title: Clinical significance of combined CYP2C9 and VKORC1 genotypes in Japanese patients requiring warfarin.
abstract: The individual management of anticoagulation therapy is important for safe medical outcomes, including those of oral surgery. Here, Japanese patients who received warfarin (n = 35) and normal controls (n = 125) were analyzed by real-time PCR to determine the frequencies of single nucleotide polymorphisms in VKORC1 (vitamin K epoxide reductase complex, subunit 1) and CYP2C9 and how these frequencies related to warfarin dose and PT-INR. The genetic polymorphisms CYP2C9(*2) (416 C > T), CYP2C9(*3) (1061 A > C), and intron 1-136 C > T in VKORC1 (1173 C > T) were measured. All patients had the wild-type CYP2C9 gene (*1/*1). All 160 cases had the wild-type (CC) type CYP2C9(*2), 93.8% had AA type CYP2C9(*3), 6.2% had AC type CYP2C9(*3), 1.2% had CC type VKORC1, 13.8% had CT type VKORC1, and 85% had TT type VKORC1. The CC type VKORC1 genetic polymorphism was associated with a significantly higher mean warfarin maintenance dose (4.5 ± 0.5 mg) than other VKORC1 genotypes (TT type 2.9 ± 0.1 mg: CT type 3.4 ± 0.3 mg). Categorization of the patients in terms of the combined CYP2C9 and VKORC1 haplotype (the warfarin-responsive index; WRI) revealed the mean daily warfarin maintenance dose was 3.0 ± 0.1 mg for WRI 1 and 3.7 ± 0.3 mg for WRI 2 (P < 0.012). The event survey revealed 2 patients with nonfatal cerebral hemorrhage had a WRI score of 2 (VKORC1 C/T heterozygosity genotype). Thus, CYP2C9 and VKORC1 haplotype analysis allows prediction of warfarin maintenance dosage. The findings may provide a personalized use of warfarin in the field of oral surgery.
authors.affiliation: Division of Oral Surgery, Faculty of Dentistry, Iwate Medical University, Iwate, Japan.
authors.forename: You
authors.initials: Y
authors.lastname: Miyagata
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakai
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000368:Aged; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000150:complications / Q000188:drug therapy* / Q000235:genetics*; D016022:Case-Control Studies; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D019647:Oral Surgical Procedures / Q000009:adverse effects; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity; D016896:Treatment Outcome; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000925:Anticoagulants; D005819:Genetic Markers; 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