Pharmacogenetic Optimization of Anticoagulation Therapy

说明(申请人提供)：尽管华法林被广泛接受用于预防缺血性中风，但由于影响其疗效和毒性的因素，华法林的使用受到阻碍。华法林由细胞色素P4502C9(细胞色素P4502C9)代谢。有几个CYP2C9等位基因，它们编码不同催化活性的酶。最近在非裔美国人中又发现了三个新的等位基因：后两个等位基因。这项研究的主要假设是，CYP2C9基因影响维持抗凝所需的华法林剂量和INR控制的变异性。第二个假设是携带不同等位基因的患者发生出血并发症的风险更高。相反，携带正常等位基因的患者可能有更高的复发血栓栓子事件的风险。这些假设将在包括非裔美国人在内的500名中风患者的队列中进行测试。患者将在开始治疗前确定，并跟踪治疗2年。这项研究将建立基因和华法林剂量之间的联系，以及基因和目标范围外INRS的频率和相关并发症(出血和血栓栓塞症)风险之间的关系。多变量分析将评估靶范围外的CYP2C9基因-华法林剂量和基因-INRS与出血和血栓栓塞症相关并发症的关系。混杂变量-药物相互作用、共病条件和依从性将被统计控制。确定CYP2C9基因的优势将提高华法林剂量的精确度，更早实现治疗性抗凝，最大限度地减少INR的变异性，降低血栓栓子/出血事件的风险，并降低医疗费用。我的职业目标是研究遗传学对药物反应的影响。在大学提供的K23奖学金、系统培训、导师指导、环境和机构支持下，我将发展在药物遗传学研究方面富有成效的职业生涯所需的技能。

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.