Drug Metabolism Genotypes in Clinical Practice

描述（由申请人提供）：个体之间的药物反应有明显的可变性。这种可变性会引起药物疗效下降或意想不到的毒性，从而造成主要的临床问题。将药物疗效或毒性预测因素纳入临床实践的能力将是一项重大进步。药物代谢酶或药物靶点的明确遗传变异有助于药物浓度的变化，从而导致反应。这些药理学发现确定了个体间药物反应可变性的可预测成分。然而，尽管有深入的研究和强有力的发现，几乎没有将药物遗传学的发现转化为临床实践。一个关键的障碍是药物遗传学在临床实践中对重要的患者结果的重要性尚未得到证明。通过随机临床试验来检验每一个药理学问题的临床重要性是不可行的。我们提出了一种新的方法：使用电子病历（EMR）与DNA生物库相关联的去识别信息来测试药物遗传学发现在临床实践中对药物治疗重要结果的临床重要性。我们将实施这种新方法，为三个不同的药物遗传学发现证明原理。之所以选择这些方法进行研究，是因为已经有大量证据表明对药物代谢有影响，因此对药代动力学或药效学测量也有影响，但基因分型在临床护理中尚未成为常规方法。我们将检验以下假设：1)与华法林剂量要求降低相关的CYP2C9和VKORC1变异与华法林剂量滴定期后INR波动较大相关；2)功能降低的CYP2C9变异与磺脲类药物引起的低血糖更频繁相关；3) CYP2D6代谢不良和中度代谢患者接受可待因镇痛后镇痛效果降低。我们的方法是定义临床重要的药理学问题，并结合生物信息学、流行病学和遗传学专业知识，在150多万患者的大型电子病历中测试它们的临床重要性，这些患者与拥有157,719个DNA样本的DNA库有关。这些研究将对公共卫生产生重大影响，不仅在将药物遗传研究结果转化为改善所研究药物的患者护理方面，而且在开发新方法以测试未来药物遗传观察在临床实践中的重要性方面。

DESCRIPTION (provided by applicant): There is marked variability in drug response among individuals. This variability poses a major clinical problem by causing decreased drug efficacy or unexpected toxicity. The ability to incorporate predictors of drug efficacy or toxicity into clinicl practice would be a major advance. Well-defined genetic variations in drug metabolizing enzymes or drug targets contribute to variability in drug concentration and therefore response. These pharmacogenetic findings define a predictable component of variability in drug response among individuals. However, despite intensive research and robust findings, there has been almost no translation of pharmacogenetic findings into clinical practice. A critical barrier is tha the importance of pharmacogenetics has not been demonstrated for important patient outcomes in clinical practice. It is not feasible perform a randomized clinical trial to test the clinical importance of every pharmacogenetic question. We propose a novel approach: to use an electronic medical record (EMR) with de-identified information linked to a DNA biobank to test the clinical importance of pharmacogenetic findings for important outcomes of drug therapy in clinical practice. We will implement this novel approach, demonstrating proof-of-principle for three distinct pharmacogenetic findings. These have been chosen for study because there is already overwhelming evidence of an effect on drug metabolism, and consequently pharmacokinetic or pharmacodynamic measures, but genotyping is not yet routine in clinical care. We will test the hypotheses that: 1) CYP2C9 and VKORC1 variants associated with reduced warfarin dose-requirements are associated with greater fluctuation in INR after the warfarin dose-titration phase; 2) CYP2C9 variants with reduced function are associated with more frequent hypoglycemia with sulfonylureas; 3) CYP2D6 poor- and intermediate-metabolizer patients have reduced analgesic effects after receiving codeine for pain. Our approach is to define clinically important pharmacogenetic questions and to test their clinical importance using a combination of bioinformatic, epidemiologic and genetic expertise in a large EMR of more than 1.5 million patients linked to a DNA bank of >157,719 DNA samples. These studies will have high public health impact, not only in translating pharmacogenetic findings to improved patient care for the drugs studied, but also in developing new approaches to testing the importance of future pharmacogenetic observations in clinical practice.