Drug Metabolism Genotypes in Clinical Practice

描述（由申请方提供）：个体间药物反应存在显著差异。这种变异性通过引起药物功效降低或意外毒性而引起主要临床问题。将药物疗效或毒性的预测因子纳入临床实践的能力将是一个重大的进步。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异性，从而导致反应。这些药物遗传学发现定义了个体间药物反应变异性的可预测成分。然而，尽管有深入的研究和强大的发现，几乎没有将药物遗传学发现转化为临床实践。一个关键的障碍是药物遗传学的重要性尚未在临床实践中证明对重要的患者结局。进行随机临床试验来测试每个药物遗传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：使用带有与DNA生物库链接的去识别信息的电子病历（EMR）来测试药物遗传学发现对临床实践中药物治疗重要结局的临床重要性。我们将实施这种新的方法，证明三个不同的药物遗传学研究结果的原理证明。之所以选择这些基因进行研究，是因为已经有压倒性的证据表明其对药物代谢以及药代动力学或药效学指标有影响，但基因分型在临床护理中尚未成为常规。我们将检验以下假设：1）与华法林剂量需求降低相关的CYP 2C 9和VKORC 1变异体与华法林剂量滴定期后INR波动较大相关; 2）功能降低的CYP 2C 9变异体与磺脲类药物更频繁发生的低血糖相关; 3）CYP 2D 6弱代谢型和中代谢型患者在接受可待因治疗疼痛后镇痛作用降低。我们的方法是定义临床上重要的药物遗传学问题，并使用生物信息学，流行病学和遗传学专业知识的组合，在超过150万患者的大型EMR中测试其临床重要性，该患者与> 157，719个DNA样本的DNA库相关联。这些研究将具有很高的公共卫生影响，不仅在转化药物遗传学研究结果，以改善患者护理的药物研究，而且在开发新的方法来测试未来的药物遗传学观察在临床实践中的重要性。

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.