THE UNIVERSITY OF OXFORD MEDICAL SCIENCES DIVISION Final Report to Cure Crohn s Colitis MARCH 2008
CONTENTS Introduction 2 Project background 3 Crohn s and Colitis research at Oxford 4 Project progress 4 Project funding 5 Conclusion 6 Contact details 7 Appendix 1: Publications supported by Cure Crohn s Colitis 8 Appendix 2: Dr Fraser Cumming s Curriculum Vitae 9 1
INTRODUCTION The University of Oxford is most grateful to Cure Crohn s Colitis for its generosity in supporting the Gastroenterology Unit at Oxford under Professor Derek Jewell between 2005 and 2007. We are delighted to submit a final progress report to the Trustees of Cure Crohn s Colitis for review. Generous funding totalling 150,000 was pledged over a three-year period by Cure Crohn s Colitis. The gifts from Cure Crohn s Colitis were used to support Dr Fraser Cummings research into the genetics of inflammatory bowel disease (IBD) at the Wellcome Centre for Human Genetics. This report includes a background of research into Crohn s and ulcerative colitis at Oxford; an update of Dr Fraser Cummings activities and achievements and an overview of how this research has contributed to ongoing research in this area, enabled by the support of Cure Crohn s Colitis. The appendices include a list of relevant publications to which Dr Fraser Cummings has contributed during this time and his Curriculum Vitae. Wellcome Centre for Human Genetics 2
PROJECT BACKGROUND Identifying genes involved in colitis and Crohn s Disease Ulcerative colitis and Crohn s disease are two inflammatory diseases of the intestine affecting three to four people in every 1,000 in the UK. They are both chronic disorders but are characterised by often long periods of remission between episodes of disease activity. Ulcerative colitis affects the colon, or the rectum, in some individuals but can extend to affect the whole organ; whereas Crohn s disease can affect any part of the gastro-intestinal tract, although most commonly the lower ileum and the proximal colon. The causes of these diseases are unknown and so treatment is generally directed towards controlling the inflammation with steroid drugs, immunosuppressant drugs and newer methods including directing monoclonal antibodies towards specific mediators of inflammation. Surgery is frequently required: removal of the whole colon in the case of ulcerative colitis and resection of inflamed portions of the small or large intestine for Crohn s disease. However, despite high morbidity and poor quality of life during periods of disease activity, quality of life is good during remission and life expectancy is near normal, particularly for ulcerative colitis. In the 1960s, researchers recognised that more than one member of a family could be affected although the pattern of inheritance did not conform to that seen in single gene disorders like colour blindness or haemophilia. In the 1980s and 1990s, the familial incidence of Crohn s disease was well documented as being about 18%, with a lower incidence of 10-12% for ulcerative colitis. Furthermore, in studies of identical twins whose DNA is identical, there was a very high risk that both members of a pair would be affected if one member developed the disease. This provided good clinical evidence to support the proposition that a genetic susceptibility might make individuals more likely to develop either disease in response to some exogenous trigger, such as bacteria, dietary constituents or other environmental factors. When technology became available in the early 1990s making it possible to link disease with regions of chromosomes, it allowed researchers to identify genetic regions containing putative genes without presupposing the involvement of specific genes. Expression of genes in Crohn s Disease 3
CROHN S AND COLITIS RESEARCH AT OXFORD The Oxford group was one of the first to perform linkage studies suggesting that there were multiple genes involved, not only determining an overall susceptibility to Crohn s and Colitis but also other genes that might influence the anatomical distribution and severity of the inflammation. Within the last 15 years, enormous progress has been made in identifying these genes and the study of Crohn s disease has now become the paradigm of a polygenic disorder. The Oxford group had studied a number of specific genes located within a region of linkage on chromosome 19 which provided further support to the hypothesis that this region contained genes relevant to the pathogenesis of both Crohn s disease and ulcerative colitis. Cure Crohn s and Colitis s vital support, has allowed Dr Fraser Cummings to examine this chromosome in detail under the supervision of Dr Lon Cardon and Professor Derek Jewell. PROJECT PROGRESS Epidemiological and genetic studies support a role for genetics in determining susceptibility to the inflammatory bowel diseases (IBD), Crohn s disease and ulcerative colitis. Linkage analyses have identified a number of regions of the human genome that harbour inflammatory bowel disease genes including the IBD6 loci. By typing many single nucleotide polymorphisms across the chromosome, Dr Cummings has been able to locate the regions of genetic association more closely. One of the regions contains genes relevant to the presentation of antigens (such as bacterial peptides) to certain populations of T lymphocytes. It is a very complex region but preliminary typing for polymorphisms in some of these specific genes has already produced interesting new insights. During this period of research Dr Cummings was also an active member of the Wellcome Trust Case Control Consortium Inflammatory Bowel Disease group. Other research experience included running a clinical pilot study involving the use of leukocytapheresis in ulcerative colitis. The studies supported by Cure Crohn s Colitis, and other studies published worldwide, clearly demonstrate that if the mechanisms for protecting us from all the millions of bacteria within the intestine are defective by virtue of changes in specific genes, there is considerable risk that a chronic inflammatory disease will develop. Genetic variation may also predict individuals response to specific therapies. Thus greater understanding of pharmacogenetics (the study or clinical testing of genetic variation that gives rise to differing response to drugs), may allow individualised treatment plans with greater therapeutic outcomes. Dr Fraser Cummings has published two papers recently acknowledging support of Cure Crohn s Colitis that Professor Jewell has sent previously to Mr Ivor Tiefenbrun. A complete list of papers produced by Dr Cummings during this period appears in Appendix 2. Cure Crohn s Colitis s generosity has also enabled the University to contribute to the UK Consortium of research funded by the Wellcome Trust. This has allowed very large numbers of cases to be studied already identifying new genes 4
that appear to be significant for both Crohn s disease and ulcerative colitis. Thus out of all the diseases in which multiple genes are thought to play a part, Crohn s disease and ulcerative colitis are currently leading the field in terms of identifying relevant genes and understanding their function. Professor Jewell will retire from his personal Chair at the end of this academic year. It is through his endeavours that Oxford has built its outstanding reputation in gastroenterology. Dr Fraser Cummings has now moved into a clinical role at the John Radcliffe Hospital where he is able to translate the knowledge gained through his work with Professor Jewell into clinical practice. The gastroenterology unit at the John Radcliffe is a centre for the treatment of life-threatening gastrointestinal haemorrhage and Dr Cummings is involved with the emergency treatment and endoscopic management of these patients. 5
CONCLUSION It is estimated that some 240,000 people in the UK are affected by distressing, and often severely debilitating, chronic bowel diseases such as ulcerative colitis and Crohn s disease. However, studies such as those supported by Cure Crohn s Colitis in molecular genetics and cellular immunology are now helping scientists and clinicians to improve wider understanding of bowel diseases and how they may be prevented and treated more effectively. The University would like to reiterate its appreciation of Cure Crohn s Colitis generous support to Professor Jewell s team and for the Trustees commitment to funding research into Crohn s and ulcerative colitis. Enlightened engagement such as this contributes to a broader understanding of the causes of inflammatory bowel disease and will ultimately benefit the many sufferers of these conditions. 6
CONTACT DETAILS For more information, please contact: Miss Diana Stent Head of Development Medical Sciences University of Oxford Development Office University Offices Wellington Square Oxford OX1 2JD T: +44 (0)1865 611535 E: diana.stent@devoff.ox.ac.uk http://www.medicine.ox.ac.uk Professor Derek Jewell Professor of Gastroenterology & Consultant Physician Gastroenterology Unit University of Oxford Gibson Laboratories (2nd Floor) Radcliffe Infirmary Woodstock Road Oxford OX2 6HE T: +44 (0)1865 224829 E: derek.jewell@ndm.ox.ac.uk http://www.medicine.ox.ac.uk/gastro 7
Appendix 1 Publications supported by Cure Crohn s Colitis Funding: 1. 2. 3. 4. 5. 6. 7. Cummings JRF, Ahmad T, Geremia A, Beckly J, Cooney R, Hancock L, Pathan S, Guo C, Cardon LR, Jewell DP, Contribution of the novel IBD susceptibility gene IL23R to disease susceptibility and phenotype, Inflamm Bowel Dis. 2007: No.13:1063-8 Cummings JRF, Cooney R, Pathan S, Anderson CA, Barrett JC, Beckly J, et al, Confirmation of the role of ATG16L1 as a Crohn s disease susceptibility gene, Inflamm Bowel Dis. 13, No.8:941-6 Cooney R, Cummings JRF, Pathan S, Geremia A, Beckly J, et al, Confirmation of an association between genetic variants in Myosin IX B and Inflammatory Bowel Disease. Submitted for review Tremelling M*, Cummings JRF*, Fisher SA*, Mansfield J, Gwilliam R, Keniry A, et al, IL23R variation determines susceptibility but not disease phenotype in Inflammatory Bowel Disease, Gastroenterology 2007, No. 132:1657-64 *Joint first author Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls, Nature 2007, No. 447:661-78. Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA et al, Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn s disease susceptibility, Nat Genet, 2007, Vol. 39:830-2. Jones DC, Edgar RS, Ahmad T, Cummings JRF, Jewell DP, Trowsdale J, Young NT, Killer Ig-like receptor (KIR) genotype and HLA ligand combinations in ulcerative colitis susceptibility, Genes and Immunity 2006, Vol. 7:576-582 Papers in preparation supported by Cure Crohn s Colitis Funding: 1. 2. The genetics of nod-like receptors in Crohn s disease Accepted as an abstract by the British Society of Gastroenterology and The European Crohn s Colitis Organisation Killer Ig-like receptor (KIR) genotype in inflammatory bowel disease (IBD) susceptibility 8
Appendix 2 Dr Fraser Cummings Curriculum Vitae: Dr Fraser Cummings MBChB BMSc (Hons) MRCP (UK) Education Basic Qualification: MB ChB July 1995 Medical school: Dundee University Academic Distinctions and Awards BMSc. (Hons) Biochemistry 2:1 July 1992 UK Student Prize, Association for the Study of Medical Education 1994 Ethicon Trophy: Best 4th year medical student project 1995 Dundee Teaching Hospitals N.H.S. Trust and Tayside Health Board Clinical Audit Symposium Prize, 1995 Other Qualifications and Awards M.R.C.P. (U.K.) 1999 ECCO junior training course fellowship 2006 DPhil (PhD) Submitted October 2007; awaiting viva. Courses and conferences attended: Advance Life Support course 1997, 2002, October 2007 Scottish Therapeutic Endoscopy Workshop 1998-2000 Practical Gastroenterology, Oxford 1999, 2000 Research methods course. Aberdeen 2000 Royal College of Physicians of Edinburgh, 5th Advanced Course in Gastroenterolgy and Hepatology, 2001 Digestive Diseases Week, San Diego 2000, Orlando 2003, Chicago 2005 British Society of Gastroenterology meeting 2001-2006 United European Gastroenterology Week Prague 2004 Oxford Postgraduate Gastroenterology Course 2002-2007 Trainees in Gastroenterology Management Skills Workshop 2006, 2007 University of Oxford Graduate Teaching Skills Course Stage I and II 2006 Current Post SpR Gastroenterology to Dr S Travis Dr S Keshav, Dr J Collier and Dr R Chapman Gastroenterology Unit, John Radcliffe Hospital, Headley Way, Oxford Previous medical appointments November 2003-March 2007 Clinical Research Fellow and Honorary Registrar to Professor DP Jewell, Radcliffe Infirmary, Oxford 9
January 2003-November 2003 November 2001-January 2003 August 2001 - October 2001 August 2000 July 2001 June 1999 July 2000 August 1998 June 1999 SpR G(I)M and Gastroenterology to Dr D Gorard, Wycombe General Hospital, High Wycombe. SpR G(I)M and Gastroenterology to Dr J Blackwell, Stoke Mandeville Hospital, Aylesbury SpR Gastroenterology and G(I)M to Dr JF Mackenzie, Glasgow Royal Infirmary SpR G(I)M and Gastroenterology to Dr R Holden, Monklands District General Hospital, Airdrie S.H.O. III G(I)M to Prof AR Lorimer, Glasgow Royal Infirmary SHO III General Medicine and Diabetes Dr RJ Weir, Gartnavel General Hospital, Glasgow Western Infirmary, Glasgow Senior House Officer Rotational Training Programme August 1996- August 1998 August 1996-November 1996 November 1996-February 1997 February 1997 - August 1997 August 1997-November 1997 November 1997-February 1998 February 1998-August 1998 February 1996-August 1996 August 1995-January 1996. Dermatology Professor R MacKie, Western Infirmary General Medicine Dr D McCruden, Vale of Leven Hospital, General Medicine, stroke medicine and hypertension. Professor JL Reid, Western Infirmary Respiratory Medicine Professor N. Thomson, Gartnavel General Hospital Cardiology Dr J. Kennedy, Western Infirmary General Medicine and Diabetes Dr M. Small, Gartnavel General Hospital House Surgeon, Dumfries and Galloway Royal Infirmary. House Physician, Ninewells Hospital, Dundee Clinical Experience Gastroenterology For the last 8 months I have worked in the tertiary referral GI unit at the John Radcliffe hospital, Oxford which has balanced my 3 years of general clinical gastroenterology SpR training in district general hospitals prior to my period of research. I have received excellent clinical training in the management of complex IBD as well as carrying out both basic science and clinical research. Other areas of specialist training have included clinical nutrition and hepatology. I have a 1:6 on-call commitment for 10
gastroenterology at the John Radcliffe which is the regional unit for life-threatening gastrointestinal haemorrhage and involves the emergency endoscopic management of these patients. I have now performed over 2400 upper gastrointestinal endoscopies and 900 Colonoscopies (caecal intubation rate 91.8%). I am continuing to gain experience in therapeutic endoscopy and colonoscopy. Managerial Experience President of the Medical Student Council, Dundee University 1994-1995 Medicine representative on Junior Doctors Forum, Western Infirmary 1997-1998 MRCP Part II exam February, October 2000 Medical Unit registrar representative, Stoke Mandeville Hospital, 2001-2002 Gastroenterology Unit management meeting SpR representative 03/07- Research Experience Ongoing research projects: Biological markers to predict outcome in acute severe ulcerative colitis. The prevalence of primary sclerosing cholangitis in IBD patients with colonic dysplasia. Retrospective audit of adalimumab use in the John Radcliffe hospital DPhil (PhD) Research (Supported by Cure Crohn s Colitis) Epidemiological and genetic studies support a role for genetics in determining susceptibility to the inflammatory bowel diseases (IBD), Crohn s disease and ulcerative colitis. Linkage analyses have identified a number of regions of the human genome that harbour IBD genes including the IBD6 loci. When the Oxford linkage data was stratified on carriage of CARD15 and IBD5 susceptibility haplotype carriage significant peaks of linkage were identified. My DPhil project was to carry out a 2 stage project across the whole of chromosome 19 in order to identify the putative susceptibility genes contained within the IBD6 linkage area using a linkage disequilibrium mapping approach. This project has now been completed and my thesis has been submitted. During this period of research I was an active member of the Wellcome Trust Case Control Consortium IBD group. Other research experience included running a clinical pilot study involving the use of leukocytapheresis in ulcerative colitis. 11