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

描述（由申请人提供）：克罗恩病（CD）和溃疡性结肠炎（UC）影响超过140万美国人。在过去的15年中，针对肿瘤坏死因子（anti-TNF）的单克隆抗体在治疗CD和UC方面取得了相当大的进展，这是最重要的治疗突破。然而，许多患者没有充分的反应。最近的全基因组关联研究（GWAS）大大增加了我们对CD和UC发病机制的理解。这些遗传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定义。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性问题。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性。鉴于先天免疫在IBD发病机制中的关键作用，这些共享多态性是否也会影响抗tnf治疗的感染风险，此前尚未研究过。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满足的关键需求。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素。为了实现这些目标，我们将利用两个大型队列的互补优势-一个前瞻性注册队列

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.