessive anticoagulation, but this risk does not appear to be associated with higher bleeding rates when anticoagulation status is closely monitored.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hylton V
authors.initials: HV
authors.lastname: Joffe
authors.forename: Ruliang
authors.initials: R
authors.lastname: Xu
authors.forename: F Bradley
authors.initials: FB
authors.lastname: Johnson
authors.forename: Janina
authors.initials: J
authors.lastname: Longtine
authors.forename: Nils
authors.initials: N
authors.lastname: Kucher
authors.forename: Samuel Z
authors.initials: SZ
authors.lastname: Goldhaber
mesh_terms: D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000706:statistics & numerical data; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D012044:Regression Analysis; D012189:Retrospective Studies; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism
chemical_list: D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases