Genetic predictors of anti-TNF treatment response and infections in IBD

描述(申请人提供)：克罗恩病(CD)和溃疡性结肠炎(UC)影响着超过140万美国人。在过去的15年里，CD和UC的治疗取得了长足的进步，抗肿瘤坏死因子的单抗是最重要的治疗突破。然而，许多患者没有做出足够的反应。最近的全基因组关联研究(GWAS)极大地提高了我们对CD和UC发病机制的理解。这些基因变异在预测抗肿瘤坏死因子治疗反应中的作用尚未得到充分的确定。此外，在高达10%的患者发生严重感染的情况下，使用这些药物仍然存在重大的安全问题。对感染的易感性有很强的遗传成分，特别是涉及先天免疫的多态。鉴于先天免疫在IBD发病机制中的关键作用，这些共有的基因多态性是否也会影响抗肿瘤坏死因子治疗的感染风险，此前还没有进行过研究。因此，开发工具来确定治疗反应和感染的可能性是该领域尚未得到满足的一个关键需求。我们的首要目标是确定抗肿瘤坏死因子治疗的短期和长期反应以及感染性并发症的临床和遗传预测因子。为了实现这些目标，我们将利用两个大群体的互补优势--一个预期的登记群体 超过1200名CD或UC患者，以及一个新的基于EMR的队列，该队列包括超过11,000名CD或UC患者，这些患者与生物谱系资料库相关联。这项建议利用了分析遗传学、翻译免疫学和生物信息学等关键领域的导师和重要专业知识，并允许候选人在这些新的内容领域和研究方法方面发展基本技能。NIH资助的整合生物学和床边的信息学中心、炎症性肠病研究中心和博德研究所的专业知识是这一应用程序的关键优势。这一职业发展奖将在提供生物信息学和遗传流行病学方面的培训方面发挥关键作用，从而有助于 候选人的长期目标是建立独立的IBD研究生涯，专注于定义高危队列和个性化治疗。该奖项的培训部分包括哈佛医学院、公共卫生学院和麻省理工学院的基因流行病学和生物信息学相关内容领域的研究生水平课程。候选人将继续积极参与已经建立的多学科研究小组，他们已经证明了基于EMR的方法的实用性，以准确地定义自身免疫性疾病，将其与生物样本收集联系起来，并成功地将其用于基因分型-表型研究。这将有助于促进未来提案的协作开发，因为本申请中提议的工作有可能适用于 其他同龄人。 与公共卫生相关：从这项研究中获得的关于治疗反应和感染并发症的遗传预测因素的新信息有可能改变临床实践，使临床试验集中在最有可能对不良事件风险较低的疗法有反应的患者队列中，从而防止不必要地暴露在潜在毒性疗法中，受益可能性较低。这项工作是朝着开发个性化药物方法的方向迈出的一步，以便根据受益和风险的可能性进行量身定制的治疗。这里开发的方法学也将应用于其他基于EMR的队列，以研究新的治疗药物和疾病结果。

DESCRIPTION (provided by applicant): Crohn's disease (CD) and ulcerative colitis (UC) affect over 1.4 million Americans. Over the past 15 years, considerable progress has been made in the therapy of CD and UC with monoclonal antibodies against tumor necrosis factor ¿ (anti-TNF) representing the most significant therapeutic breakthrough. However, many patients fail to respond adequately. Recent genome wide associations studies (GWAS) have significantly increased our understanding of the pathogenesis of CD and UC. The role of these genetic variants in predicting response to anti-TNF therapy is yet to be defined adequately. In addition, significant safety concerns remain with the use of these agents with serious infections occurring in up to 10% of patients. There is a strong genetic component to susceptibility to infections, in particular involving polymorphisms in innate immunity. Given the key role of innate immunity in IBD pathogenesis, whether such shared polymorphisms also influence risk of infections on anti-TNF therapy has not been examined previously. Thus, the development of tools to define likelihood of treatment response and infections are a key unmet need in the field. Our overarching objective is to identify clinical and genetic predictors of both short-term and long-term response as well as infectious complications of anti-TNF therapy. To achieve these aims, we will utilize the complementary strengths of two large cohorts - a prospective registry cohort of over 1200 patients with CD or UC, and a novel EMR-based cohort of over 11,000 patients with CD or UC linked to a biospecimen repository. This proposal utilizes the mentorship and significant expertise in key areas including analytical genetics, translational immunology, and bioinformatics and allows the candidate to develop fundamental skills in these novel content areas and research methods. The access to expertise at the NIH-funded center Informatics for Integrating Biology and the Bedside, the Center for Study of Inflammatory Bowel Disease, and the Broad Institute is a key strength of this application. This career development award will be critical in providing training in bioinformatics and genetic epidemiology, thus contributing to the candidate's long-term goal of establishing an independent IBD research career with focus on defining at-risk cohorts and personalizing therapy. The training component of the award includes graduate-level courses in the relevant content areas in genetic epidemiology, and bioinformatics at the Harvard Medical School, School of Public Health, and Massachusetts Institute of Technology. The candidate will continue to actively engage with an established group of multidisciplinary researchers who have demonstrated the utility of the EMR-based approach to accurately define autoimmune diseases, link it to biospecimen collection, and use it successfully for genotyping-phenotype research. This will help foster collaborative development of future proposals as the work proposed in this application has the potential for applicability in other cohorts. PUBLIC HEALTH RELEVANCE: The novel information gained from this study regarding genetic predictors of treatment response and infectious complications has the potential to transform clinical practice by leading to clinical trials focused on selected cohorts of patients most likely to respond to therapies with low risk of adverse events, thus preventing unnecessary exposure to potentially toxic therapies with low likelihood of benefit. Such work is a step toward developing personalized medicine approaches to tailor therapy based on likelihood of benefit and risk. The methodology developed here will also have applications in other EMR-based cohorts to investigate novel therapeutic agents and disease outcomes.