Date of Award

10-2014

Document Type

Thesis

Degree Name

Master of Science in Medical Sciences (MSMS)

Department

Medical Education

First Advisor

Bassam R. Ali

Second Advisor

Lihadh AJ-Gazali

Third Advisor

George P. Patrinos

Abstract

Warfarin is the most commonly used oral anticoagulant medication given as a prophylaxis and/or treatment of venous and arterial thromboembolic disorders. Warfarin doses vary up to 10-fold among patients due to pharmacokinetics, pharmacodynamics and pharmacogenomics factors. In addition, Warfarin has a low therapeutic index with the risk of developing serious side effects such as severe bleeding or failure of therapy. Therefore, the main challenge to achieve the therapeutic goal in warfarin treatment is estimating the appropriate dose for each patient. It is estimated that pharmacogenomics factors contribute to more than 60% of dose variability. The gene encoding for the target enzyme of Warfarin, vitamin K epoxide reductase complex 1 (VKORCI), is a highly polymorphic gene and contributes to about 30% of this variability. The US Food and Drug Administration (FDA) recommends genetic testing to determine the VKORCI genotype prior to using Warfarin. However, there are no data on VKORCI alleles and genotypes or their frequencies among Emiratis. Therefore, the current approach is trial and error with warfarin doses which might lead to some serious complications for patients receiving this medication. In this thesis, we used PCR amplification and direct DNA Sanger sequencing to genotype the two most important variants in VKORCI gene (namely, rs9923231 and rs7294). The sample consist of 117 healthy Emirati nationals as control and 96 patients on stable Warfarin therapy. The alleles and genotypes frequencies were determined for both groups. In addition, the daily warfarin maintenance dose for patients was examined for associations with the VKORCI genotypes at the rs9923231 and rs7294 positions. There was no significant difference in allele frequencies between the controls and patients for either SNP. The genotypes frequencies for rs9923231 were 25%, 48.4%, 26% for GG, GA, AA genotypes, respectively. In addition, genotypes frequencies for rs7294 variant were 44%, 44%, 12% GG, GA, AA genotypes, respectively. Crucially, both VKORCI polymorphisms were found to be strongly associated with Warfarin doses required to achieve the target international normalized ratio INR (p < 0.0001). The results of this study confirm the suitability of VKORCI genotyping to guide the use of the appropriate warfarin dosage for Emiratis.

Keywords: Warfarin dosage, s9923231, rs7294, VKORCI, pharmacokinetics of Emiratis, Pharmacogenomics

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