Clinical Significance of Combined CYP2C9 and VKORC1 Genotypes in Japanese Patients Requiring Warfarin

Abstract

SummaryThe 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 VKO-RC1, 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 warfarinresponsive 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. (Int Heart J 2011; 52: 44-49)

The Active Metabolite of Warfarin (3'-Hydroxywarfarin) and Correlation with INR, Warfarin and Drug Weekly Dosage in Patients under Oral Anticoagulant Therapy: A Pharmacogenetics Study

“…Accordingly, heterozygotes had a significant intermediate daily dose. This independent finding is in accordance with previous reports [30, 37, 38] and its validity belong to the fact that the three VKORC1 genotype’s groups had undistinguishable mean, median and range distribution of the INR value at the day of assessment, being referred to long time established OAT patients. In addition, to determine whether the second key gene in warfarin metabolism (i.e.…”

“…Approximately, more than 50% of inter-individual variation is due to SNPs in VKORC1 and CYP2C9 genes, and also considering age, concomitant therapy, diet and patient compliance, the remaining percentage of variations remains in part unexplained. Pharmacogenetics investigations to recognize patients a priori with regard to drug dosage and clinical response was recommended by FDA in 2007 for old and new drugs on based evidence, suggesting and encouraging to include also warfarin treatment [37–39]. For these reasons, only INR monitoring could be limited for dose-adjustment or for target-INR reaching.…”

Genotype‐guided warfarin therapy: Still of only questionable value two decades on

“…Apart from atrial fibrillation (AF), indications studied include stroke, prophylaxis associated with the use of artificial heart valves and continuous‐flow left ventricular assist devices, deep venous thrombosis and pulmonary embolism . Patients studied came from diverse ethnic/racial backgrounds and included not only adult but also paediatric populations …”

Effect of impaired renal function on the maintenance dose of warfarin in Japanese patients

“…Inter-individual variability in dose response to warfarin is associated with various demographic, clinical, and genetic factors [20]. A number of algorithms have been developed to quantitatively predict the maintenance dose of warfarin in multiple ethnicities [21,22] including Japanese [23][24][25][26][27][28].…”