Identifying Pharmacogenomic Predictors of Methotrexate Response and Metabolite Biotransformation in JIA

项目概述：甲氨蝶呤(MTX)是一种叶酸拮抗剂，已成为应用最广泛的疾病-- 改良抗风湿药物(DMARD)治疗青少年特发性关节炎25例 好几年了。然而，药物疗效存在巨大的变异性，在治疗开始时是不可预测的。虽然 大多数儿童风湿科医生使用甲氨蝶呤作为治疗多关节JIA的一线药物，它是一种缓慢的 作用药物使临床医生陷入让患者接受他们不知道的治疗的困境 最终在几个月内有效。有越来越多的证据表明治疗的早期“机会之窗” 炎症性关节炎，许多临床医生已经求助于启动额外的生物(抗肿瘤坏死因子)疗法 在治疗过程中尽早联合甲氨蝶呤，将永久性关节损伤、残疾、 以及糟糕的长期结果。MTX反应的预测指标将通过关注早期的 对不太可能对MTX有反应的患者给予生物制剂，从而避免适当治疗的延误 以及糟糕的长期结果。或者，在预测对MTX有反应的患者中，升级为生物 可以避免治疗，从而将额外的风险和费用降至最低。MTX当前不包括在 &gt；100 FDA批准了在标签中包含药物遗传学的药物。然而，最近全基因组和 候选基因研究和越来越多的证据表明遗传因素对重要的细胞生物标志物的影响 MTX代谢需要确定MTX反应的药物基因组预测因子，这是总体 这个项目的目标。为了实现这一目标，我们将利用现有的患者队列，即一组合作者 有了一致的研究兴趣，儿童关节炎风湿病研究联盟的基础设施 (CARA)和儿科风湿病护理和结果改善网络(PR-COIN)为 前瞻性患者招募，以聚集大量接受MTX治疗的JIA患者的良好表型队列。 我们将使用这个队列来检验我们的总体假设，即：JIA中的甲氨蝶呤反应依赖于基因 影响药物新陈代谢和药物生物利用度的变异“，解决以下目标： 目的1.确定基因对临床药物反应的贡献。 ·目的2：了解基因对药物反应的细胞生物标志物的贡献。 ·目标3：开发一种预测工具，为临床使用甲氨蝶呤提供信息。 这个项目提供了在临床和临床上了解MTX反应的遗传基础的机会 并代表了一种真正的翻译方法，它利用了 多名研究人员将资源和策略结合起来，为JIA儿童提供个性化的药物。 从这项工作中获得的知识将直接转化为临床环境，以指导JIA的早期治疗 也将影响使用MTX治疗的其他疾病以及叶酸代谢和调节 对增长和发展至关重要。

Project Summary: Methotrexate (MTX), a folate antagonist and has been the most widely used disease- modifying anti-rheumatic drug (DMARD) in the treatment of Juvenile Idiopathic Arthritis (JIA) over the last 25 years. However, there is vast variability in drug efficacy that is unpredictable at the onset of therapy. Although the majority of pediatric rheumatologists use MTX as their first line agent to treat polyarticular JIA, it is a slow acting drug leaving clinicians in the difficult position of exposing patients to a therapy they will not know is ultimately effective for several months. With mounting evidence of an early “window of opportunity” to treat inflammatory arthritis, many clinicians have resorted to initiating additional biologic (anti-TNFalpha) therapies in conjunction with MTX early in the treatment course to minimize the chance of permanent joint damage, disability, and poor long-term outcomes. Predictors of MTX response would personalize therapy by focusing the early administration of biologic agents to patients unlikely to respond to MTX, thus avoiding delays in adequate therapy and poor long term outcomes. Alternatively, in patients predicted to respond to MTX, escalation to biologic therapies could be avoided thereby minimizing additional risk and expense. MTX is not currently included in the >100 FDA approved drugs that include pharmacogenetics in their label. However, recent genome-wide and candidate gene studies and mounting evidence of the genetic influences on important cellular biomarkers of MTX metabolism warrant the identification of pharmacogenomic predictors of MTX response, which is the overall goal of this project. To accomplish this goal, we will leverage existing patient cohorts, a group of collaborators with aligned research interests, the infrastructure of the Childhood Arthritis Rheumatology Research Alliance (CARRA) and the Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) for prospective patient recruitment to assemble a large well-phenotyped cohort of JIA patients treated with MTX. We will use this cohort to test our overall hypothesis that: “methotrexate response in JIA is dependent on genetic variation influencing drug metabolism and drug bioavailability” by addressing the following aims: • Aim 1. To determine the genetic contribution to clinical drug response. • Aim 2: To understand the genetic contribution to cellular biomarkers of drug response. • Aim 3: To develop a predictive tool to inform methotrexate use in the clinic. This project provides the opportunity to understand the genetic basis for MTX response both at a clinical and cellular level and represents a truly translational approach that draws on the expertise and collaboration of multiple investigators to combine resources and strategies to personalize medicine for children with JIA. Knowledge gained from this work will translate directly into the clinical setting to guide early treatment for JIA and will also impact other diseases treated with MTX and conditions where folate metabolism and regulation is critical to growth and development.