Polymorphisms in VKORC1 have more impact than CYP2C9 polymorphisms on early warfarin International Normalized Ratio control and bleeding rates

Abstract

SummaryPoor warfarin control with resultant high International Normalized Ratios (INRs) and bleeding events is most common during the first months of treatment. The effects of genetic polymorphisms at the vitamin K epoxide reductase [VKORC1] and cytochrome P450 2C9 [CYP2C9] loci have been increasingly acknowledged as contributory factors of enhanced warfarin sensitivity. In our prospective, blinded study, 557 patients (49·1% male, mean age 65·4 years, range 18-91 years) commencing warfarin (target INR 2·5) were genotyped and monitored through the first 3 months of anticoagulation. Homozygosity for the À1639 G>A single nucleotide functional promoter polymorphism of the VKORC1 gene (genotype AA; 14·5% of cases) was associated with a significantly shortened time to therapeutic INR ! 2 (P < 0·01), reduced stable warfarin dose (P < 0·01), and an increased number of INRs > 5 (P < 0·001) and occurrence of bleeding events (P < 0·01) during the first month, as compared to the GG genotype. CYP2C9 genetic variations *2 and *3 were not associated with significant effect on these factors. Neither VKORC1 nor CYP2C9 polymorphisms influenced these parameters beyond the first month of treatment. These findings imply possible benefits of assessing VKORC1 polymorphisms prior to anticoagulation, particularly as a low dose induction regime in VKORC1 AA individuals appears to reduce the incidence of high INRs.

Genotype and Risk of Major Bleeding During Warfarin Treatment

“…Nevertheless, VKORC1 and CYP2C9*3 variants have approximately the same magnitude of effect on warfarin dose requirements [9]. Previously, we and others have found that VKORC1 variants increase the risk of over-coagulation before a stable dose of warfarin is reached [11,12,20,29,36–38]. However, VKORC1 variants were not associated with increased risk of bleeding in either our study or a meta-analysis of previous reports [20].…”

Conserved Loop Cysteines of Vitamin K Epoxide Reductase Complex Subunit 1-like 1 (VKORC1L1) Are Involved in Its Active Site Regeneration

“…Since the identification of the VKORC1 gene (1,2), single nucleotide polymorphisms have been found in the coding as well as non-coding regions of VKORC1 in warfarin-resistant/sensitive patients. These genetic variations have been successfully used as a marker for managing warfarin maintenance dosage (10,11).…”

Evaluation of the effects of single‐nucleotide polymorphisms in CYP3A4 and CYP4F2 on stable phenprocoumon and acenocoumarol maintenance doses: comment

“…As compared with the GG and GA genotypes, homozygosity for the -1639G>A single-nucleotide functional promoter polymorphism of the VKORC1 gene (genotype AA, 14.5% of cases) was associated with a significantly shortened time to a therapeutic INR of ≥ 2 (median time: AA, 4 days; GA, 5 days; GG, 5 days; AA vs. GA or GG, P < 0.01), a reduced stable warfarin dose (AA, 2 mg; GA, 4 mg; GG, 4.5 mg; AA vs. GA or GG, P < 0.01), an increased number of INRs of > 5 (AA, 32%; GA, 12.4%; GG, 5.7%; AA vs. GA or GG, P < 0.001) and the occurrence of bleeding events (AA, 4.9%; GA, 2.3%; GG, 0.47%; AA vs. GG, P < 0.01) during the first month of treatment. The CYP2C9*2 variant was also associated with reduced warfarin maintenance dose requirements, but had no effect on the other outcome measures [2].…”

“…We have previously reported on a prospective observational study examining the influence of the coumarin-sensitizing polymorphisms VKORC1 and CYP2C9 on International Normalized Ratio (INR) control, maintenance dose requirement and bleeding events during the first 3 months of warfarin therapy in 557 adults [2]. The study was approved by the local ethics review board.…”