The UK Inflammatory Bowel Disease Bioresource: Progressing from Genetics to Function and Clinical Translation in Crohn's Disease & Ulcerative Colitis

我们建议开发一个集中的全国性可回收生物资源，其中包括25,000名克罗恩病或溃疡性结肠炎（集体炎症性肠病）患者，以支持具有全球竞争力的IBD科学和临床研究。IBD生物资源将具有以下主要特征：从全英国招募的25000名IBD患者的DNA和血清+临床和遗传数据——全部存储在英国国立卫生研究院资助的中央生物库中，技术输入来自UK Biobank2。1000名新诊断的IBD患者。3.未受治疗或手术影响的详细样本，加上随访样本（包括粪便）+临床资料。第一个可召回的IBD生物资源——允许按临床亚型或携带特定IBD遗传风险变异进行分层的患者被招募进行分层的“2期”科学研究或临床试验（每个2期研究将需要单独的资助和每个受试者的新同意）。每1000名欧洲人中就有4人患有IBD，发病高峰为年轻人。尽管使用类固醇、免疫抑制和抗体治疗，仍有50%的患者因治疗失败或疾病并发症需要大手术+/-结肠造口术。英国每年的直接医疗费用超过10亿英镑。鉴于对健康、教育、人际关系和工作的重大不利影响，迫切需要了解IBD的病因并开发更好的治疗方法。自2007年以来，我们的小组（英国IBD遗传学联盟）通过国家队列建设，国际合作和使用领先技术，在了解IBD的遗传基础方面取得了巨大进展。在确定bbbb160个不同的遗传风险因素时，我们发现了IBD遗传分层的证据，也发现了IBD与许多其他自身免疫性疾病之间重叠的证据。下一步，为了充分利用最近的遗传学进展，需要对相关变异进行功能分析，以了解它们如何干扰细胞功能导致IBD；并将这些知识转化为临床效益。这些关键步骤是分层医学的核心——它们都严重依赖于获得已知或可确定基因型患者的大量生物资源，如我们所提议的那样，以获得新的样本进行分析或招募患者进行分层临床试验。“可召回性”是一个关键的新功能-将我们现有的14,000个DNA样本的“被动”收集转变为25,000个患者的新互动资源，这些患者完全参与并可被来自医学，科学或工业的任何英国研究者领导的分层研究。初始队列将允许研究生物标志物，微生物触发和表观遗传学不受药物影响。此外，许多非IBD研究人员，例如来自牛皮癣、关节炎和结肠癌的研究人员，已经表达了对使用生物资源的支持和兴趣，其中遗传风险变异与他们“自己的”疾病和/或治疗与IBD重叠，以询问疾病和药物无反应的共同机制。在此，我们请求MRC提供为期5年的合作资助，其中MRC支持4名关键的IBD生物资源人员，与（NIHR资助的）临床研究网络（CRN）分担与患者招募和样本收集相关的成本，临床研究网络（CRN）的参与将由MRC资助。而剑桥生物医学研究中心（BRC）已经同意，如果该申请成功，将资助与集中样品处理、质量控制和存储相关的所有费用，以及IT支持和一名IBD数据管理人员。考虑到它的规模和雄心，我们相信这个提议是物有所值的。IBD生物资源将为科学和临床利用IBD遗传学方面的最新重大进展提供一个关键平台，将促进跨疾病合作，并大大促进与工业界的互动。这样一来，它将在未来10年支撑英国具有全球竞争力的IBD和炎症研究。

We are proposing to develop a centralised national recallable bioresource of 25,000 patients with Crohn's disease or ulcerative colitis (collectively inflammatory bowel disease) to support globally competitive scientific and clinical IBD research. The IBD Bioresource would have the following key features:1. DNA and serum + clinical and genetic data from 25,000 IBD patients recruited UK-wide - all stored in a central NIHR funded biorepository with technical input from UK Biobank2. 1000 newly diagnosed IBD patients. Detailed samples unconfounded by treatment or surgery, plus follow-up samples (including stool) + clinical data 3. The first recallable IBD bioresource - allowing patients stratified by clinical subtype or carriage of specific IBD genetic risk variants to be recruited for stratified 'stage 2' scientific studies or clinical trials (each stage 2 study would require separate funding and new consent for each subject).IBD affects 4 per 1000 Europeans, with peak onset in young adults. Despite steroids, immunosuppression and antibody therapies ~50% of patients require major surgery +/- colostomy for treatment failure or disease complications. Direct UK healthcare costs exceed £1billion/yr. Given major adverse impacts on health, education, relationships and jobs there is a pressing need to understand the causes of IBD and develop better treatments.Since 2007 our group (the UK IBD Genetics Consortium) has, through national cohort building, international collaboration and use of leading technologies, made huge progress in understanding the genetic basis of IBD. In identifying >160 distinct genetic risk factors we have found evidence both of genetic strata within IBD and also of overlap between IBD and many other autoimmune diseases. The next steps, to fully capitalise on recent genetic advances, require functional analysis of the associated variants, to understand how they disturb cell function to cause IBD; and translation of this knowledge for clinical benefit. These key steps sit at the heart of stratified medicine - and both critically depend on access to a large Bioresource of patients of known or ascertainable genotype such as we are proposing, to obtain fresh samples for analysis or to recruit patients to stratified clinical trials.'Recall-ability' is a key novel feature - transforming our existing 'passive' collection of 14,000 DNA samples into a new interactive resource of 25,000 patients fully engaged and recallable for stratified studies led by any UK investigator from medicine, science or industry. The inception cohort will allow study of biomarkers, microbial triggers and epigenetics unconfounded by drug effects. Further, many non-IBD investigators, for example from psoriasis, arthritis and colon cancer, have expressed support and interest in using the Bioresource where genetic risk variants are shared with their 'own' disease and / or therapies overlap with IBD - to interrogate shared mechanisms of disease and drug non-response.Here we are requesting a 5 year partnership grant in which the MRC supports 4 key IBD Bioresource personnel, sharing costs related to patient recruitment and sample gathering with the (NIHR funded) Clinical Research Network (CRN) whose involvement would be mandated by the MRC funding; while Cambridge Biomedical Research Centre (BRC) have agreed if this application is successful to fund all costs related to centralised sample processing, quality control and storage, together with IT support plus one IBD data manager. Given its scale and ambition we believe this proposal represents excellent value for money. The IBD Bioresource would provide a key platform for the scientific and clinical exploitation of recent dramatic advances in IBD genetics, would foster cross-disease collaboration and substantially facilitate interaction with industry. In so-doing it would underpin globally competitive IBD and inflammation research in the UK for the next 10 years.