The effect of CYP2C9 and VKORC1 genetic polymorphism to warfarin dose requirements in Turkish pediatric patients

Warfarin is the most commonly prescribed anticoagulant drug for the prophlaxis and treatment of venous and arterial tromboembolic disorders for decades. Despite the limitations of a narrow therapeutic range, the broad variation of intra and inter-individual drug requirement, and relatively high incidence of bleeding complications, therapy with coumarins is rising in industrialised countries. The effectiveness and safety of warfarin is critically dependent on maintaining the prothrombin time, expressed as the international normalized ratio (INR).The anticoagulant response to warfarin is affected by both environmental influences and also by genetically determined levels of critical enzymes. These include; the cytochrome P-450 2C9 (CYP2C9) enzyme that is involved in the metabolism of warfarin, and also vitamin K epoxide reductase (VKORC1), which is the enzyme inhibited by warfarin. The clearence of warfarin in almost entirely the result of hepatic metabolism, and CYP2C9 is the most important enzyme mediating its clearance. The polymorphisms in CYP2C9 are; CYP2C9*2 and CYP2C9*3. VKORC1 is the target of warfarin that function as competitive inhibitors. The polymorphisms in VKORC1 (GG) are; VKORC1 (GA) and VKORC1 (AA). Previous studies have showed that, the mean warfarin daily dose requirement was highest in CYP2C9 wild-type patients, compared with the variant *2 and *3 alleles and also was higher in patients with the VKORC1 GG genotype compared with those with either GA or AA.The study population consisted of 58 pediatric patients who are taking warfarin treatment and 149 healty voluntary control children. We took 5 cc blood from all of the population and isolated their DNA from the blood. We invastigated CYP2C9*2, CYP2C9*3 and VKORC1 genetic polymorphisms from the isolated DNA samples using PZR. Thus we confirmed that the frequencies of CYP2C9 and VKORC1 genetic polymorphisms in Turkish pediatric population.We determined the requirements of warfarin dose for each patient by INR controls. We calculated ideal warfarin dose for all patients using age, height and CYP2C9*2, CYP2C9*3 and VKORC1 genetic polymorphisms. This study showed that the patients who have allelic variants require lower warfarin doses.We compared the doses of we gave and the ideal doses. In conclusion we confirmed %65 correlation between ideal doses and the doses that the patients use.In our study, we have proved that if the clinicians calculate the warfarin doses with considering CYP2C9 and VKORC1 genetic polymorphisms before the beginning of warfarin treatment, reaching the ideal INR values will be easier and the bleeding complications will be lower.