title: The influence of VKORC1 and CYP2C9 gene sequence variants on the stability of maintenance phase warfarin treatment.
abstract: BACKGROUND
  A substantial part of the inter-individual variation in vitamin K-antagonist dose can be explained by certain sequence variants in the genes CYP2C9 (NG_008385.1:g.8633C>T or *1/*2, NG_008385.1:g.47639A>C or *1/*3) and VKORC1 (NG_011564.1:g.6399C>T). Patients possessing these variant alleles require lower doses and have increased risk of overanticoagulation.
  
  
  METHODS
  We investigated the influence of the above sequence variants on stability of maintenance phase warfarin therapy in a prospective study of 300 consecutive patients followed for one year at an anticoagulant clinic.
  
  
  RESULTS
  Patients having one VKORC1 variant allele (n=144) had a time in therapeutic range of INR (TTR) of 71.4%, significantly lower (p=0.02) than the 76.7% TTR of patients with none (n=96) or two (n=46) variant alleles. Patients carrying the CYP2C9 *3 allele (n=40) trended towards lower TTR than patients without this variant allele (69.8% vs. 74.7%, p=0.09). Six patients possessed two variant alleles of CYP2C9 (*2/*3 or *3/*3) and had significantly lower TTR (60.5% vs. 74.3%, p=0.012) and higher risk of an INR>4.5 (67% vs. 23%, p=0.03) compared with the remaining patients.
  
  
  CONCLUSIONS
  We observed modest effects of common gene sequence variants in CYP2C9 and VKORC1 on stability of maintenance phase warfarin therapy. Patients attending an anticoagulant clinic using computer-assisted dosage were safely monitored regardless of these sequence variants, but for the small subgroup of patients with the CYP2C9 genotype *2/*3 or *3/*3, treatment stability was reduced.
authors.affiliation: Unit for Thrombosis Research, Institute of Public Health, University of Southern Denmark. jskov@health.sdu.dk
authors.forename: Jane
authors.initials: J
authors.lastname: Skov
authors.forename: Else-Marie
authors.initials: EM
authors.lastname: Bladbjerg
authors.forename: Anja
authors.initials: A
authors.lastname: Leppin
authors.forename: Jørgen
authors.initials: J
authors.lastname: Jespersen
mesh_terms: D000368:Aged; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001777:Blood Coagulation / Q000187:drug effects* / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D011446:Prospective Studies; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases