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

IBD 抗 TNF 治疗反应和感染的遗传预测因子

• 批准号: 9070599
• 负责人: Ashwin N Ananthakrishnan
• 金额: $ 16.96万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9070599
• 关键词: Address; Adverse event; Affect; Age; Algorithms; American; Anti-Tumor Necrosis Factor Therapy; Antibodies; Area; Autoimmune Diseases; Award; Benefits and Risks; Bioinformatics; Biology; CD14 gene; Clinical; Clinical Data; Clinical Trials; Collection; Comorbidity; Computerized Medical Record; Crohn' s disease; Data; Data Set; Development; Disease; Disease Outcome; Disease remission; Exposure to; Fostering; Funding; Future; Genes; Genetic; Genetic Polymorphism; Genetic Research; Genotype; Goals; Health; Human Genetics; IL1R1 gene; Immune response; Immunology; Immunosuppressive Agents; Infection; Inflammatory Bowel Diseases; Informatics; Institutes; Institution; Interferons; K-Series Research Career Programs; Link; Machine Learning; Massachusetts; Mentors; Mentorship; Methodology; Monoclonal Antibodies; Morbidity - disease rate; Natural Immunity; Natural Language Processing; Outcome; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Pneumonia; Predisposition; Public Health Schools; Registries; Research; Research Methodology; Research Personnel; Risk; Role; Safety; Sepsis; Source; Structure; TNF gene; Technology; Therapeutic; Therapeutic Agents; Training; Treatment outcome; Tumor Necrosis Factor Therapy; Ulcerative Colitis; United States National Institutes of Health; Work; adaptive immunity; base; career; clinical practice; clinical predictors; cohort; cost; genetic epidemiology; genetic predictors; genetic variant; genome wide association study; immune function; medical schools; multidisciplinary; novel; novel therapeutics; patient registry; personalized medicine; predicting response; prevent; prospective; repository; response; skills; tool development; translational genetics; treatment response

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.

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年里，CD和UC的治疗取得了相当大的进展，抗肿瘤坏死因子（抗TNF）的单克隆抗体代表了最重要的治疗突破。然而，许多患者没有做出充分的反应。最近的全基因组关联研究（GWAS）显著增加了我们对CD和UC发病机制的理解。这些遗传变异在预测抗TNF治疗反应中的作用还有待充分确定。此外，使用这些药物仍存在重大安全性问题，高达10%的患者发生严重感染。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，这些共有的多态性是否也影响抗TNF治疗的感染风险以前尚未研究。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满足的关键需求。我们的首要目标是确定抗TNF治疗的短期和长期反应以及感染并发症的临床和遗传预测因子。为了实现这些目标，我们将利用两个大型队列的互补优势-一个前瞻性登记队列， 超过1200例CD或UC患者，以及一个新的基于EMR的队列，其中超过11，000例CD或UC患者与生物样本库相关联。该提案利用了包括分析遗传学，翻译免疫学和生物信息学在内的关键领域的指导和重要专业知识，并允许候选人在这些新的内容领域和研究方法中发展基本技能。在NIH资助的中心信息学整合生物学和床边，炎症性肠病研究中心和布罗德研究所的专业知识的访问是这个应用程序的关键优势。这一职业发展奖对于提供生物信息学和遗传流行病学方面的培训至关重要，从而有助于 候选人的长期目标是建立一个独立的IBD研究生涯，重点是定义高危人群和个性化治疗。该奖项的培训部分包括在哈佛医学院、公共卫生学院和马萨诸塞州理工学院开设遗传流行病学和生物信息学相关内容领域的研究生课程。候选人将继续积极参与一组多学科研究人员，他们已经证明了基于EMR的方法的实用性，可以准确定义自身免疫性疾病，将其与生物标本收集联系起来，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合作开发，因为本申请中提出的工作具有适用于以下方面的潜力： 其他同伙。