Influence of Renal Impairment and Genetic Subtypes on Warfarin Control in Japanese Patients

Abstract

The genotypes of vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) can influence therapeutic warfarin doses. Conversely, nongenetic factors, especially renal function, are associated with warfarin maintenance doses; however, the optimal algorithm for considering genes and renal dysfunction has not been established. This single-center prospective cohort study aimed to evaluate the factors affecting warfarin maintenance doses and develop pharmacogenetics-guided algorithms, including the factors of renal impairment and others. To commence, 176 outpatients who were prescribed warfarin for thromboembolic stroke prophylaxis in the stroke center, were enrolled. Patient characteristics, blood test results, dietary vitamin K intake, and CYP2C9 and VKORC1 (−1639G > A) genotypes were recorded. CYP2C9 and VKORC1 (−1639G>A) genotyping revealed that 80% of the patients had CYP2C9*1/*1 and VKORC1 mutant AA genotypes. Multiple linear regression analysis demonstrated that the optimal pharmacogenetics-based model comprised age, body surface area, estimated glomerular filtration rate (eGFR), genotypes, vitamin K intake, aspartate aminotransferase levels, and alcohol intake. eGFR exercised a significant impact on the maintenance doses, as an increase in eGFR of 10 mL/min/1.73 m2 escalated the warfarin maintenance dose by 0.6 mg. Reduced eGFR was related to lower warfarin maintenance doses, independent of VKORC1 and CYP2C9 genotypes in Japanese patients.

Correlation between Metabolic Parameters and Warfarin Dose in Patients with Heart Valve Replacement of Different Genotypes

“…Their findings showed that more than 99 percent of participants were advised to reduce their warfarin dose based on genetic factors. Our data showed that the maintenance dose of warfarin anticoagulation in patients undergoing mechanical heart valve replacement was highest in the CYP2C9 *1/*1/ VKORC1 (GA+GG) group, followed by CYP2C9*1/*3/ VKORC1 (GA+GG) group and CYP2C9*1/*1/ VKORC1 mutant AA group, and the lowest in the CYP2C9*1/*3 / VKORC1 mutant AA group, which is consistent with a previous study [ 13 ]. These data indicate that genotyping can provide an initial dose range for clinical warfarin anticoagulation.…”

Special Issue: “Genomics of Stroke”

“…However, warfarin has a narrow therapeutic range and shows a wide variation in doses between patients because of numerous environmental and genetic factors that influence warfarin pharmacokinetics and pharmacodynamics. Moreover, the genotypes of vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) can influence therapeutic warfarin doses [ 9 , 10 , 11 , 12 ]. The variant CYP2C9 and wild-type VKORC1, which affect the action of warfarin, are relatively rare in the Japanese population.…”

“…Tanaka et al enrolled 176 Japanese outpatients who were prescribed warfarin for thromboembolic stroke prophylaxis in the stroke center in their study. Patient characteristics, blood test results, dietary vitamin K intake, and CYP2C9 and VKORC1 (−1639G>A) genotypes were recorded [ 9 ]. CYP2C9 and VKORC1 (−1639G>A) genotyping revealed that 80% of the patients had CYP2C9 *1/*1 and VKORC1 mutant AA genotypes.…”

“…CYP2C9 and VKORC1 (−1639G>A) genotyping revealed that 80% of the patients had CYP2C9 *1/*1 and VKORC1 mutant AA genotypes. Multiple linear regression analysis demonstrated that the optimal pharmacogenetics-based model comprised age, body surface area, estimated glomerular filtration rate (eGFR), genotypes, vitamin K intake, aspartate aminotransferase levels, and alcohol intake [ 9 ].…”