Association between Cytochrome P۴۵۰ ۲ C۹ and Vitamin K Epoxide Reductase Complex Subunit ۱ Polymorphisms with Warfarin dose among Iranian Patients

Background: Warfarin is a common anticoagulant drug that has a narrow therapeutic index; higher dose causes excessive bleeding and lower dose leads to cerebrovascular clotting and stroke in patients. Genetic factors that have been associated with warfarin response are the genes of cytochrome P۴۵۰ ۲C۹ (CYP۲C۹), which metabolize the more active S-enantiomer of warfarin, and vitamin K epoxide reductase (VKOR), the target site for warfarin. The present study was conducted to investigate the association between CYP۲C۹*۲, CYP۲C۹*۳ and VKORC۱ (-۱۶۳۹ G>A) polymorphisms with warfarin daily dose on  Iranian patients under warfarin treatment. Materials and Methods: This study is comprised of ۱۱۸ Iranian patients on warfarin treatment who attended the PT Clinic. Genotyping of CYP۲C۹*۲, CYP۲C۹*۳ and VKORC۱ (-۱۶۳۹ G>A) was performed by PCR-RFLP method. Multiple regression model was performed for statistical analyses and P<۰.۰۵ was considered as significance level. Results: The allelic frequencies of CYP۲C۹*۲ and CYP۲C۹*۳ were ۱۹% and ۷%, respectively. Patients with ≥۱ CYP۲C۹ variant allele had a significantly lower mean warfarin daily dose compared with patients with the wild-type genotype. The allelic frequencies of VKORC۱ were ۱۴.۴%, ۵۷.۶% and ۲۷.۹% for GG, GA, and AA genotypes, respectively. The mean (SD) warfarin daily dose in patients with the VKORC۱ (–۱۶۳۹) GG genotype was significantly higher than GA and AA patients. Conclusion: CYP۲C۹*۲, CYP۲C۹*۳ and VKORC۱ (-۱۶۳۹ G>A) polymorphisms had significant association with warfarin daily dose; furthermore, the daily warfarin dose was not influenced by age, height, weight and sex.

Keywords:

CYP۲C۹*۲ , CYP۲C۹*۳ , VKORC۱ , Warfarin , RFLP