الفهرس 
AcknowledgementOnly 14 pages are availabe for public view
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Abstract
Warfarin is a well-accepted therapy used for the the treatment and prevention of thromboembolic events in patients with chronic atrial fibrillation, prosthetic heart valves, venous thrombosis and pulmonary embolism, unfortunately, however, warfarin is one of the leading causes of visits to the emergency department and hospitalizations owing to adverse drug events. The safe use of warfarin is challenging due to its narrow therapeutic index and the substantial interindividual variability in dosing requirements leading to an inability to predict stable therapeutic doses of the drug. The narrow therapeutic index is overcome by frequent monitoring of the international normalized ratio [INR] to optimize anticoagulation and reduce the risk of hemorrhagic events. However, the potential factors that influence variability in watrfarin dose requirements remained to be elucidated. Numerous genetic and clinical factors have been associated with variability in maintenance warfarin dose requirements , including age, race, weight, height, smoking status, medications and polymorphisms of the CYP2C9 and VKORC1 genes which encode for enzymes important in warfarin pharmacology. Differences in the genes encoding the cytochrome p450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKOR) enzymes account for about 15% and 25%, respectively, of the variation in warfarin dose requirements,while drug interactions account for 5-10%,age, weight,and height 10-20% and other undetermined factors account for 30-40%. Several SNPs in various regions of VKORC1 gene have been identified. These regions are also referred to as haplotypes. Five haplotypes have been found to commonly occur in the population. Two of the haplotypes (H1 and H2) are typically grouped together and called group A and are associated with lower warfarin dosage requirements. Three of the haplotypes (H7, H8, and H9) are grouped together and called group B and are associated with higher warfarin dosage requirements.Group A include -1639A, 1173T. I542C. 2255C, and 3730A,while group B include -1639G. 1173C, 1542G, 2255T. and 3730G. Conclusion: CYP2C9*2, CYP2C9*3 and VKORC1 3673 (−1639G>A) are the only SNPs(single nucleotide polymorphisms)currently approved by FDA for clinical testing. FDA has cleared for marketing 4 warfarin sensitivity genotyping methods including Nanosphere, AutoGenomics Infiniti, ParagonDx real-time PCR and Osmetech eSensor to detect the presence of CYP2C9 (*2 and *3) and VKORC1 3673 polymorphisms so as to facilitate the uptake of genotyping for warfarin dosing into clinical practice.