title: Warfarin pharmacogenetics: a controlled dose-response study in healthy subjects.
abstract: The aim of this study was to determine how genetic variants contribute to warfarin dosing variability when non-genetic factors are controlled. Thirty healthy subjects were subjected to a warfarin dosing algorithm with daily international normalized ratio (INR) measurements to INR ≥ 2.0, then off warfarin to INR ≤ 1.2. The primary outcome was the cumulative dose required to achieve INR ≥ 2.0 for 2 consecutive days. CYP2C9 (p=0.004) and VKORC1 (p=0.02) variant carriers required lower cumulative doses, and CYP4F2 carriers required higher doses (p=0.04). Subjects with variants in both CYP2C9 and VKORC1 required fewer days to reach INR ≥ 2.0 than wild-type subjects or those with variants in CYP2C9 or VKORC1 (p=0.01). Genetic contribution to dose variability (~62%) was greater than previously reported, suggesting that uncontrolled clinical variables influence the effect of these variants. In conclusion, genotype-guided warfarin-dosing algorithms may rely more on genetic variables in healthier individuals than in patients with clinical confounders.
authors.affiliation: Vascular Medicine Section, The Zena and Michael A Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Daniella L
authors.initials: DL
authors.lastname: Kadian-Dodov
authors.forename: Sarina A
authors.initials: SA
authors.lastname: van der Zee
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Scott
authors.forename: Inga
authors.initials: I
authors.lastname: Peter
authors.forename: Suparna
authors.initials: S
authors.lastname: Martis
authors.forename: Dana O
authors.initials: DO
authors.lastname: Doheny
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Rothlauf
authors.forename: Steven A
authors.initials: SA
authors.lastname: Lubitz
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Halperin
mesh_terms: D000328:Adult; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D004305:Dose-Response Relationship, Drug; D005260:Female; D014644:Genetic Variation; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D015999:Multivariate Analysis; D064417:Vitamin K Epoxide Reductases / Q000235:genetics* / Q000378:metabolism; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
keywords: CYP2C9; CYP4F2; VKORC1; coagulation; dose–response; healthy subjects; pharmacogenetics; warfarin