title: An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patients.
abstract: The objective of this study was to assess the relative influence of VKORC1 and CYP2C9 genetic variants on several clinical outcomes related to warfarin treatment. We conducted a retrospective cohort analysis of 172 anticoagulation clinic patients followed from warfarin initiation. We assessed the following clinical outcomes: time to stable dose; time in, above, and below therapeutic range; the probability of overanticoagulation (international normalized ratio [INR] >5); frequency of anticoagulation clinic visits; and the contribution of genetics to maintenance dose. Patients with CYP2C9 variants, compared to those without, achieved stable dose 48% later (p < 0.01), spent a higher proportion of time above range in the first month of therapy (14% vs. 25%, p = 0.07), and had a higher odds ratio (OR) of an INR >5 (OR: 4.15, p = 0.03). In contrast, the only statistically significant effect with VKORC1 was a higher odds of an INR >5 (OR: 4.47, p = 0.03) for patients homozygous for the VKORC1 low-dose haplotype (AA) compared to heterozygotes. We did not detect an influence of CYP2C9 nor VKORC1 on the frequency of clinic visits. CYP2C9 alone, VKORC1 alone, and a combination of genetic and clinical factors explained 12%, 27%, and 50%, respectively, of the variation in warfarin maintenance dose. In conclusion, genetic variation in VKORC1 appears to have a different influence than CYP2C9 on anticoagulation-related outcomes such as bleeding events and time in therapeutic range. This difference may be due, in part, to pharmacokinetics factors (e.g. drug half-life), which are influenced primarily by CYP2C9; these findings should be confirmed in additional studies.
authors.affiliation: University of Washington, Department of Pharmacy, Seattle, WA 98195, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Meckley
authors.forename: Ann K
authors.initials: AK
authors.lastname: Wittkowsky
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: Allan E
authors.initials: AE
authors.lastname: Rettie
authors.forename: David L
authors.initials: DL
authors.lastname: Veenstra
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D014644:Genetic Variation; D006470:Hemorrhage / Q000139:chemically induced* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics; D012044:Regression Analysis; D012189:Retrospective Studies; D012307:Risk Factors; D013923:Thromboembolism / Q000453:epidemiology / Q000517:prevention & control*; D016896:Treatment Outcome; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics
chemical_list: D000925:Anticoagulants; 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