Influence of Vitamin K Epoxide Reductase Complex 1 Gene Polymorphisms on Anticoagulation with Acenocoumarol in Patients with Cerebral Venous Thrombosis

Abstract

Aims: Acenocoumarol, a commonly prescribed oral anticoagulant drug, exhibits wideinter-individual variability in response. This study aimed at evaluating the contribution of genetic variations in Vitamin K epoxide reductase complex, subunit 1 (VKORC1), to variability in the response to acenocoumarol, in patients with cerebral venous thrombosis (CVT). Place and Duration of Study: National Institute of Mental Health and Neuro Sciences, Bangalore, India, between September 2009 and January 2013. Methodology: 476 acenocoumarol-treated aseptic CVT patients (153 males, 323 females) were genotyped for VKORC1 -1639G>A and 1173C>T polymorphisms. Mean daily acenocoumarol dose for achieving and maintaining the optimum international normalized ratio (INR) was calculated for different genotypes. Results: Genotype distribution of VKORC1-1639G>A was as follows: 69.7% were wild, 25.6% heterozygous and 4.6%, mutant. Mean acenocoumarol dose required to achieve the optimum INR was lower in heterozygous (1.82±0.71mg/day) and homozygous mutants (1.75±0.69mg/day) when compared to wild type patients (2.31±0.89mg/day). Bearing the VKORC1 -1639A allele independently increased the odds of requiring a low dose (Adjusted OR 3.9; 95% CI 1.97-7.73; p<0.0001). Significant differences in dose requirement during maintenance phase were observed in patients of different genotypes. VKORC1-1639G>A and 1173C>T were observed to be tightly linked (r2=0.98) and no difference in the genotype distributions was observed between the two polymorphisms. Factors such as age and co-medication with phenytoin were also found to influence the drug dosage. Conclusion: Our findings support the use of VKORC1 genotyping during anticoagulation with acenocoumarol in patients with CVT.