title: An evaluation of nine genetic variants related to metabolism and mechanism of action of warfarin as applied to stable dose prediction.
abstract: Warfarin anticoagulation is complicated by the highly variable inter-individual response. Approximately 50% of the dose variability arises from clinical factors and variants in two genes, CYP2C9 (*2 and *3 variants) and VKORC1 -1173 C > T. We tested variants in five additional genes (EPHX1, PROC, APOE, CYP4F2, CALU and a new variant in VKORC1 in an attempt to further reduce the variability in predicted stable warfarin dose. Consecutive consenting outpatients requiring anticoagulation on stable warfarin dose (target INR 2-3) were genotyped; the association of SNP genotypes with stable warfarin dose was evaluated using the test of linear contrasts in analysis of variance (ANOVA). Study participants were 71 ± 13 years, 53% female, 85 ± 23 kg, body mass index 29 ± 7 kg/m(2). Genotypes were in Hardy-Weinberg equilibrium with the exception of VKORC1 -1639. Weekly stable dosages were 31.7 ± 13.9 mg/week; median: 30 mg/week, range: 11-70 mg/week. Significant associations with dose were seen for VKORC1 -1639 (P < 0.001), CYP2C9*2 (P = 0.005) and *3 (P = 0.003), the CYP4F2 SNP (P-trend = 0.00037), and VKORC1 3730 (p-trend = 0.042). In linear regression, age, sex, weight, and CYP2C9 *2 and *3 and VKORC1-1639 genotype explained 42% of variance. The addition of CYP4F2 genotype to the regression model increased the degree of variance explained to 47%. Addition of VKORC1 SNP -1639 to a model eliminated the association of VKORC1 3730 with warfarin dose (P-trend = 0.74), but -1639 remained highly significant. No impact on dose was observed for the other tested genetic variants.
authors.affiliation: Cardiovascular Department, Intermountain Medical Center, 5121 South Cottonwood Street, Murray, UT 84157, USA. john.carlquist@imail.org
authors.forename: John F
authors.initials: JF
authors.lastname: Carlquist
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Horne
authors.forename: Chrissa
authors.initials: C
authors.lastname: Mower
authors.forename: James
authors.initials: J
authors.lastname: Park
authors.forename: John
authors.initials: J
authors.lastname: Huntinghouse
authors.forename: Jason T
authors.initials: JT
authors.lastname: McKinney
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Muhlestein
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D004351:Drug Resistance / Q000235:genetics*; D004851:Epoxide Hydrolases / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D006801:Humans; D008297:Male; D051379:Mice; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D011486:Protein C / Q000235:genetics; D064417:Vitamin K Epoxide Reductases
chemical_list: D001057:Apolipoproteins E; C510527:CALU protein, human; D002135:Calcium-Binding Proteins; D011486:Protein C; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; 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; D004851:Epoxide Hydrolases; C522330:EPHX1 protein, human