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Crohn Disease: HELP
Articles from University of Edinburgh
Based on 73 articles published since 2008

These are the 73 published articles about Crohn Disease that originated from University of Edinburgh during 2008-2019.
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Guideline Surgical Management of Crohn Disease in Children: Guidelines From the Paediatric IBD Porto Group of ESPGHAN. 2017

Amil-Dias, Jorge / Kolacek, Sanja / Turner, Dan / Pærregaard, Anders / Rintala, Risto / Afzal, Nadeem A / Karolewska-Bochenek, Katarzyna / Bronsky, Jiri / Chong, Sonny / Fell, John / Hojsak, Iva / Hugot, Jean-Pierre / Koletzko, Sibylle / Kumar, Devinder / Lazowska-Przeorek, Izabella / Lillehei, Craig / Lionetti, Paolo / Martin-de-Carpi, Javier / Pakarinen, Mikko / Ruemmele, Frank M / Shaoul, Ron / Spray, Christine / Staiano, Annamaria / Sugarman, Ian / Wilson, David C / Winter, Harland / Kolho, Kaija-Leena / Anonymous611001. ·*Department of Pediatrics, Centro Hospitalar, S. João, Porto, Portugal †Children's Hospital Zagreb, Faculty of Medicine, Zagreb, Croatia ‡The Juliet Keidan Institute of Pediatric Gastroenterology & Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel §Department of Pediatrics, Hvidovre University Hospital, Hvidovre, Denmark ||Pediatric Surgery, Children's Hospital, University of Helsinki, Helsinki, Finland ¶Department of Pediatric Gastroenterology, University Hospital Southampton, Southampton, UK #Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw, Warsaw, Poland **Department of Pediatrics, University Hospital Motol, Prague, Czech Republic ††Queen Mary's Hospital for Children, Epsom and St Helier NHS Trust, Surrey ‡‡Chelsea and Westminster Hospital, London, UK §§Paris-Diderot Sorbonne-Paris-Cité University and Robert Debré Hospital, Paris, France ||||Pediatric Gastroenterology and Hepatology, Dr. von Hauner Children's Hospital, Ludwig Maximilians-University, Munich, Germany ¶¶St George's, University of London, London, UK ##Boston Children's Hospital and Harvard Medical School, Boston, MA ***Department NEUROFARBA, University of Florence - Meyer Hospital, Florence, Italy †††Unit for the Comprehensive Care of Pediatric Inflammatory Bowel Disease, Hospital Sant Joan de Déu, Barcelona, Spain ‡‡‡Department of Pediatric Gastroenterology, Necker Enfants Malades University Hospital, Sorbonne Paris Cité University, Paris Descartes University, Institut IMAGINE - INSERM U1163, Paris, France §§§Pediatric Gastroenterology Institute, Ruth Children's Hospital, Rambam Medical Center, Haifa, Israel ||||||Department of Pediatric Gastroenterology, Bristol Royal Hospital for Children, Bristol, UK ¶¶¶Department of Translational Medical Science, Section of Pediatrics, University of Naples "Federico II," Naples, Italy ###Department of Pediatric Surgery, Leeds Children's Hospital, Leeds General Infirmary, Leeds, UK ****Child Life and Health, University of Edinburgh, Scotland, UK ††††MassGeneral Hospital for Children, Harvard Medical School, Boston, MA ‡‡‡‡Children's Hospital, University of Helsinki, Helsinki, Finland. ·J Pediatr Gastroenterol Nutr · Pubmed #28267075.

ABSTRACT: The incidence of Crohn disease (CD) has been increasing and surgery needs to be contemplated in a substantial number of cases. The relevant advent of biological treatment has changed but not eliminated the need for surgery in many patients. Despite previous publications on the indications for surgery in CD, there was a need for a comprehensive review of existing evidence on the role of elective surgery and options in pediatric patients affected with CD. We present an expert opinion and critical review of the literature to provide evidence-based guidance to manage these patients. Indications, surgical options, risk factors, and medications in pre- and perioperative period are reviewed in the light of available evidence. Risks and benefits of surgical options are addressed. An algorithm is proposed for the management of postsurgery monitoring, timing for follow-up endoscopy, and treatment options.

2 Guideline ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. 2014

Levine, Arie / Koletzko, Sibylle / Turner, Dan / Escher, Johanna C / Cucchiara, Salvatore / de Ridder, Lissy / Kolho, Kaija-Leena / Veres, Gabor / Russell, Richard K / Paerregaard, Anders / Buderus, Stephan / Greer, Mary-Louise C / Dias, Jorge A / Veereman-Wauters, Gigi / Lionetti, Paolo / Sladek, Malgorzata / Martin de Carpi, Javier / Staiano, Annamaria / Ruemmele, Frank M / Wilson, David C / Anonymous3320775. ·*Pediatric Gastroenterology and Nutrition Unit, Wolfson Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel †Dr von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany ‡Pediatric Gastroenterology Unit, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Israel §Pediatric Gastroenterology, Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands ||Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Italy ¶Children's Hospital, University of Helsinki, Helsinki, Finland #Semmelweis University, Budapest, Hungary **Department of Paediatric Gastroenterology and Nutrition, Yorkhill Children's Hospital, Glasgow, UK ††Department of Paediatrics, Hvidovre University Hospital, Copenhagen, Denmark ‡‡St.-Marien-Hospital, Department of Pediatrics, Bonn, Germany §§Department of Diagnostic Imaging, The Hospital for Sick Children ||||Department of Medical Imaging, University of Toronto, Toronto Canada ¶¶Hospital S. João, Porto, Portugal ##Pediatric Gastroenterology and Nutrition, UZ Brussels, Brussels, Belgium ***Departement Neurofarba, University of Florence, Meyer Children Hospital, Florence, Italy †††Department of Pediatrics, Gastroenterology and Nutrition, Jagiellonian University Medical College, Cracow, Poland ‡‡‡Department of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital Sant Joan de Déu, Barcelona, Spain §§§Department of Translational Medical Sciences, Section of Pediatrics, University of Naples "Federico II," Naples, Italy ||||||Université Sorbonne Paris Cité, Université Paris Descartes, INSERM U989, AP-HP, Hôpital Necker Enfants Malades, Service de Gastroentérologie Pédiatrique, Paris, France ¶¶¶Child Life and Health, University of Edinburgh, Edinburgh, UK. ·J Pediatr Gastroenterol Nutr · Pubmed #24231644.

ABSTRACT: BACKGROUND: The diagnosis of pediatric-onset inflammatory bowel disease (PIBD) can be challenging in choosing the most informative diagnostic tests and correctly classifying PIBD into its different subtypes. Recent advances in our understanding of the natural history and phenotype of PIBD, increasing availability of serological and fecal biomarkers, and the emergence of novel endoscopic and imaging technologies taken together have made the previous Porto criteria for the diagnosis of PIBD obsolete. METHODS: We aimed to revise the original Porto criteria using an evidence-based approach and consensus process to yield specific practice recommendations for the diagnosis of PIBD. These revised criteria are based on the Paris classification of PIBD and the original Porto criteria while incorporating novel data, such as for serum and fecal biomarkers. A consensus of at least 80% of participants was achieved for all recommendations and the summary algorithm. RESULTS: The revised criteria depart from existing criteria by defining 2 categories of ulcerative colitis (UC, typical and atypical); atypical phenotypes of UC should be treated as UC. A novel approach based on multiple criteria for diagnosing IBD-unclassified (IBD-U) is proposed. Specifically, these revised criteria recommend upper gastrointestinal endoscopy and ileocolonscopy for all suspected patients with PIBD, with small bowel imaging (unless typical UC after endoscopy and histology) by magnetic resonance enterography or wireless capsule endoscopy. CONCLUSIONS: These revised Porto criteria for the diagnosis of PIBD have been developed to meet present challenges and developments in PIBD and provide up-to-date guidelines for the definition and diagnosis of the IBD spectrum.

3 Editorial Top-down in the Long Term in Crohn's Disease. 2018

Boyapati, R K / Ho, G T / Satsangi, J. ·Department of Gastroenterology, Monash Health, and Department of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia. · MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, and Department of Gastroenterology, Western General Hospital, Edinburgh, UK. · College of Medicine & Veterinary Medicine, University of Edinburgh, and Department of Clinical Medicine, University of Oxford, Oxford, UK. ·J Crohns Colitis · Pubmed #29548025.

ABSTRACT: -- No abstract --

4 Editorial Editorial: the influence of genetic factors in mediating the effects of tobacco smoke in IBD. 2018

Adams, A / Kalla, R / Satsangi, J. ·Institute of Genetics and Molecular Medicine, University of Edinburgh School of Molecular Genetic and Population Sciences, Edinburgh, UK. · Department of Gastroenterology, Bolton NHS Foundation Trust, Bolton, UK. ·Aliment Pharmacol Ther · Pubmed #29265462.

ABSTRACT: -- No abstract --

5 Editorial Can Thiopurines Prevent Formation of Antibodies Against Tumor Necrosis Factor Antagonists After Failure of These Therapies? 2017

Boyapati, Ray K / Ho, Gwo-Tzer / Satsangi, Jack. ·MRC Centre for Inflammation Research, Queens Medical Research Institute, Edinburgh, United Kingdom; Department of Gastroenterology, Monash Health, Melbourne, Australia. · MRC Centre for Inflammation Research, Queens Medical Research Institute, Edinburgh, United Kingdom; Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom. · Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom. ·Clin Gastroenterol Hepatol · Pubmed #27720912.

ABSTRACT: -- No abstract --

6 Review Overview of paediatric IBD. 2017

Wilson, David C / Russell, Richard K. ·Child Life and Health, University of Edinburgh, Edinburgh EH9 1UW, Scotland, UK; Royal Hospital for Sick Children, Edinburgh, Scotland, UK. Electronic address: d.c.wilson@ed.ac.uk. · Department of Paediatric Gastroenterology, Royal Hospital for Children, Glasgow, Scotland, UK. ·Semin Pediatr Surg · Pubmed #29126501.

ABSTRACT: Inflammatory bowel disease (IBD) is a chronic complex disease of children and adults requiring a range of medications and surgical techniques to induce and maintain remission. In common with other immune-mediated inflammatory disorders, it has shown an ever-increasing rise in incidence worldwide over the last 50 years. The cause of IBD arises from interactions between the microbiome in the gut and the gastrointestinal and systemic immune system in genetically susceptible persons, and with environmental triggers to both develop IBD and have relapses of IBD. The burden of IBD in children and adolescents can be high, and treatment needs a multi-disciplinary approach aiming to abolish symptoms, promote growth and development, and support a restriction-free life. Achieving healing of the intestinal mucosa promotes long-term remission and helps to avoid disease complications.

7 Review The Disease Burden and Clinical Characteristics of Inflammatory Bowel Disease in the Chinese Population: A Systematic Review and Meta-Analysis. 2017

Li, Xue / Song, Peige / Li, Jun / Tao, Yuchang / Li, Guowei / Li, Xiumin / Yu, Zengli. ·School of Public Health, Xinxiang Medical University, Xinxiang 453003, China. xue.li@ed.ac.uk. · Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK. xue.li@ed.ac.uk. · School of Public Health, Xinxiang Medical University, Xinxiang 453003, China. p.song@sms.ed.ac.uk. · Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK. p.song@sms.ed.ac.uk. · The 153 Hospital of People's Liberation Army, Zhengzhou 450001, China. shuaidexue@126.com. · School of Public Health, Xinxiang Medical University, Xinxiang 453003, China. yuyuzaijia@163.com. · Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, ON L8S 4L8, Canada. lig28@mcmaster.ca. · Department Gastroenterology, the First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, China. lxm3029981@126.com. · School of Public Health, Xinxiang Medical University, Xinxiang 453003, China. yuzengli@outlook.com. ·Int J Environ Res Public Health · Pubmed #28264519.

ABSTRACT: The temporal trend of inflammatory bowel disease (IBD) incidence is reported to be increasing in worldwide regions; however, reports focusing on China are sparse. The aim of this study was to provide an overview of the disease burden and clinical features of IBD in the Chinese population. We searched Medline, EMBASE, and another two Chinese databases. A parallel literature review and data extraction were conducted. Meta-analysis was performed to estimate the summary incidence rate of Crohn's disease (CD) and ulcerative colitis (UC). The constituent ratios with 95% CI were calculated for clinical phenotypes and classifications. The literature review included 47 publications. The summary incidence rate of IBD was 1.74 (95% CI: 1.08; 2.40) per 100,000 person years, and the corresponding incidence rates of CD and UC were 0.40 (95% CI: 0.23; 0.57) and 1.18 (95% CI: 0.81; 1.56) per 100,000 person years, respectively. The sex distribution analysis indicated a male predominance in both CD (sex ratio: 1.64; 95% CI: 1.47-1.84) and UC (sex ratio: 1.29; 95% CI: 1.21-1.38). The clinical characteristics were summarized using data from 2283 CD cases and 17,958 UC cases; in which the majority of CD patients were diagnosed between 17-40 years of age, with non-stricturing and non-penetrating disease, varied disease locations, and less extra-intestinal manifestation. UC cases were featured with later disease diagnosis, a more severe disease course, more segmental lesions, and less extra-intestinal manifestations. Our study provided an estimated disease burden of IBD and demonstrated distinct clinical features in the Chinese population. Large-scale population-based studies are needed to further evaluate these findings.

8 Review Inflammatory Bowel Disease Drugs: A Focus on Autophagy. 2017

Hooper, Kirsty M / Barlow, Peter G / Stevens, Craig / Henderson, Paul. ·School of Life, Sport & Social Sciences, Edinburgh Napier University, Edinburgh, UK. · Child Life and Health, University of Edinburgh, Edinburgh, UK. · Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK. ·J Crohns Colitis · Pubmed #27381462.

ABSTRACT: Inflammatory bowel disease [IBD] is characterized by chronic inflammation of the gastrointestinal tract. Medications such as corticosteroids, thiopurines, immunomodulators and biologic agents are used to induce and maintain remission; however, response to these drugs is variable and can diminish over time. Defective autophagy has been strongly linked to IBD pathogenesis, with evidence showing that enhancing autophagy may be therapeutically beneficial by regulating inflammation and clearing intestinal pathogens. It is plausible that the therapeutic effects of some IBD drugs are mediated in part through modulation of the autophagy pathway, with studies investigating a wide range of diseases and cell types demonstrating autophagy pathway regulation by these agents. This review will highlight the current evidence, both in vitro and in vivo, for the modulation of autophagy by drugs routinely used in IBD. A clearer understanding of their mechanisms of action will be invaluable to utilize these drugs in a more targeted and personalized manner in this diverse and often complex group of patients.

9 Review Systematic Review of Effects of Withdrawal of Immunomodulators or Biologic Agents From Patients With Inflammatory Bowel Disease. 2015

Torres, Joana / Boyapati, Ray K / Kennedy, Nicholas A / Louis, Edouard / Colombel, Jean-Frédéric / Satsangi, Jack. ·Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: joana.torres@mssm.edu. · Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland. Electronic address: ray.boyapati@ed.ac.uk. · Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland. · Department of Gastroenterology, University Hospital CHU of Liège, Liège, Belgium. · Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York. ·Gastroenterology · Pubmed #26381892.

ABSTRACT: Little is known about the optimal duration of therapy with an anti-tumor necrosis factor (TNF) agent and/or an immunomodulator for patients with inflammatory bowel disease (IBD). We performed a systematic search of the literature to identify studies reporting after de-escalation (drug cessation or dose reduction) of anti-TNF agents and/or immunomodulators in patients in remission from IBD. Studies were reviewed according to the type of IBD and drug. Rates of relapse, factors associated with relapse, and response to re-treatment were determined. Our search yielded 6315 unique citations; we analyzed findings from 69 studies (18 on de-escalation [drug cessation or dose reduction] of immunomodulator monotherapy, 8 on immunomodulator de-escalation from combination therapy, and 43 on de-escalation of anti-TNF agents, including 3 during pregnancy) comprising 4672 patients. Stopping immunomodulator monotherapy after a period of remission was associated with high rates of relapse in patients with Crohn's disease or ulcerative colitis (approximately 75% of patients experienced a relapse within 5 years after therapy was stopped). Most studies of patients with Crohn's disease who discontinued an immunomodulator after combination therapy found that rates of relapse did not differ from those of patients who continued taking the drug (55%-60% had disease relapse 24 months after they stopped taking the immunomodulator). The only study in patients with ulcerative colitis supported continued immunomodulator use. Approximately 50% of patients who discontinued anti-TNF agents after combination therapy maintained remission 24 months later, but the proportion in remission decreased with time. Markers of disease activity, poor prognostic factors, and complicated or relapsing disease course were associated with future relapse. In conclusion, based on a systematic review, 50% or more of patients with IBD who cease therapy have a disease relapse. Further studies are required to accurately identify subgroups of patients who are good candidates for discontinuation of treatment. The decision to withdraw a drug should be made for each individual based on patient preference, disease markers, consequences of relapse, safety, and cost.

10 Review Systematic review with meta-analysis: endoscopic balloon dilatation for Crohn's disease strictures. 2015

Morar, P S / Faiz, O / Warusavitarne, J / Brown, S / Cohen, R / Hind, D / Abercrombie, J / Ragunath, K / Sanders, D S / Arnott, I / Wilson, G / Bloom, S / Arebi, N / Anonymous2040842. ·Department of Surgery and Cancer, Imperial College, London, UK. · St Mark's Hospital, London, UK. · Sheffield Teaching Hospitals, Sheffield, UK. · University College Hospital, London, UK. · Clinical Trials Research Unit, University of Sheffield, Sheffield, UK. · NIHR Nottingham Digestive Disease Biomedical Research Unit, Queen's Medical Centre Campus, Nottingham University Hospitals NHS Trust, Nottingham, UK. · Departments of Gastroenterology and Colorectal Surgery, Western General Hospital, Edinburgh, UK. ·Aliment Pharmacol Ther · Pubmed #26358739.

ABSTRACT: BACKGROUND: Endoscopic balloon dilatation (EBD) is recognised treatment for symptomatic Crohn's strictures. Several case series report its efficacy. A systematic analysis for overall efficacy can inform the design of future studies. AIM: To examine symptomatic (SR) and technical response (TR) and adverse events (AE) of EBD. Stricture characteristics were also explored. METHODS: A systematic search strategy of COCHRANE, MEDLINE and EMBASE was performed. All original studies reporting outcomes of EBD for Crohn's strictures were included. SR was defined as obstructive symptom-free outcome at the end of follow-up, TR as post-dilatation passage of the endoscope through a stricture, and adverse event as the presence of complication (perforation and/or bleeding). Pooled event rates across studies were expressed with summative statistics. RESULTS: Twenty-five studies included 1089 patients and 2664 dilatations. Pooled event rates for SR, TR, complications and perforations were 70.2% (95% CI: 60-78.8%), 90.6% (95% CI: 87.8-92.8%), 6.4% (95% CI: 5.0-8.2) and 3% (95% CI: 2.2-4.0%) respectively. Cumulative surgery rate at 5 year follow-up was 75%. Pooled unweighted TR, SR, complication, perforation and surgery rates were 84%, 45%, 15%, 9% and 21% for de novo and 84%, 58%, 22%, 5% and 32% for anastomotic strictures. Outcomes between two stricture types were no different on subgroup meta-analysis. CONCLUSIONS: Efficacy and complication rates for endoscopic balloon dilatation were higher than previously reported. From the few studies with 5 year follow-up the majority required surgery. Future studies are needed to determine whether endoscopic balloon dilatation has significant long-term benefits.

11 Review Crohn's disease. 2014

Kalla, Rahul / Ventham, Nicholas T / Satsangi, Jack / Arnott, Ian D R. ·Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh EH4 2XU, UK. · Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh EH4 2XU, UK ian.arnott@nhslothian.scot.nhs.uk. ·BMJ · Pubmed #25409896.

ABSTRACT: -- No abstract --

12 Review The diagnostic approach to monogenic very early onset inflammatory bowel disease. 2014

Uhlig, Holm H / Schwerd, Tobias / Koletzko, Sibylle / Shah, Neil / Kammermeier, Jochen / Elkadri, Abdul / Ouahed, Jodie / Wilson, David C / Travis, Simon P / Turner, Dan / Klein, Christoph / Snapper, Scott B / Muise, Aleixo M / Anonymous291012. ·Translational Gastroenterology Unit, University of Oxford, Oxford, England; Department of Pediatrics, University of Oxford, Oxford, England. Electronic address: holm.uhlig@ndm.ox.ac.uk. · Translational Gastroenterology Unit, University of Oxford, Oxford, England. · Dr von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany. · Great Ormond Street Hospital London, London, England; Catholic University, Leuven, Belgium. · Great Ormond Street Hospital London, London, England. · SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. · Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts; Division of Gastroenterology and Hepatology, Brigham & Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts. · Child Life and Health, University of Edinburgh, Edinburgh, Scotland; Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Royal Hospital for Sick Children, Edinburgh, Scotland. · Pediatric Gastroenterology Unit, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel. ·Gastroenterology · Pubmed #25058236.

ABSTRACT: Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel disease (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histological features of Crohn's disease, ulcerative colitis, or IBD unclassified. Defects in interleukin-10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histological and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extraintestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. In addition, we provide approaches for identifying patients likely to have these disorders. We also discuss classic approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects.

13 Review Systematic review: The use of thiopurines or anti-TNF in post-operative Crohn's disease maintenance--progress and prospects. 2014

Jones, G R / Kennedy, N A / Lees, C W / Arnott, I D / Satsangi, J. ·Department of Gastroenterology, Western General Hospital, Edinburgh, UK. ·Aliment Pharmacol Ther · Pubmed #24738574.

ABSTRACT: BACKGROUND: Post-operative recurrence of Crohn's disease is an important management challenge, with 2-year recurrence rates defined by clinical, endoscopic and radiological parameters of up to 77%, 64% and 49%. Clinical and severe endoscopic recurrence vary widely in controlled trials from 13% to 36% and 22% to 56% with thiopurine treatment or 0% and 9% with infliximab treatment respectively at 1 year. AIMS: To provide a review of the evidence for thiopurine or anti-TNF use in post-operative Crohn's disease, and to assess the ability to identify those patients at highest risk of recurrent disease. METHODS: A literature search was undertaken using Medline, Embase and Cochrane databases to identify studies using search terms 'thiopurine', 'azathioprine', 'mercaptopurine', 'Infliximab', 'adalimumab', 'Anti-TNF', 'Crohn's disease', 'post-operative' and 'recurrence'. RESULTS: Trials to examine this important area have proved difficult to execute, with recruitment and retention of patients posing major challenges to randomised clinical trials. There have been four RCTs of 433 patients of thiopurine therapy (with three meta-analyses of these data), and one of anti-TNF therapy involving 24 patients. Overall the efficacy data for thiopurine use in this setting are inconclusive, and other than smoking, there are no consistent predictors of post-operative relapse. CONCLUSIONS: At present, evidence for routine use of thiopurine treatment in post-operative Crohn's disease is heterogeneous and unconvincing. Stratification by risk of relapse emerges as a key challenge in post-operative management that needs to be addressed, using clinical parameters and emerging biomarkers. The evidence for prophylactic anti-TNF use is limited though promising, with its routine use guided by early assessment of relapse.

14 Review A trial of mercaptopurine is a safe strategy in patients with inflammatory bowel disease intolerant to azathioprine: an observational study, systematic review and meta-analysis. 2013

Kennedy, N A / Rhatigan, E / Arnott, I D R / Noble, C L / Shand, A G / Satsangi, J / Lees, C W. ·Gastrointestinal Unit, Western General Hospital, Edinburgh, UK; Gastrointestinal research, Centre for molecular medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK. ·Aliment Pharmacol Ther · Pubmed #24117596.

ABSTRACT: BACKGROUND: Thiopurines maintain remission and modify disease course in inflammatory bowel disease. Use is limited by intolerance and subsequent drug withdrawal in approximately 17% of patients treated with azathioprine. Previous case series have addressed the success rates of re-treatment with mercaptopurine in these individuals. AIMS: To determine the rate of tolerance when trialling mercaptopurine in azathioprine-intolerant patients and the factors predictive of success, and to perform a systematic review and meta-analysis of these data with other published data sets. METHODS: A retrospective observational study of 149 patients with IBD (82 with Crohn's disease and 67 with ulcerative colitis) previously intolerant of azathioprine subsequently treated with mercaptopurine was performed. A meta-analysis was undertaken of all published studies of mercaptopurine use in azathioprine-intolerant patients (455 patients in 11 included studies). RESULTS: Mercaptopurine was tolerated by 58% of azathioprine-intolerant patients in the Edinburgh cohort. In the meta-analysis, 68% tolerated mercaptopurine. A higher proportion of those in the meta-analysis with GI toxicity (62%) or hepatotoxicity (81%) were able to tolerate mercaptopurine than those with flu-like illness (36%). Among those patients who ceased mercaptopurine for further adverse effects, 59% experienced the same adverse effect as they had with azathioprine. CONCLUSIONS: This meta-analysis shows that switching to mercaptopurine is a safe therapeutic strategy for over two-thirds of azathioprine-intolerant patients and may help optimise immunomodulatory therapy in inflammatory bowel disease. A trial of mercaptopurine should be attempted in IBD patients (except those with acute pancreatitis or bone marrow aplasia) before considering thiopurine intolerance.

15 Review Beyond gene discovery in inflammatory bowel disease: the emerging role of epigenetics. 2013

Ventham, Nicholas T / Kennedy, Nicholas A / Nimmo, Elaine R / Satsangi, Jack. ·Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland. nventham@staffmail.ed.ac.uk ·Gastroenterology · Pubmed #23751777.

ABSTRACT: In the past decade, there have been fundamental advances in our understanding of genetic factors that contribute to the inflammatory bowel diseases (IBDs) Crohn's disease and ulcerative colitis. The latest international collaborative studies have brought the number of IBD susceptibility gene loci to 163. However, genetic factors account for only a portion of overall disease variance, indicating a need to better explore gene-environment interactions in the development of IBD. Epigenetic factors can mediate interactions between the environment and the genome; their study could provide new insight into the pathogenesis of IBD. We review recent progress in identification of genetic factors associated with IBD and discuss epigenetic mechanisms that could affect development and progression of IBD.

16 Review New IBD genetics: common pathways with other diseases. 2011

Lees, C W / Barrett, J C / Parkes, M / Satsangi, J. ·Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Edinburgh, UK. charlie.lees@ed.ac.uk ·Gut · Pubmed #21300624.

ABSTRACT: Complex disease genetics has been revolutionised in recent years by the advent of genome-wide association (GWA) studies. The chronic inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis have seen notable successes culminating in the discovery of 99 published susceptibility loci/genes (71 Crohn's disease; 47 ulcerative colitis) to date. Approximately one-third of loci described confer susceptibility to both Crohn's disease and ulcerative colitis. Amongst these are multiple genes involved in IL23/Th17 signalling (IL23R, IL12B, JAK2, TYK2 and STAT3), IL10, IL1R2, REL, CARD9, NKX2.3, ICOSLG, PRDM1, SMAD3 and ORMDL3. The evolving genetic architecture of IBD has furthered our understanding of disease pathogenesis. For Crohn's disease, defective processing of intracellular bacteria has become a central theme, following gene discoveries in autophagy and innate immunity (associations with NOD2, IRGM, ATG16L1 are specific to Crohn's disease). Genetic evidence has also demonstrated the importance of barrier function to the development of ulcerative colitis (HNF4A, LAMB1, CDH1 and GNA12). However, when the data are analysed in more detail, deeper themes emerge including the shared susceptibility seen with other diseases. Many immune-mediated diseases overlap in this respect, paralleling the reported epidemiological evidence. However, in several cases the reported shared susceptibility appears at odds with the clinical picture. Examples include both type 1 and type 2 diabetes mellitus. In this review we will detail the presently available data on the genetic overlap between IBD and other diseases. The discussion will be informed by the epidemiological data in the published literature and the implications for pathogenesis and therapy will be outlined. This arena will move forwards very quickly in the next few years. Ultimately, we anticipate that these genetic insights will transform the landscape of common complex diseases such as IBD.

17 Review Genetics of inflammatory bowel disease: implications for disease pathogenesis and natural history. 2009

Lees, Charlie W / Satsangi, Jack. ·Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK. charlie.lees@ed.ac.uk ·Expert Rev Gastroenterol Hepatol · Pubmed #19817673.

ABSTRACT: Epidemiological data, detailed molecular studies and recent genome-wide association studies strongly suggest that ulcerative colitis (UC) and Crohn's disease (CD) are related polygenic diseases that share some susceptibility loci, but differ at others. To date, there are more than 50 confirmed inflammatory bowel disease genes/loci, a number that is widely anticipated to at least double in the next 2 years. Germline variation in IL23R, IL12B, JAK2 and STAT3 is associated with inflammatory bowel disease susceptibility, consistent with the newly described role for IL23 signaling and Th17 cells in disease pathogenesis. Several genes involved in different aspects of bacterial handling are defective only in CD, including NOD2 and the autophagy genes ATG16L1 and IRGM. IL10 and ECM1 are associated with UC, while inherited variation at the HLA region is related to an inflammatory colonic phenotype. The application of genome-wide association studies to inflammatory bowel disease has been successful in defining the genetic architecture of CD and UC and in delivering genuinely novel and important insights into disease pathogenesis. This has unearthed a plethora of attractive targets for the development of future therapeutics. Insights into the natural history of these complex diseases will follow and may enable appropriate patient selection for early aggressive therapy with the view to modifying the disease course.

18 Review Gene discovery in IBD: a decade of progress. 2008

Satsangi, Jack. ·Edinburgh University, Edinburgh, UK. ·J Pediatr Gastroenterol Nutr · Pubmed #18354311.

ABSTRACT: -- No abstract --

19 Article Case of steroid-resistant Crohn's-associated bronchiolitis in the setting of quiescent gastrointestinal disease treated with infliximab. 2018

Chuah, Cher Shiong / Noble, Colin / Leitch, Andrew. ·Department of Gastroenterology, Western General Hospital, Edinburgh, UK. · Department of Respiratory Medicine, Western General Hospital, Edinburgh, UK. ·BMJ Case Rep · Pubmed #30567117.

ABSTRACT: A fit, 36-year-old man with a history of Crohn's disease previously treated with azathioprine, presented acutely with progressive shortness of breath on exertion and pleuritic chest pain. At the time of presentation, his Crohn's disease was quiescent, supported by a normal faecal calprotectin. The initial chest CT suggested the presence of a diffuse inflammatory disorder and he was subsequently started on high dose oral steroids. Despite 4 months of steroid therapy, there was minimal improvement. Following discussion at the inflammatory bowel disease multidisciplinary team meeting, a decision was made to commence infliximab. Subsequently, he made a dramatic clinical and physiological recovery. His forced expiratory volume in 1 s improved from 2.22 L/min (50% predicted) to 3.65 L/min (93% predicted) and he returned to baseline levels of exercise.

20 Article Promoter methylation of the 2018

Klasić, Marija / Markulin, Dora / Vojta, Aleksandar / Samaržija, Ivana / Biruš, Ivan / Dobrinić, Paula / Ventham, Nicholas T / Trbojević-Akmačić, Irena / Šimurina, Mirna / Štambuk, Jerko / Razdorov, Genadij / Kennedy, Nicholas A / Satsangi, Jack / Dias, Ana M / Pinho, Salome / Annese, Vito / Latiano, Anna / D'Inca, Renata / Anonymous1901202 / Lauc, Gordan / Zoldoš, Vlatka. ·1Department of Biology, Division of Molecular Biology, Faculty of Science, University of Zagreb, Horvatovac 102a, 10000 Zagreb, Croatia. · 2Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 6XU UK. · Genos Glycoscience Research Laboratory, Borongajska cesta 83h, 10000 Zagreb, Croatia. · 5IBD Pharmacogenetics, University of Exeter, Exeter, UK. · 10Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK. · 6Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal. · 7Department of Medical and Surgical Sciences, Division of Gastroenterology, University Hospital Careggi, Florence, Italy. · Department of Medical Sciences, Division of Gastroenterology, IRCCS-CSS Hospital, Viale Cappuccini, Rotondo, Italy. · 9Gastrointestinal Unit, University of Padua, Padua, Italy. · 4Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia. ·Clin Epigenetics · Pubmed #29991969.

ABSTRACT: Background: Many genome- and epigenome-wide association studies (GWAS and EWAS) and studies of promoter methylation of candidate genes for inflammatory bowel disease (IBD) have demonstrated significant associations between genetic and epigenetic changes and IBD. Independent GWA studies have identified genetic variants in the Methods: Using bisulfite pyrosequencing, we analyzed CpG methylation in promoter regions of these five genes from peripheral blood of several hundred IBD patients and healthy controls (HCs) from two independent cohorts, respectively. Results: We found significant differences in the methylation levels in the Conclusions: Our results suggest that epigenetic deregulation of key glycosylation genes might lead to an increase in pro-inflammatory properties of IgG in IBD through a decrease in galactosylation and sialylation and an increase of bisecting GlcNAc on digalactosylated glycan structures. Finally, we showed that CpG methylation in the promoter of the

21 Article IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes. 2018

Momozawa, Yukihide / Dmitrieva, Julia / Théâtre, Emilie / Deffontaine, Valérie / Rahmouni, Souad / Charloteaux, Benoît / Crins, François / Docampo, Elisa / Elansary, Mahmoud / Gori, Ann-Stephan / Lecut, Christelle / Mariman, Rob / Mni, Myriam / Oury, Cécile / Altukhov, Ilya / Alexeev, Dmitry / Aulchenko, Yuri / Amininejad, Leila / Bouma, Gerd / Hoentjen, Frank / Löwenberg, Mark / Oldenburg, Bas / Pierik, Marieke J / Vander Meulen-de Jong, Andrea E / Janneke van der Woude, C / Visschedijk, Marijn C / Anonymous9331104 / Lathrop, Mark / Hugot, Jean-Pierre / Weersma, Rinse K / De Vos, Martine / Franchimont, Denis / Vermeire, Severine / Kubo, Michiaki / Louis, Edouard / Georges, Michel. ·Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 1 Avenue de l'Hôpital, Liège, 4000, Belgium. · Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Science, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan. · Laboratory of Thrombosis and Hemostasis, GIGA-R, University of Liège (B34), 1 Avenue de l'Hôpital, 4000, Liège, Belgium. · Moscow Institute of Physics and Technology, Institutskiy Pereulok 9, Dolgoprudny, 141700, Russian Federation. · Novosibirsk State University, Pirogova ave. 2, Novosibirsk, 630090, Russian Federation. · PolyOmica, Het Vlaggeschip 61, 's-Hertogenbosch, 5237 PA, The Netherlands. · Institute of Cytology and Genetics SD RAS, Lavrentyeva ave. 10, 630090, Novosibirsk, Russia. · Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UK. · Gastroentérologie Médicale, Faculté de Médicine, Université Libre de Bruxelles, Route de Lennik 808, Anderlecht, 1070, Belgium. · Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, 1081 HV, The Netherlands. · Department of Gastroenterology and Hepatology, University Medical Centre St. Radboud, Nijmegen, 6525 GA, The Netherlands. · Department of Gastroenterology and Hepatology, Amsterdam Medical Centre, Amsterdam, 1105 AZ, The Netherlands. · Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, 3584 cX, Utrecht, The Netherlands. · Department of Gastroenterology and Hepatology, University Medical Centre Maastricht, Maastricht, 6229 HX, The Netherlands. · Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, 2333 ZA, The Netherlands. · Department of Gastroenterology and Hepatology, Erasmus Medical Centre, Rotterdam, 3015 CE, The Netherlands. · Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Hanzeplein 1, Groningen, 9713 GZ, The Netherlands. · McGill University Centre for Molecular and Computational Genomics, 740 Dr. Penfield Avenue, Montreal, H3A 0G1, QC, Canada. · UMR 1149 INSERM/Université Paris-Diderot Sorbonne Paris-Cité, Assistance Publique Hôpitaux de Paris, 48 Bd Sérurier, Paris, 75019, France. · Department of Gastroenterology, University Hospital, De Pintelaan 185, Gent, 9000, Belgium. · Translational Research in Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, UZ Herestraat 49, Leuven, 3000, Belgium. · CHU-Liège and Unit of Gastroenterology, GIGA-R & Faculty of Medicine, University of Liège, 1 Avenue de l'Hôpital, Liège, 4000, Belgium. · Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 1 Avenue de l'Hôpital, Liège, 4000, Belgium. michel.georges@ulg.ac.be. ·Nat Commun · Pubmed #29930244.

ABSTRACT: GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.

22 Article The Frequency of Clinic Visits Was Not Associated with Medication Adherence or Outcome in Children with Inflammatory Bowel Diseases. 2018

Kluthe, Cheryl / Tsui, Jenkin / Spady, Donald / Carroll, Matthew / Wine, Eytan / Huynh, Hien Quoc. ·Edmonton Pediatric IBD Clinic (EPIC), Edmonton, AB, Canada. · University of Edinburgh, Edinburgh, UK. · Division of Pediatric GI Nutrition, Stollery Children's Hospital, University of Alberta, Edmonton, AB, Canada. ·Can J Gastroenterol Hepatol · Pubmed #29682493.

ABSTRACT: Background: Medication nonadherence is a challenge in pediatric patients with inflammatory bowel diseases (IBD). Poor adherence can result in disease flare-ups, disease complicationstherapy escalation, and the need for corticosteroids. The aim was to determine if clinic visit frequency was associated with treatment adherence. Methods: A retrospective chart review of patients attending the Edmonton Pediatric IBD Clinic (EPIC) at the Stollery Children's Hospital from January 2012 to December 2013 was completed. Correlations were made between frequency of clinic visit, percentage of prescriptions filled, percentage of requisitioned blood work completed, rural or urban residence, and steroid-free remission status of patients for the 6 months after the chart review. Results: 127 patients were reviewed with 82 patients diagnosed with Crohn's disease (CD) and 46 with ulcerative colitis (UC) which included one IBD-Unclassified. Mean age at diagnosis is 9.17 years and median duration of follow-up is 3.2 years. Almost all patients on infliximab infusions received them "within window." Immunomodulator median adherence rate was 88%. 5-ASA adherence was 82%. A median of 67% of patients had blood work completed as requested. Clinic visit frequency was not associated with adherence to blood work or to medications. Duration of disease was the only independent factor found to be associated with a reduction in blood work and immunomodulator adherence ("OR 0.86 and 95% CI: 0.74-0.99" and "OR 0.82 and 95% CI: 0.71-0.97") per year, respectively. Patients who remained corticosteroid-free in the 6 months after the 2 years' adherence review had an overall median medication adherence rate of 86% compared to only 53% for those who relapsed and required corticosteroids ( Conclusion: Clinic visit frequency was not associated with patient adherence to medications or blood work. However, disease duration was found to be associated with medication adherence. Adherent patients were more likely to remain in steroid-free remission.

23 Article Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease. 2018

Baillie, J Kenneth / Bretherick, Andrew / Haley, Christopher S / Clohisey, Sara / Gray, Alan / Neyton, Lucile P A / Barrett, Jeffrey / Stahl, Eli A / Tenesa, Albert / Andersson, Robin / Brown, J Ben / Faulkner, Geoffrey J / Lizio, Marina / Schaefer, Ulf / Daub, Carsten / Itoh, Masayoshi / Kondo, Naoto / Lassmann, Timo / Kawai, Jun / Anonymous6311104 / Mole, Damian / Bajic, Vladimir B / Heutink, Peter / Rehli, Michael / Kawaji, Hideya / Sandelin, Albin / Suzuki, Harukazu / Satsangi, Jack / Wells, Christine A / Hacohen, Nir / Freeman, Thomas C / Hayashizaki, Yoshihide / Carninci, Piero / Forrest, Alistair R R / Hume, David A. ·Division of Genetics and Genomics, The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom. · Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom. · Intensive Care Unit, Royal Infirmary Edinburgh, Edinburgh, United Kingdom. · Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom. · Edinburgh Parallel Computing Centre, The University of Edinburgh, Edinburgh, United Kingdom. · Statistical Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom. · Center for Statistical Genetics, Icahn School of Medicine at Mount Sinai, New York, United States of America. · The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark. · Department of Statistics, University of California, Berkeley, United States of America. · Mater Research Institute, University of Queensland, University of Queensland, Brisbane, Australia. · RIKEN Omics Science Center, Yokohama, Japan, Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Japan. · Department for Infectious Disease Informatics, Public Health England, Colindale, United Kingdom. · RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Japan. · King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center, Thuwal, Kingdom of Saudi Arabia. · German Center for Neurodegenerative Diseases, Tübingen, Germany. · Dept. Hematology, University Hospital Regensburg, Regensburg, Germany. · Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, Brisbane Australia. · Broad Institute of Harvard and MIT, Cambridge, United States of America. · Harry Perkins Institute of Medical Research, and the Centre for Medical Research, University of Western Australia, QEII Medical Centre, Nedlands, Perth, Western Australia, Australia. ·PLoS Comput Biol · Pubmed #29494619.

ABSTRACT: Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA). For most traits studied, phenotype-associated variants in regulatory regions were linked to tightly-coexpressed networks that are likely to share important functional characteristics. Coexpression provides a new signal, independent of phenotype association, to enable fine mapping of causative variants. The NDA coexpression approach identifies new genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn's disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely to respond differently to pharmacological therapy. Together, these findings enable a deeper biological understanding of the causal basis of complex traits.

24 Article The Impact of NOD2 Variants on Fecal Microbiota in Crohn's Disease and Controls Without Gastrointestinal Disease. 2018

Kennedy, Nicholas A / Lamb, Christopher A / Berry, Susan H / Walker, Alan W / Mansfield, John / Parkes, Miles / Simpkins, Rachel / Tremelling, Mark / Nutland, Sarah / Anonymous2911168 / Parkhill, Julian / Probert, Chris / Hold, Georgina L / Lees, Charlie W. ·GI Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. · IBD Pharmacogenetics Group, University of Exeter, UK. · Institute of Cellular Medicine, Newcastle University, UK. · Gastrointestinal Research Group, University of Aberdeen, Aberdeen, UK. · Pathogen Genomics Group, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK. · Microbiology Group, The Rowett Institute, University of Aberdeen, Aberdeen, UK. · Dept of Gastroenterology, Royal Victoria Infirmary, Newcastle, UK. · Dept of Gastroenterology, Addenbrookes Hospital, Cambridge, UK. · Cambridge BioResource, Cambridge. · Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, UK. · Institute of Translational Medicine, University of Liverpool, UK. ·Inflamm Bowel Dis · Pubmed #29462388.

ABSTRACT: Background/Aims: Current models of Crohn's disease (CD) describe an inappropriate immune response to gut microbiota in genetically susceptible individuals. NOD2 variants are strongly associated with development of CD, and NOD2 is part of the innate immune response to bacteria. This study aimed to identify differences in fecal microbiota in CD patients and non-IBD controls stratified by NOD2 genotype. Methods: Patients with CD and non-IBD controls of known NOD2 genotype were identified from patients in previous UK IBD genetics studies and the Cambridge bioresource (genotyped/phenotyped volunteers). Individuals with known CD-associated NOD2 mutations were matched to those with wild-type genotype. We obtained fecal samples from patients in clinical remission with low fecal calprotectin (<250 µg/g) and controls without gastrointestinal disease. After extracting DNA, the V1-2 region of 16S rRNA genes were polymerase chain reaction (PCR)-amplified and sequenced. Analysis was undertaken using the mothur package. Volatile organic compounds (VOC) were also measured. Results: Ninety-one individuals were in the primary analysis (37 CD, 30 bioresource controls, and 24 household controls). Comparing CD with nonIBD controls, there were reductions in bacterial diversity, Ruminococcaceae, Rikenellaceae, and Christensenellaceae and an increase in Enterobacteriaceae. No significant differences could be identified in microbiota by NOD2 genotype, but fecal butanoic acid was higher in Crohn's patients carrying NOD2 mutations. Conclusions: In this well-controlled study of NOD2 genotype and fecal microbiota, we identified no significant genotype-microbiota associations. This suggests that the changes associated with NOD2 genotype might only be seen at the mucosal level, or that environmental factors and prior inflammation are the predominant determinant of the observed dysbiosis in gut microbiota.

25 Article Differentiation of Inflammatory From Fibrotic Ileal Strictures among Patients with Crohn's Disease Based on Visual Analysis: Feasibility Study Combining Conventional B-Mode Ultrasound, Contrast-Enhanced Ultrasound and Strain Elastography. 2018

Quaia, Emilio / Gennari, Antonio Giulio / Cova, Maria Assunta / van Beek, Edwin J R. ·Edinburgh Imaging Facility, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, United Kingdom. Electronic address: equaia@exseed.ed.ac.uk. · Department of Radiology, Cattinara Hospital, University of Trieste, Trieste, Italy. · Edinburgh Imaging Facility, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, United Kingdom. ·Ultrasound Med Biol · Pubmed #29331357.

ABSTRACT: The aim of this pilot study was to assess prospectively the feasibility of conventional B-mode ultrasound (US) and contrast-enhanced ultrasound (CEUS) combined with real-time strain elastography (SE) in the differentiation of inflammatory from fibrotic ileal strictures among patients with Crohn's disease (CD) based on visual analysis. Twenty non-consecutive patients (15 male and 5 female; mean age ± standard deviation, 40.2 ± 10.22 y) with CD and stricture of the terminal ileal loop were scanned by conventional B-mode US and CEUS and, subsequently, by real-time SE. Two independent readers visually classified each bowel stricture as fibrotic or inflammatory based on conventional B-mode US, CEUS, SE, individually and then for all techniques combined. All techniques combined had a higher (p <0.05) sensitivity (reader 1, 9/20 [45%]; reader 2, 7/20 [35%]), specificity (reader 1, 5/20 [25%]; reader 2, 8/20 [40%]) and diagnostic accuracy (reader 1, 14/20 [70%]; reader 2, 15/20 [75%]) and higher (p <0.05) area under the receiver operating characteristic curve (reader 1, 0.953; reader 2, 0.921) than individual techniques. Inter-reader agreement was fair for conventional B-mode US (k = 0.46) and CEUS (k = 0.39), moderate for SE (k = 0.6) and fair for all techniques combined (k = 0.38). Conventional B-mode US and CEUS, in combination with SE, may improve differentiation of inflammatory from fibrotic ileal strictures among patients with CD based on visual analysis.