Association of Genetic Polymorphisms of CYP2C9 and VKORC1 with Bleeding Following Warfarin: A Case-Control Study

Introduction: Various factors have been shown to increase the risk of bleeding with warfarin. This study aimed to assess the association of CYP2C9 and VKORC1 with the development of bleeding following warfarin. Study Methods: A case control study was initiated after obtaining institutional ethics committee clearance and written informed consent from patients. Cases were defined as those who bled within three months of warfarin initiation and controls as those who did not have any episode of bleeding within three months. Genotyping for CYP2C9 (*1, *2, *3) and VKORC1 1639 (GG, GA and AA) was performed by PCRRFLP. Chi square test was used to find out the association and trend of CYP2C9 and VKORC1 genotypes with odds ratio (95% CI) for strength of association. A binary logistic regression model was developed associating age, body weight, sex, CYP2C9 and VKORC1 status with risk of bleeding. Results: A total of 100 controls and 38 cases were studied from Oct 2009 to July 2011. A significant association (P < 0.0001) and trend (P = 0.027) of mutant alleles of CYP2C9 and VKORC1 were noted with bleeding with odds ratios of 7.8 [3.4, 17.9] and 2.7 [1.3, 5.7] respectively. Weekly dose requirement was significantly lower with the presence of *3 allele relative to *1 in CYP2C9 (P < 0.001). The regression model showed an accuracy of 80% and could explain 35.3% of the variability. Conclusion: A significant association between CYP2C9 (*1,*2,*3) genotype and VKORC1 (1639 G>A) haplotype status has been found with increased bleeding tendency to warfarin. This may help to individualize therapy.