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|Title||Allelic Variants of CYP2C9 and VKORC1 Genes and their Relation to Warfarin Metabolism in Patients Under Warfarin Therapy in Gaza Strip|
Background: Warfarin is the most widely prescribed oral anticoagulant for thromboembolic therapy, patient management is difficult because of significant differences in metabolic rates as a result of allelic variation in its metabolizing enzyme. CYP2C9 gene encoding the enzyme that catalyzes the conversion of Warfarin to inactive metabolites, and the VKORC1 gene encoding the enzyme responsible for reducing vitamin K 2,3-epoxide to the enzymatically activated form. Three single nucleotide polymorphisms (SNPs), two in the CYP2C9 gene and one in the VKORC1 gene, have been found to play key roles in determining the effect of Warfarin therapy on coagulation. The presence of CYP2C9*2 and CYP2C9*3 variant alleles decrease the enzymatic activity which cause the elongation of half-life and reduced rate of clearance of Warfarin. Objectives: The aim of this study was to determine the allelic varints of CYP2C9 gene (alleles *1, *2 and *3) and VKORC1 (alleles 1639-G and 1639-A) in Gaza strip, and to determine the relation between the Warfarin anticoagulation and the genotype of the two genes CYP2C9 and VKORC1. Methods: Whole blood samples were collected from 101 patients under Warfarin therapy who visited anti-coagulation clinics of Alshifa and Gaza European hospitals then subjected to DNA extraction. Allelic variants of CYP2C9 and VKORC1 genes were determined by PCR-RFLP technique. Also sodium citrated whole blood samples were collected and plasma were separated for the determination of their Prothrombin time/international normalized ratio (PT/INR) level in order to establish a relationship between the CYP2C9 and VKORC1 allelic variants and the Warfarin anticoagulation. Results: It was found that none of the patients who are receiving the Warfarin has achieved the therapeutic range during the first month of Warfarin medication. There is a statistically significant difference in average INR between patients who have homozygote or heterozygote CYP2C9*2 and that who have the wild type CYP2C9*1/*1 and VKORC1(G/G) genotypes (3.1±1.29) and (2.05±0.92) respectively (P-Value=0.02, 95% C.I.), but when comparing the average actual weekly dose of Warfarin between the two groups it was found that there is no statistically significant difference (49.38±20.99 mg/week) and (48.45±14.22) respectively (P-Value=0.89, 95% C.I.). According to VKORC1 gene, it was found that there is no statistically significant difference in the average INR between patients who have homozygote or heterozygote VKORC1-1639A and that who have VKORC1(G/G) genotype (2.48±1.61) and (2.34±1.12) respectively (P-Value= 0.67, 95% C.I.), but there is a statistically significant difference in the average weekly dose between the two groups (40.36±14.04 mg/week) and (48.71±15.96 mg/week) respectively (P-Value=0.01, 95% C.I.). Also when averages of INR were compared between patients who have at least one copy of VKORC1-1639A allele and those who have CYP2C9*1/*1 and VKORC1(G/G), it was found that there is no statistically significant difference between the two means (2.4±1.23) and (2.05±0.92) respectively (P-Value=0.24, 95% C.I.), but there is a statistically significant difference in the average weekly dose of Warfarin between the two groups (40.63±14.13) and (48.45±14.22) respectively (P-Value=0.04, 95% C.I.). Conclusion: We conclude that the presence of at least one copy of CYP2C9*2 or VKORC1-1639A alleles or both is observed to be a cause for an increased sensitivity to Warfarin therapy and increased INR level. Therefore we recommend testing for these alleles as a part of the patient management.
|Publisher||الجامعة الإسلامية - غزة|
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