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

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 Biobank
2. 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.

Our main objective is to establish a centralised national Inflammatory Bowel Disease (IBD) Bioresource of 25,000 patients, from which subjects meeting inclusion criteria for approved downstream functional and clinical studies can be identified and recalled.

Subjects would be recruited from our existing network of UK IBD Genetics Consortium (UKIBDGC) collaborating hospitals. The study coordinators will train CRN (clinical research network) nurses in each site to organise recruitment, consent, sample and data collection. Such CRN nurses are paid by the NIHR: their contribution to this study would be mandated if it is funded by the MRC.

All IBD samples and data will be submitted to the NIHR BRC-MRC BioRepository team at Addenbrooke's, Cambridge. They have substantial expertise in high-throughput biological sample management, using LIMS tracking with automated storage and retrieval. Processing of all IBD samples will be undertaken by BioRepository personnel using established SOP's. DNA and serum will be extracted and quality checked using automated systems and deposited in fully monitored low temperature storage.

Dr Tim Peakman, Executive Director of UK Biobank, will provide strategic guidance on biobanking issues. Once UK Biobank BioRepository South is complete the intention is to move the IBD Bioresource to this new facility.

An IBD Bioresource management committee co-chaired by PI Parkes will, with the study coordinators, oversee recruitment and liaison with clinical centres. Proposals to use the IBD Bioresource will be reviewed by the NIHR BioResource scientific advisory board, including UKIBDGC representatives. Recall of patients for approved projects will be handled through the existing Cambridge NIHR BioResource mechanism.

Data generated on IBD Bioresource subjects (existing genotyping and sequencing data generated from our UKIBDGC studies) will be held on the central NIHR BioResource database and accessible to collaborating researchers.

A national inflammatory bowel disease (IBD) Bioresource that capitalises on recent genetics advances and on existing UK-wide recruitment pipelines would be transformative for UK IBD research. For the first time it would bring together large, motivated and precisely characterised IBD patient cohorts with UK investigators from medicine, science or industry. By providing a platform for downstream studies, it would directly aid translation of new genetics knowledge to improved IBD treatment - as well as fostering collaborations across several disease areas and facilitating interactions with industry.

Beneficiaries
1. Patients with IBD, by galvanising research, improving treatments and driving towards a cure - so improving their confidence in and enthusiasm for research, and ultimately their health, wellbeing and economic productivity.

2. Individuals at risk of IBD, helped by biomarkers of risk prediction and the development of preventative strategies

3. Academics in IBD investigating
a.pharmacogenetics + low-frequency/rare genetic variants
b.epigenetics
c.biomarkers of prognosis
d.functional / immunological impact of risk variants
e.microbial triggers of IBD flares

4. Funding agencies (NIHR, MRC, WT) - who can access an engaged patient population to ascertain their research priorities

5. Academics outside IBD - from diseases where genetics, mechanistic pathways and therapies are shared with IBD. The cross-cutting utility is a key feature: investigators from rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, psoriasis, TB and colorectal cancer have already expressed their wish to use the IBD Bioresource.

6. Industry - both existing (MSD, Novartis and GSK) and new partners from biotech and pharmaceutical industries. Collaborations would encompass all stages from drug development to clinical trials / stratified and experimental medicine.

7. The NIHR Bioresource programme: as Dr Bradley indicates in his Project Partner letter - 'The high level vision of the NIHR BioResource is to promote recruitment of well genotyped and phenotyped patients .. in collaboration with the Clinical Research Network, and an initial focus is immunological and inflammatory disease'

8. Crohn's and Colitis UK - the patients' charity who keenly support this proposal for the sense of purpose, progress and optimism it will bring to the 150,000+ UK sufferers of IBD who would have the opportunity to participate in research wherever they live in the UK.

9. Developers of IBD health policy who will benefit from advances in biomarkers and methods of IBD stratification to improve targeting of high cost therapies.

Inherent in the proposal is direct patient engagement in research - for the first time joining together a large IBD patient cohort with investigators. 25,000 patients with IBD (representing ~15% of the UK total) would be informed of research studies for which their clinical or genetic profiles matched inclusion criteria, and where appropriate would be encouraged to participate.

Patient involvement will include a mechanism to survey views for example regarding IBD research priorities and relevant health policy such as NICE guidance - so allowing patients to directly influence these.

Such patient interaction is strongly supported by the NIHR and by the national patient support group charity Crohn's and Colitis UK.

Patients and users will be engaged through a variety of media including a website, social networking, lectures and lay / academic publications. Success will be gauged by numbers of patients recruited and outputs in terms of projects, grants and papers resulting; collaborations established; and new therapies tested through the IBD Bioresource.

Of note, there are no other recallable IBD Bioresources elsewhere. This emphasises the opportunity to provide a unique platform to support globally competitive IBD research over the next 10 years.