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

英国炎症性肠病生物资源：克罗恩病从遗传学到功能和临床转化的进展

• 批准号: MR/M00533X/1
• 负责人: Miles Parkes
• 金额: $ 84.11万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM00533X%2F1
• 关键词: UK; Inflammatory; Bowel; Disease; Bioresource

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.

我们建议开发一个集中的国家可召回的生物资源，其中包括25，000名克罗恩病或溃疡性结肠炎（统称炎症性肠病）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关键特征：1。来自英国范围内招募的25，000名IBD患者的DNA和血清+临床和遗传数据-所有数据均存储在中央NIHR资助的生物储存库中，技术输入来自英国生物库2。1000例新发IBD患者。未受治疗或手术混淆的详细样本，加上随访样本（包括粪便）+临床数据3。第一个可召回的IBD生物资源-允许通过临床亚型或携带特定IBD遗传风险变体分层的患者被招募用于分层的“第2阶段”科学研究或临床试验（每个第2阶段研究将需要单独的资金和每个受试者的新同意）IBD影响每1000个欧洲人中有4个，在年轻成人中发病高峰。尽管使用类固醇、免疫抑制剂和抗体治疗，约50%的患者因治疗失败或疾病并发症需要进行大手术+/-结肠造口术。英国的直接医疗费用超过10亿英镑/年。鉴于IBD对健康、教育、人际关系和就业的重大不利影响，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，我们的团队（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。在识别>160个不同的遗传风险因素中，我们发现了IBD内遗传分层以及IBD与许多其他自身免疫性疾病之间重叠的证据。为了充分利用最近的遗传学进展，下一步需要对相关变体进行功能分析，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益处。这些关键步骤是分层医学的核心，它们都严重依赖于获得大量已知或可确定基因型患者的生物资源，如我们所建议的，以获得新鲜样本进行分析或招募患者进行分层临床试验。“召回能力”是一个关键的新功能-将我们现有的14，000个DNA样本的“被动”收集转化为一个新的25，000名患者的互动资源，这些患者完全参与并可召回由任何英国医学，科学或工业研究人员领导的分层研究。初始队列将允许研究不受药物作用混淆的生物标志物、微生物触发物和表观遗传学。此外，许多非IBD研究者，例如来自牛皮癣、关节炎和结肠癌的研究者，已经表达了对使用生物资源的支持和兴趣，在生物资源中，遗传风险变体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。在这里，我们请求5年的合作伙伴关系资助，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采集相关的成本，CRN的参与将由MRC资助;而剑桥生物医学研究中心（BRC）已同意，如果该申请成功，将资助与集中样本处理、质量控制和存储相关的所有成本，以及IT支持和一名IBD数据管理员。鉴于其规模和雄心，我们认为这一建议物有所值。IBD Bioresource将为IBD遗传学最新重大进展的科学和临床开发提供一个关键平台，将促进跨疾病合作，并大大促进与行业的互动。这样做将在未来10年内为英国具有全球竞争力的IBD和炎症研究奠定基础。

项目成果

COVID-19 vaccine-induced antibody and T-cell responses in immunosuppressed patients with inflammatory bowel disease after the third vaccine dose (VIP): a multicentre, prospective, case-control study.

• DOI: 10.1016/s2468-1253(22)00274-6
• 发表时间: 2022-11
• 期刊: LANCET GASTROENTEROLOGY & HEPATOLOGY
• 影响因子: 35.7
• 作者: Alexander, James L.;Liu, Zhigang;Sandoval, Diana Munoz;Reynolds, Catherine;Ibraheim, Hajir;Anandabaskaran, Sulak;Saifuddin, Aamir;Seoane, Rocio Castro;Anand, Nikhil;Nice, Rachel;Bewshea, Claire;D'Mello, Andrea;Constable, Laura;Jones, Gareth R.;Balarajah, Sharmili;Fiorentino, Francesca;Sebastian, Shaji;Irving, Peter M.;Hicks, Lucy C.;Williams, Horace R. T.;Kent, Alexandra J.;Linger, Rachel;Parkes, Miles;Kok, Klaartje;Patel, Kamal V.;Teare, Julian P.;Altmann, Daniel M.;Goodhand, James R.;Hart, Ailsa L.;Lees, Charlie W.;Boyton, Rosemary J.;Kennedy, Nicholas A.;Ahmad, Tariq;Powell, Nick
• 通讯作者: Powell, Nick

OP08 Multi-ancestry genome-wide association study of inflammatory bowel disease identifies 125 novel loci and directly implicates new genes in disease susceptibility

OP08 炎症性肠病的多祖先全基因组关联研究确定了 125 个新基因座并直接暗示了疾病易感性中的新基因

• DOI: 10.1093/ecco-jcc/jjad212.0008
• 发表时间: 2024
• 期刊: Journal of Crohn's and Colitis
• 作者: Fachal L

Development and initial psychometric validation of a patient-reported outcome measure for Crohn's perianal fistula: the Crohn's Anal Fistula Quality of Life (CAF-QoL) scale.

• DOI: 10.1136/gutjnl-2019-320553
• 发表时间: 2021-09
• 期刊: Gut
• 影响因子: 24.5
• 作者: Adegbola SO;Dibley L;Sahnan K;Wade T;Verjee A;Sawyer R;Mannick S;McCluskey D;Bassett P;Yassin N;Warusavitarne J;Faiz O;Phillips R;Tozer PJ;Norton C;Hart AL
• 通讯作者: Hart AL

Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.

• DOI: 10.1038/ng.3760
• 发表时间: 2017-02
• 期刊: Nature genetics
• 影响因子: 30.8
• 作者: de Lange KM;Moutsianas L;Lee JC;Lamb CA;Luo Y;Kennedy NA;Jostins L;Rice DL;Gutierrez-Achury J;Ji SG;Heap G;Nimmo ER;Edwards C;Henderson P;Mowat C;Sanderson J;Satsangi J;Simmons A;Wilson DC;Tremelling M;Hart A;Mathew CG;Newman WG;Parkes M;Lees CW;Uhlig H;Hawkey C;Prescott NJ;Ahmad T;Mansfield JC;Anderson CA;Barrett JC
• 通讯作者: Barrett JC

OP07 Consistent IBD treatment approaches across South Asian and White ethnicities despite phenotypic variations: a study of 33,157 patients using the IBD BioResource

OP07 尽管存在表型差异，但南亚和白人的 IBD 治疗方法一致：使用 IBD BioResource 对 33,157 名患者进行的研究

• DOI: 10.1093/ecco-jcc/jjad212.0007
• 发表时间: 2024
• 期刊: Journal of Crohn's and Colitis
• 作者: Balarajah S