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

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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.