Effects of CYP2C9 and VKORC1 polymorphisms on warfarin sensitivity and responsiveness during the stabilization phase of therapy

The main objective of this study is to assess the effects of CYP2C9 and VKORC1 polymorphisms on warfarin sensitivity and responsiveness in a Jordanian population during the stabilization phase of treatment. This study was conducted at the Queen Alia Heart Institute (QAHI) anticoagulation clinic in Amman, Jordan. We assessed three CYP2C9 (rs1799853, rs1057910, rs4086116) and four VKORC1 (rs10871454, rs8050894, rs9934438, rs17708472) polymorphisms in 139 Jordanian cardiovascular patients. Demographic and clinical data were also collected. Of the 139 patients in the cohort, 80% had the VKORC1 polymorphisms rs10871454 and rs9934438, while 22.3% and 24.5% of patients had the rs1799853 and rs1057910 CYP2C9 alleles, respectively. Carriers of the CYP2C9 polymorphisms rs1057910 and rs4086116 had an increased risk of warfarin sensitivity compared to subjects with no or only one polymorphism. Similarly, carriers of all four VKORC1 variants had an increased risk of warfarin sensitivity (over anticoagulation) compared to those with no or only one polymorphism. Patients with a CYP2C9 or VKORC1 polymorphism required significantly lower doses than patients with no polymorphisms. The presence of any of CYP2C9 or VKORC1 polymorphisms is associated with sensitivity to warfarin during the stabilization period. Being a CYP2C9 or VKORC1 polymorphism carrier is associated with a variation in doses required to achieve the therapeutic INR compared to non-carrier patients. Keywords: CYP2C9, VKORC1, Warfarin, Warfarin maintenance phase of therapy, IN

Impact of <i>CYP2C9</i> and <i>VKORC1</i> Polymorphisms on Warfarin Sensitivity and Responsiveness in Jordanian Cardiovascular Patients during the Initiation Therapy

Warfarin is an oral anticoagulant frequently used in the treatment of different cardiovascular diseases. Genetic polymorphisms in the CYP2C9 and VKORC1 genes have produced variants with altered catalytic properties. A total of 212 cardiovascular patients were genotyped for 17 Single Nucleotide Polymorphisms (SNPs) within the CYP2C9 and VKORC1 genes. This study confirmed a genetic association of the CYP2C9*3 and VKORC1 rs10871454, rs8050894, rs9934438, and rs17708472 SNPs with warfarin sensitivity. This study also found an association between CYP2C9 and VKORC1 genetic haplotype blocks and warfarin sensitivity. The initial warfarin dose was significantly related to the CYP2C9*3 polymorphism and the four VKORC1 SNPs (p &lt; 0.001). There were significant associations between rs4086116 SNP and TAT haplotype within CYP2C9 gene and rs17708472 SNP and CCGG haplotype within VKORC1 gene and warfarin responsiveness. However, possessing a VKORC1 variant allele was found to affect the international normalized ratio (INR) outcomes during initiation of warfarin therapy. In contrast, there was a loose association between the CYP2C9 variant and INR measurements. These findings can enhance the current understanding of the great variability in response to warfarin treatment in Arabs