Prevalence of VKORC1 and CYP2C9 gene polymorphisms in Indian population and its effect on warfarin response

The clinical effectiveness of Warfarin is established. Patients require different warfarin dosages to achieve the target therapeutic anticoagulation. The variability of Warfarin dosage is largely genetically determined, and it can be partly explained by the C1173T and G-1639A polymorphisms of vitamin K epoxide reductase complex subunit 1 (VKORC1) which is its target and *2 and *3 allele of Cytochrome P-450 (CYP) 2C9 [CYP2C9] enzyme which metabolizes to its inactive form. Aim of the present study was to determine the prevalence of these variant alleles known to influence the warfarin dose and correlate genotypes with the average INR as well as mean dose of Warfarin required to maintain INR, in the Indian population.

Study population included 100 healthy individuals and 83 patients operated for Aortic or Mitral Valve replacement and prescribed warfarin thereafter. Of these 83 patients records of INR for the period of six months and mean maintenance dose (stable therapeutic dose) of warfarin required to maintain INR were available for 26 patients. For the remaining patients, apart from their demographic data only maintenance dose was available. Genotyping of above mentioned polymorphisms was carried out by using PCR-based restriction digestion method.

Although less as compared to wild type alleles, the variant alleles of CYP2C9*2 and *3 as well as of VKORC1 polymorphisms (C1173T and G-1639A) were observed in our study population. Mean maintenance dose (mg/day) of Warfarin was in the decreasing order of patients as compared to the wild type genotypes for all above mentioned polymorphisms. The decrease in the dose was in the order of heterozygotes for CYP2C9*2 to CYP2C9*3 to C1173T and G-1639A of VKORC1 (P<0.001). There was significant correlation (r=0.51, P<0.001) observed between the dose estimated by pharmacogenetic algorithm of Sconce et al (2005) and actual stable therapeutic dose. INR was high for mutant variants (3.8 to 4) after first dose suggesting that they require decreased mean daily dose of Warfarin.

In the present study the effect of CYP2C9*2, *3, and VKORC1 (C1173T and G-1639A) genotypes on warfarin dose was observed. However, the genotyping has not been incorporated into daily practice. Perhaps more practical approach would be for clinicians to take genotype information into consideration along with other factors when dosing warfarin.