Pharmacogenetics and Antithrombotic Therapy

描述(由申请人提供)： 我们的长期目标是防止血栓事件造成的死亡和残疾。 最近，我们一直在研究如何管理和剂量华法林治疗和 如何预防心房颤动患者的中风。一位少校 开华法林疗法的问题是它的治疗指标很窄 和“特殊”反应合谋，使其启动旷日持久和 危险。这项拟议的研究集中在遗传和临床因素如何 被用来预测这种反应。这两年的主要目标是 建议是构建、验证和使用华法林剂量算法 开始治疗。第二个目标是验证这一范例 药物遗传学的知识可以降低常见的 处方药。本研究有四个目的：1.构建以遗传为基础的， 将指导华法林诱导的华法林剂量算法。要开发 算法，我们将使用我们已有的临床数据和遗传样本 从298名接受长期华法林治疗的患者中获得。我们建议 完成我们对这些样本的单核苷酸多态的基因分型 细胞色素P450 2C9基因(SNPs)。我们将检验假设1： 华法林剂量算法将解释至少30%的变异 治疗剂量。2.验证基于遗传的华法林剂量算法 在250名患者的独立样本中。我们将检验假设2： 剂量算法将解释治疗中至少30%的差异 验证样本中的华法林剂量。3.使用基于基因的华法林 开始华法林治疗的50名患者的剂量。我们将使用基因- 在一项对50名患者进行的试点研究中，基于算法启动了华法林治疗。 我们将检验假设3：与华法林的历史对照 根据经验，使用基于基因的华法林剂量的参与者将 更早地被开出治疗剂量。4.将遗传和 临床因素与血浆游离华法林水平的关系。使用高 高效液相色谱学，我们将测量2个水平 华法林对映体和检验假设4：S-华法林将被清除 在2C9单核苷酸多态性存在的情况下显著降低。

DESCRIPTION (provided by applicant): Our long-term goal is to prevent death and disability from thrombotic events. Recently, we have been studying how to manage and dose Warfarin therapy and how to prevent stroke in patients who have atrial fibrillation. A major problem with prescribing Warfarin therapy is that its narrow therapeutic index and "idiosyncratic" response conspire to make its initiation protracted and dangerous. The proposed study focuses on how genetic and clinical factors can be used to predict this response. The primary objective of this 2-year proposal is to construct, validate, and use a warfarin-dosing algorithm for initiation of therapy. The secondary objective is to validate the paradigm that knowledge of pharmacogenetics can decrease the toxicity of commonly prescribed drugs. The study has 4 aims: 1. To construct a genetic-based, warfarin-dosing algorithm that will guide warfarin induction. To develop the algorithm, we will use clinical data and genetic specimens that we have obtained from 298 patients taking chronic warfarin therapy. We propose to complete our genotyping of these specimens for single nucieotide polymorphisms (SNPs) of the cytochrome P450 2C9 gene. We will test Hypothesis 1: The warfarin dosing algorithm will explain at least 30% of the variance in the therapeutic dose. 2. To validate the genetic-based, warfarin-dosing algorithm in an independent sample of 250 patients. We will test Hypothesis 2: The dosing algorithm will explain at least 30% of the variance in the therapeutic warfarin dose in the validation sample. 3. To use genetic-based warfarin dosing in 50 patients beginning warfarin therapy. We will use the genetic- based algorithm to initiate warfarin therapy in a pilot study of 50 patients. We will test Hypothesis 3: As compared to historic controls whose warfarin is initiated empirically, participants who use genetic-based warfarin dosing will be prescribed their therapeutic dose sooner. 4. To correlate genetic and clinical factors with the plasma level of free warfarin. Using high performance liquid chromatography, we will measure the levels of the 2 enantiomers of warfarin and test Hypothesis 4: Clearance of S-warfarin will be significantly decreased in the presence of 2C9 SNPs.