Pharmacogenetics to improve drug therapy

摘要 拟议的研究计划将集中在两个药物遗传学的挑战，拥有巨大的潜力， 改善患者治疗。1)第一个挑战是确定已知药物遗传学的临床重要性， 与药物毒性和治疗失败相关-任何治疗的常见结局。的 遗传对药代动力学和药效学变异性的贡献，因此可能 药物反应的差异是公认的。然而，尽管进行了深入的研究，但这项工作几乎没有 转化为临床实践。一个关键的障碍是基因型对有意义的患者结局的影响， 临床实践尚不清楚。理想情况下，大型随机对照试验将确定基因型对 临床结果，一些这样的研究正在进行中。然而，鉴于这些审判的费用，许多人 基因型，药物和感兴趣的结果，以及从精确的临床试验推断的困难， 由于临床实践不精确，这种方法是有限的。因此，将科学转化为 实践不明确。因此，我们提出了一种新颖的，具有成本效益的方法：使用去识别的电子 将医疗记录（EHR）与超过200，000名患者（BioVU）的DNA生物库相关联，以确定临床重要性 影响药物代谢或反应的基因变异。这一工作领域的长期目标是 制定和实施方法，以确定遗传变异对药物治疗结果的重要性 在真实的临床实践中。2)第二个挑战是利用遗传学来预测意外的毒性， 药物的好处。随着时间的推移，大多数新引入市场的药物被发现具有额外的 治疗适应症以及意外的毒性。一个关键的障碍是，传统的后营销 确定这些影响的方法往往需要数十年的研究。在此期间，患者将 不需要的目前未知的副作用，并放弃潜在的脱靶获益。遗传学方法可以 提供信息以加快这一进程。一些药物的作用机制（例如，依折麦布抑制 Nieman-Pick C1-like 1（NPC 1 L1））被基因变异（NPC 1 L1）模仿。通过研究那些 携带这些变体，并使用称为 全表型关联研究（PheWAS），然后进行精细表型分型，我们可以推断潜在的结果 当病人接触到药物时。这一工作领域的长期目标是制定和实施 利用遗传信息发现药物意外益处和风险的方法。两 药物遗传学挑战领域将是研究计划的基础， 影响，不仅在转化基础科学，以改善病人护理的药物研究，而且在提供 测试一系列药物/基因型问题的临床重要性的新方法。

ABSTRACT The proposed research program will focus on two pharmacogenetic challenges that hold great potential for improving patient therapy. 1) The first challenge is to define the clinical importance of known pharmacogenetic associations, as related to drug toxicity and therapeutic failure—common outcomes of any therapy. The genetic contribution to variability in pharmacokinetics and pharmacodynamics, and thus potentially to differences in drug response, is well recognized. However, despite intensive research, little of this work has translated to clinical practice. A critical barrier is that the effect of genotype on meaningful patient outcomes in clinical practice is not known. Ideally, large randomized controlled trials would define the effect of genotype on clinical outcomes, and a few such studies are underway. However, given the expense of such trials, the many genotypes, drugs, and outcomes of interest, as well as the difficulties extrapolating from precise clinical trials to imprecise clinical practice, this approach is limited. Consequently, the path forward to translate science into practice is unclear. Accordingly, we propose a novel, cost effective approach: to use a de-identified electronic medical record (EHR) linked to a DNA biobank with >200,000 patients (BioVU) to define the clinical importance of variation in genes affecting drug metabolism or response. The long-term goal of this area of work is to develop and implement methods to define the importance of genetic variation on the outcomes of drug therapy in real world clinical practice. 2) The second challenge is to use genetics to predict unexpected toxicities and benefits of drugs. Over time, most drugs newly introduced to the market are found to have additional therapeutic indications and also unexpected toxicities. A critical barrier is that traditional post-marketing approaches to define these effects often require decades of study. During this time patients would accrue unwanted currently unknown adverse effects and forgo potential off-target benefits. Genetic approaches can provide information to speed this process. The mechanism of action of some drugs (e.g., ezetimibe that inhibits Nieman-Pick C1-like 1 (NPC1L1)) are mimicked by variations in genes (NPC1L1). By studying individuals who carry these variants and determining their outcomes in large EHR databases using a technique called phenome-wide association studies (PheWAS) followed by fine-phenotyping we can infer potential outcomes when patients are exposed to the drug. The long-term goal of this area of work is to develop and implement methods to use genetic information to discover unexpected benefits and risks of drugs. The two pharmacogenetic challenge areas that will be the foundation of the research program have high public health impact, not only in translating basic science to improved patient care for the drugs studied, but also in providing new approaches for testing the clinical importance of a range of drug/genotype questions.