Pharmacogenetics to improve drug therapy

摘要 拟议的研究计划将专注于两个具有巨大潜力的药物遗传学挑战 改进患者治疗。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有关的关联--任何治疗的常见结果。这个 基因对药代动力学和药效学的变异性的贡献，从而潜在地 药物反应的差异，是公认的。然而，尽管进行了密集的研究，但这些工作几乎没有 转化为临床实践。一个关键的障碍是基因对有意义的患者预后的影响 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对 临床结果，一些这样的研究正在进行中。然而，考虑到此类审判的费用，许多 基因类型、药物和感兴趣的结果，以及从精确的临床试验到 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 目前还不清楚具体做法。因此，我们提出了一种新的、具有成本效益的方法：使用未识别的电子设备 医疗记录(EHR)链接到包含200,000名患者(BioVU)的DNA生物库，以定义临床重要性 影响药物新陈代谢或反应的基因变异。这方面工作的长期目标是 制定和实施确定基因变异对药物治疗结果的重要性的方法 在现实世界的临床实践中。2)第二个挑战是使用遗传学预测意想不到的毒性和 毒品的好处。随着时间的推移，大多数新进入市场的药物被发现具有额外的 治疗适应症和意想不到的毒性。一个关键障碍是传统的后营销 定义这些影响的方法通常需要数十年的研究。在这段时间里，患者会不断增加 不受欢迎的目前未知的不良影响，并放弃潜在的偏离目标的好处。遗传方法可以 提供信息以加快这一过程。某些药物的作用机制(例如，抑制 NPC1L1)是通过基因变异(NPC1L1)来模仿的。通过研究那些 携带这些变体，并使用一种名为 全基因组关联研究(Phewas)在精细表型分析之后，我们可以推断潜在的结果 当患者接触到这种药物时。这方面工作的长期目标是制定和实施 方法利用遗传信息发现药物的意想不到的益处和风险。两个人 将作为研究计划基础的药物遗传学挑战领域具有很高的公共卫生水平 影响，不仅在将基础科学转化为改善对所研究药物的患者护理方面，而且在提供 测试一系列药物/基因问题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.