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: 8545840
• 负责人: Ashwin N Ananthakrishnan
• 金额: $ 16.86万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8545840
• 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; 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; Medicine; 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-alpha; Ulcerative Colitis; United States National Institutes of Health; Work; adaptive immunity; base; career; clinical practice; cohort; cost; genetic epidemiology; genetic variant; genome wide association study; immune function; medical schools; multidisciplinary; novel; novel therapeutics; patient registry; prevent; prospective; public health relevance; repository; response; skills; tool development; 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) 影响着超过 140 万美国人。在过去 15 年中，使用抗肿瘤坏死因子的单克隆抗体治疗 CD 和 UC 取得了相当大的进展。 （抗 TNF）代表了最重要的治疗突破，然而，最近的全基因组关联研究 (GWAS) 显着增加了我们对 CD 和 UC 发病机制的了解。抗 TNF 治疗的反应尚未充分确定。此外，使用这些药物仍存在重大安全问题，高达 10% 的患者会发生严重感染。特别涉及先天的多态性鉴于先天免疫在 IBD 发病机制中的关键作用，这种共同的多态性是否也会影响抗 TNF 治疗的感染风险，因此，开发确定治疗反应和感染可能性的工具是关键。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，我们将利用两种药物的互补优势。大队列——前瞻性登记队列的 该提案利用了分析遗传学、转化免疫学和生物信息学等关键领域的指导和重要专业知识，包括超过 1200 名 CD 或 UC 患者，以及一个由超过 11,000 名 CD 或 UC 患者组成的新型 EMR 队列。允许候选人发展这些新颖的内容领域和研究方法的基本技能 获得美国国立卫生研究院资助的生物学和床边信息学中心的专业知识，炎症性肠病研究中心和布罗德研究所是该应用程序的关键优势，该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，从而为该应用程序做出贡献。 候选人的长期目标是建立独立的 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哈佛医学院遗传流行病学和生物信息学相关内容领域的研究生课程。候选人将继续与麻省理工学院、公共卫生学院和麻省理工学院的多学科研究人员积极合作，这些研究人员已经证明了基于 EMR 的方法在准确定义自身免疫性疾病方面的实用性，并将其与生物样本联系起来。收集，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，因为本申请中提出的工作具有适用性的潜力。 其他群体。