Pharmacogenetic Optimization of Anticoagulation Therapy

描述（由申请人提供）：华法林虽然被广泛接受用于预防缺血性卒中，但其疗效和毒性的影响因素阻碍了华法林的使用。华法林通过细胞色素P4502C9 （CYP2C9）代谢。有几个CYP2C9等位基因，它们编码不同催化活性的酶。CYP2C9*1、CYP2C9*2和CYP2C9*3均有相关文献记载。最近发现了另外三个等位基因：CYP2C9*4、CYP2C9*5和CYP2C9*6（后两个在非裔美国人中）。本研究的主要假设是CYP2C9基因型影响维持抗凝所需的华法林剂量和INR控制的可变性。第二种假设是携带变异等位基因的患者发生出血性并发症的风险更高。相反，携带正常等位基因的患者可能有更高的复发性血栓栓塞事件的风险。这些假设将在包括非裔美国人在内的500名中风患者中进行测试。患者将在治疗开始前确定，并随访2年。该研究将确定基因型与华法林剂量之间的关系，以及基因型与靶范围外INRs发生频率以及相关出血和血栓栓塞并发症风险之间的关系。多变量分析将评估CYP2C9基因型-华法林剂量和基因型-靶范围外inrs与相关出血和血栓栓塞并发症的关系。混杂变量-药物相互作用，合并症和依从性将被统计控制。确定CYP2C9基因型的优势将提高华法林给药的准确性，更早地实现抗凝治疗，最大限度地减少INR的变异性，降低血栓栓塞/出血事件的风险，降低医疗成本。我的职业目标是研究基因对药物反应的影响。在K23基金的资助下，在导师的指导下，在大学提供的环境和制度支持下，我将培养在药物遗传学研究领域取得丰硕成果所必需的技能。

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.