title: The effect of CYP2C9, VKORC1 and CYP4F2 polymorphism and of clinical factors on warfarin dosage during initiation and long-term treatment after heart valve surgery.
abstract: The dosage of warfarin is restricted due to its narrow therapeutic index, so, the required dose must be adapted individually to each patient. Variations in warfarin dosage are influenced by genetic factors, the changes in patient diet, anthropometric and clinical parameters. To determine whether VKORC1 G3730A and CYP4F2 G1347A genotypes contribute to warfarin dosage in patients during initiation and long-term anticoagulation treatment after heart valve surgery. From totally 307 patients, who underwent heart valve surgery, 189 patients (62 %) who had been treated with warfarin more than 3 months, were included into the study. A hierarchical stepwise multivariate linear regression model showed, that during initiation clinical factors can explain 17 % of the warfarin dose variation. The addition of CYP2C9 and VKORC1 G-1639A genotype raises the accuracy about twice-to 32 %. The CYP4F2 G1347A genotype can add again about 2-34 %. During long-term treatment clinical factors explain about 26 % of warfarin dose variation. If the CYP2C9 *2, *3, VKORC1*2 alleles are detected, model can explain about 49 % in dose variation. The *3 allele of VKORC1 raises the accuracy by 1-50 %. The carriers of CYP4F2 A1347A genotype required higher daily warfarin doses during initiation of warfarin therapy after heart valve surgery than comparing to G/G and G/A carriers, but during the longer periods of warfarin use, the dosage of warfarin depended significantly on VKORC1 *3 allele (G3730A polymorphism) and on the thyroid stimulating hormone level in the blood plasma.
authors.affiliation: Institute of Cardiology, Lithuanian University of Health Sciences, Sukileliu 17, 50009, Kaunas, Lithuania, vaciss@yahoo.fr.
authors.forename: Vacis
authors.initials: V
authors.lastname: Tatarunas
authors.forename: Vaiva
authors.initials: V
authors.lastname: Lesauskaite
authors.forename: Audrone
authors.initials: A
authors.lastname: Veikutiene
authors.forename: Pranas
authors.initials: P
authors.lastname: Grybauskas
authors.forename: Povilas
authors.initials: P
authors.lastname: Jakuska
authors.forename: Laima
authors.initials: L
authors.lastname: Jankauskiene
authors.forename: Ruta
authors.initials: R
authors.lastname: Bartuseviciute
authors.forename: Rimantas
authors.initials: R
authors.lastname: Benetis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage*; 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; D005260:Female; D006349:Heart Valve Diseases / Q000097:blood / Q000235:genetics / Q000601:surgery; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D064417:Vitamin K Epoxide Reductases / Q000235:genetics* / Q000378:metabolism; D014859:Warfarin / Q000008:administration & dosage*
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