Association Between CYP2C9 Genetic Variants and Anticoagulation-Related Outcomes During Warfarin Therapy

Abstract

The results of our study suggest that the CYP2C9*2 and CYP2C9*3 polymorphisms are associated with an increased risk of overanticoagulation and of bleeding events among patients in a warfarin anticoagulation clinic setting, although small numbers in some cases would suggest the need for caution in interpretation. Screening for CYP2C9 variants may allow clinicians to develop dosing protocols and surveillance techniques to reduce the risk of adverse drug reactions in patients receiving warfarin.

Common VKORC1 and GGCX polymorphisms associated with warfarin dose

“…Polymorphisms in the liver enzyme CYP2C9, which metabolises warfarin, are known to be associated with warfarin sensitivity. [1][2][3]5,11,[20][21][22][23][24] Our subjects have previously been genotyped for CYP2C9, and the frequency of CYP2C9 homozygous extensive metabolisers was 66.7%, heterozygous extensive metabolisers 31.3% and poor metabolisers 2.0%. 3 The combined effect of VKORC1 and CYP2C9 on warfarin dose is presented in Figure 6, which shows that VKORC1 has a clear effect on all extensive metabolisers.…”

“…19 A large number of studies concerning the influence of CYP2C9 genotype on warfarin dose have been published. [1][2][3]5,11,[20][21][22][23][24] There is as yet limited information regarding pharmacodynamic factors involved in variable response to warfarin. Warfarin acts through interference with the vitamin K cycle in the liver (Figure 1).…”

Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin

“…Recently, different groups of investigators have reported the relation between CYP2C9 polymorphisms (ie, CYP2C9*2 and CYP2C9*3) and the daily dose requirement of warfarin and risks of bleeding complications during anticoagulation therapy. [22][23][24][25][26][27][28][29][30][31][32] These studies support an idea that the genetic polymorphisms of CYP2C9 would contribute to the interindividual variability of the anticoagulation responses to warfarin along with the previously known clinical and environmental variables (eg, age, concomitantly administered drugs, foods and clinical indications). 33,34 Our knowledge about pharmacodynamic factors associated with the variability in the anticoagulation of warfarin is relatively limited.…”

“…Tables 1 and 2 summarize the data obtained from previous studies investigating the relation between the CYP2C9 genotypes and the maintenance daily dose of warfarin associated with therapeutic anticoagulation. Available data [22][23][24][25][26][27][28][29][30][31] agree with the notion that the stable maintenance dose of warfarin would differ significantly among the patients possessing distinct CYP2C9 genotypes and that the magnitude of impact by CYP2C9*3 variant on the dose requirement of warfarin would be greater than that by CYP2C9*2 variant.…”

The genetics of vitamin K antagonists

“…Each CYP 2C9*2 allele is associated with a 19% decrease in warfarin requirements and each CYP 2C9*3 allele is associated with a 30% decrease in warfarin requirements. As approximately 30% of Americans carry at least one of the variants, and because the variants double or triple the risk of hemorrhage in patients initiating warfarin, 6,7 in the future clinicians may initiate coumarins with a pharmacogenetic-based dose. 8 Such an approach could also incorporate clinical factors and genetic variability in the coagulation factors themselves.…”