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.