Pharmacogenetic Optimization of Anticoagulation Therapy

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DESCRIPTION (provided by applicant): The use of warfarin, although widely accepted for ischemic stroke prevention, is hindered by factors influencing its efficacy and toxicity. Warfarin is metabolized by Cytochrome P4502C9 (CYP2C9). There are several CYP2C9 alleles, which encode for enzymes with different catalytic activity. These have been documented for CYP2C9*1, CYP2C9*2, and CYP2C9*3. Recently three additional alleles have been identified: CYP2C9*4, CYP2C9*5, and CYP2C9*6 the latter two in African -Americans. The primary hypothesis of the study is that the CYP2C9 genotype influences the dose of warfarin required to maintain anticoagulation and the variability in INR control. The secondary hypothesis is that patients carrying variant alleles are at a higher risk for hemorrhagic complications. Conversely the patients who carry the normal allele may be at a higher risk of recurrent thromboembolic events. These hypotheses will be tested in a cohort of 500 stroke patients, including African-Americans. Patients will be identified prior to initiation of therapy and followed for 2 years. The study will establish the association between genotype and warfarin dose and the association between genotype and the frequency of INRs outside target range and the risk of associated complications both hemorrhagic and thromboembolic. Multivariate analysis will evaluate the association of CYP2C9 genotype-warfarin dose and genotype-INRs outside target range and associated complications both hemorrhagic and thromboembolic. Confounding variables - drug interactions, co-morbid conditions, and compliance will be statistically controlled. The advantage of defining CYP2C9 genotype will increase precision of warfarin dosing, achieve therapeutic anticoagulation earlier, minimize variability in INR, decrease the risk of thromboembolic/hemorrhagic events and reduce health care costs. My career goals are to investigate the influence of genetics on drug response. With the award of the K23 grant, structured training, guidance of mentors, environment and institutional support provided by the University, I will develop the skills necessary for a productive career in pharmacogenetics research.