Derek Jewell

Publications of Derek Jewell

• Association of a Functional Variant in the Wnt Co-Receptor LRP6 with Early Onset Ileal Crohn's Disease.

  Authors: Maureen J Koslowski, Zora Teltschik, Julia Beisner, Elke Schaeffeler, Guoxing Wang, Irmgard Kübler, Michael Gersemann, Rachel Cooney, Derek Jewell, Walter Reinisch, Séverine Vermeire, Paul Rutgeerts, Matthias Schwab, Eduard F Stange, Jan Wehkamp

  PLoS genetics. 02/2012; 8(2):e1002523.

  Ileal Crohn's Disease (CD), a chronic small intestinal inflammatory disorder, is characterized by reduced levels of the antimicrobial peptides DEFA5 (HD-5) and DEFA6 (HD-6). Both of these α-defensinsIleal Crohn's Disease (CD), a chronic small intestinal inflammatory disorder, is characterized by reduced levels of the antimicrobial peptides DEFA5 (HD-5) and DEFA6 (HD-6). Both of these α-defensins are exclusively produced in Paneth cells (PCs) at small intestinal crypt bases. Different ileal CD-associated genes including NOD2, ATG16L1, and recently the β-catenin-dependant Wnt transcription factor TCF7L2 have been linked to impaired PC antimicrobial function. The Wnt pathway influences gut mucosal homeostasis and PC maturation, besides directly controlling HD-5/6 gene expression. The herein reported candidate gene study focuses on another crucial Wnt factor, the co-receptor low density lipoprotein receptor-related protein 6 (LRP6). We analysed exonic single nucleotide polymorphisms (SNPs) in a large cohort (Oxford: n = 1,893) and prospectively tested 2 additional European sample sets (Leuven: n = 688, Vienna: n = 1,628). We revealed an association of a non-synonymous SNP (rs2302685; Ile1062Val) with early onset ileal CD (OR 1.8; p = 0.00034; for homozygous carriers: OR 4.1; p = 0.00004) and additionally with penetrating ileal CD behaviour (OR 1.3; p = 0.00917). In contrast, it was not linked to adult onset ileal CD, colonic CD, or ulcerative colitis. Since the rare variant is known to impair LRP6 activity, we investigated its role in patient mucosa. Overall, LRP6 mRNA was diminished in patients independently from the genotype. Analysing the mRNA levels of PC product in biopsies from genotyped individuals (15 controls, 32 ileal, and 12 exclusively colonic CD), we found particularly low defensin levels in ileal CD patients who were carrying the variant. In addition, we confirmed a direct relationship between LRP6 activity and the transcriptional expression of HD-5 using transient transfection. Taken together, we identified LRP6 as a new candidate gene in ileal CD. Impairments in Wnt signalling and Paneth cell biology seem to represent pathophysiological hallmarks in small intestinal inflammation and should therefore be considered as interesting targets for new therapeutic approaches.

• Managing the long term care of inflammatory bowel disease patients: The cost to European health care providers.

  Authors: James Buchanan, Sarah Wordsworth, Tariq Ahmad, Angela Perrin, Severine Vermeire, Miquel Sans, Jenny Taylor, Derek Jewell

  Journal of Crohn's & colitis. 09/2011; 5(4):301-16.

  Inflammatory Bowel Disease (which includes Crohn's Disease and Ulcerative Colitis), is a chronic condition characterised by substantial morbidity. Inflammatory Bowel Disease patients are consideredInflammatory Bowel Disease (which includes Crohn's Disease and Ulcerative Colitis), is a chronic condition characterised by substantial morbidity. Inflammatory Bowel Disease patients are considered expensive to manage, hence accurate estimates of care costs are crucial to help healthcare providers plan clinical management. The aim of this study is to estimate the cost of care for Crohn's Disease and Ulcerative Colitis patients in the United Kingdom and Western mainland Europe. Decision models were built to simulate the natural disease history of Crohn's Disease and Ulcerative Colitis, informed by United Kingdom and European clinical pathways. A healthcare provider perspective was adopted, model inputs were informed by published sources and expert opinion, and UK healthcare costs were used (2008 prices). Cohorts of 25 year old patients presenting with symptoms of varying severity were modelled over ten years, and annual treatment costs calculated per patient. The average annual cost of care per Crohn's Disease/Ulcerative Colitis patient was £631/£762 (United Kingdom) and £838/£796 (Europe). Most costs were incurred immediately following diagnosis, particularly in European Crohn's patients, reflecting the earlier use of more aggressive treatments. Surgery, hospitalisation, and the use of biological therapies and mesalazine (in Ulcerative Colitis) were key cost drivers. The total annual cost to the United Kingdom National Health Service of caring for Inflammatory Bowel Disease patients was estimated to be £131million. This study confirms that Inflammatory Bowel Disease patients are expensive to manage and illustrates the importance of differentiating between alternative clinical management scenarios.

• Functional consequences of mutations in the autophagy genes in the pathogenesis of Crohn's disease.

  Authors: Oliver Brain, Rachel Cooney, Alison Simmons, Derek Jewell

  Inflammatory bowel diseases. 08/2011;

  Genome-wide association studies have highlighted a number of genes involved in autophagy, which are of potential importance in the pathogenesis of Crohn's disease (CD). The associated polymorphismsGenome-wide association studies have highlighted a number of genes involved in autophagy, which are of potential importance in the pathogenesis of Crohn's disease (CD). The associated polymorphisms in ATG16L1 and IRGM have been confirmed, and functional studies have begun to shed light on how they link to CD pathogenesis. In this review we consider the most salient aspects of this rapidly expanding field. (Inflamm Bowel Dis 2011;).

• NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation.

  Authors: Rachel Cooney, John Baker, Oliver Brain, Benedicte Danis, Tica Pichulik, Philip Allan, David J P Ferguson, Barry J Campbell, Derek Jewell, Alison Simmons

  Nature medicine. 12/2009;

  Nucleotide-binding oligomerization domain-containing-2 (NOD2) acts as a bacterial sensor in dendritic cells (DCs), but it is not clear how bacterial recognition links with antigen presentation afterNucleotide-binding oligomerization domain-containing-2 (NOD2) acts as a bacterial sensor in dendritic cells (DCs), but it is not clear how bacterial recognition links with antigen presentation after NOD2 stimulation. NOD2 variants are associated with Crohn's disease, where breakdown in self-recognition of commensal bacteria leads to gastrointestinal inflammation. Here we show NOD2 triggering by muramyldipeptide induces autophagy in DCs. This effect requires receptor-interacting serine-threonine kinase-2 (RIPK-2), autophagy-related protein-5 (ATG5), ATG7 and ATG16L1 but not NLR family, pyrin domain containing-3 (NALP3).We show that NOD2-mediated autophagy is required for both bacterial handling and generation of major histocompatibility complex (MHC) class II antigen-specific CD4(+) T cell responses in DCs. DCs from individuals with Crohn's disease expressing Crohn's disease-associated NOD2 or ATG16L1 risk variants are defective in autophagy induction, bacterial trafficking and antigen presentation. Our findings link two Crohn's disease-associated susceptibility genes in a single functional pathway and reveal defects in this pathway in Crohn's disease DCs that could lead to bacterial persistence via impaired lysosomal destruction and immune mediated clearance.

• Contribution of histological, serological, and genetic factors to the clinical heterogeneity of adult-onset coeliac disease.

  Authors: Harry Thomas, Tariq Ahmad, Chandima Rajaguru, Martin Barnardo, Bryan Warren, Derek Jewell

  Scandinavian journal of gastroenterology. 07/2009;

  Objective. Although the factors predisposing to coeliac disease (CD) are largely understood, it remains unclear what determines the clinical heterogeneity of the disease. The aim of this study was toObjective. Although the factors predisposing to coeliac disease (CD) are largely understood, it remains unclear what determines the clinical heterogeneity of the disease. The aim of this study was to explore the contribution of histological, serological, and genetic factors to disease presentation. Material and methods. The study was designed as a retrospective chart review of 384 unrelated Caucasian patients diagnosed with CD after the age of 16 at a single UK centre. Results. We found that 8.8% of IgA-competent CD patients were endomysial antibody (EMA)-negative. Compared with the EMA-positive group, EMA-negative CD patients had a lower prevalence of iron deficiency (52.0% versus 72.6%, p=0.03) and Marsh IIIb-c lesions (66.7% versus 85.3%, p=0.03). Histological severity at diagnosis correlated with anaemia (p<0.01), folate deficiency (p<0.01), and iron deficiency (p=0.05), but no other laboratory or clinical features. Compared with human leucocyte antigen (HLA)-DQ2.5-positive patients, those carrying HLA-DQ2.2 were similar in terms of all the characteristics we considered, whereas those carrying HLA-DQ8 had a lower frequency of EMA positivity (62.5% versus 92.6%, p<0.01). The proportion of EMA-positive patients increased with frequency of the HLA-DQB1*0201 allele (76.7% versus 92.3% versus 96.4% for 0 versus 1 versus 2 alleles, p<0.01); no other evidence of a gene-dose effect of HLA-DQB1*0201 was observed. Conclusions. Histological severity at diagnosis of CD is associated with anaemia and some micronutrient deficiencies, but no other clinical features. The proportion of EMA-positive patients is higher amongst those carrying HLA-DQ2 than in those carrying HLA-DQ8, and is highest in HLA-DQ2 homozygotes. We found no correlation between frequency of the HLA-DQ alleles encoding HLA-DQ2.5 and CD severity.

• Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn's disease.

  Authors: Maureen J Koslowski, Irmgard Kübler, Mathias Chamaillard, Elke Schaeffeler, Walter Reinisch, Guoxing Wang, Julia Beisner, Alexander Teml, Laurent Peyrin-Biroulet, Stefan Winter, Klaus R Herrlinger, Paul Rutgeerts, Séverine Vermeire, Rachel Cooney, Klaus Fellermann, Derek Jewell, Charles L Bevins, Matthias Schwab, Eduard F Stange, Jan Wehkamp

  PLoS ONE. 02/2009; 4(2):e4496.

  Reduced expression of Paneth cell antimicrobial alpha-defensins, human defensin (HD)-5 and -6, characterizes Crohn's disease (CD) of the ileum. TCF-4 (also named TCF7L2), a Wnt signalling pathwayReduced expression of Paneth cell antimicrobial alpha-defensins, human defensin (HD)-5 and -6, characterizes Crohn's disease (CD) of the ileum. TCF-4 (also named TCF7L2), a Wnt signalling pathway transcription factor, orchestrates Paneth cell differentiation, directly regulates the expression of HD-5 and -6, and was previously associated with the decrease of these antimicrobial peptides in a subset of ileal CD. To investigate a potential genetic association of TCF-4 with ileal CD, we sequenced 2.1 kb of the 5' flanking region of TCF-4 in a small group of ileal CD patients and controls (n = 10 each). We identified eight single nucleotide polymorphisms (SNPs), of which three (rs3814570, rs10885394, rs10885395) were in linkage disequilibrium and found more frequently in patients; one (rs3814570) was thereby located in a predicted regulatory region. We carried out high-throughput analysis of this SNP in three cohorts of inflammatory bowel disease (IBD) patients and controls. Overall 1399 healthy individuals, 785 ulcerative colitis (UC) patients, 225 CD patients with colonic disease only and 784 CD patients with ileal involvement were used to determine frequency distributions. We found an association of rs3814570 with ileal CD but neither with colonic CD or UC, in a combined analysis (allele positivity: OR 1.27, 95% CI 1.07 to 1.52, p = 0.00737), which was the strongest in ileal CD patients with stricturing behaviour (allele frequency: OR 1.32, 95% CI 1.08 to1.62, p = 0.00686) or an additional involvement of the upper GIT (allele frequency: OR 1.38, 95% CI 1.03 to1.84, p = 0.02882). The newly identified genetic association of TCF-4 with ileal CD provides evidence that the decrease in Paneth cell alpha-defensins is a primary factor in disease pathogenesis.

• The genetic basis of inflammatory bowel disease.

  Authors: Rachel Cooney, Derek Jewell

  Digestive diseases (Basel, Switzerland). 01/2009; 27(4):428-42.

  Twin studies and large-scale population studies have confirmed an increased sibling risk for both Crohn's disease (CD) and ulcerative colitis (UC). Unlike single gene disorders, CD and UC are thoughtTwin studies and large-scale population studies have confirmed an increased sibling risk for both Crohn's disease (CD) and ulcerative colitis (UC). Unlike single gene disorders, CD and UC are thought to result from a complex interplay of multiple genes and environmental factors. The confirmation of CARD15/NOD2 as a CD susceptibility gene in the late 1990s caused much excitement in the field of complex diseases in general and since then, the rapid rate of progress in molecular genetics, with the advent of large-scale affordable genotyping techniques, has resulted in large collaborations and the identification of over 30 inflammatory bowel disease (IBD)-associated genes. In particular, the importance of the innate immune system has been reaffirmed with the identification of IRGM and ATG16L1 genes in the autophagy pathway as CD susceptibility genes. Disturbance in the adaptive immune system, in particular the IL-23/Th17 axis, has also shown to be of importance for IBD overall. In this era of genome-wide association studies it may be possible to, at last, identify the multiple genes involved in IBD and thus improve our understanding of the genotype-phenotype correlation and improve treatment.

• Clinical and molecular characteristics of isolated colonic Crohn's disease.

  Authors: Laura Hancock, John Beckly, Alessandra Geremia, Rachel Cooney, Fraser Cummings, Saad Pathan, Changun Guo, Bryan F Warren, Neil Mortensen, Tariq Ahmad, Derek Jewell

  Inflammatory bowel diseases. 12/2008; 14(12):1667-77.

  Clinical, serological, and molecular data support the existence of discrete subsets of Crohn's disease (CD) defined by location of disease. Little is known about the epidemiology and natural historyClinical, serological, and molecular data support the existence of discrete subsets of Crohn's disease (CD) defined by location of disease. Little is known about the epidemiology and natural history of isolated CD of the colon (Montreal Classification L2) because most studies have not accurately distinguished it from ileocolonic disease. Our objectives were to describe the clinical features and natural history of isolated colonic CD in a rigorously characterized patient cohort and to investigate the association of polymorphisms in a number of genes with colonic location of disease and disease behavior. Patients with L2 disease were identified from a database of 675 CD patients. Only patients with a normal small bowel enema (70%), ileoscopy alone (30%), or both (20%) were included. Genotyping was performed using PCR-SSP or the iPLEX platform. In all, 135 patients were classified with L2 disease. L2 disease was more common in women (74.0% versus 58.0%; P = 0.0004; odds ratio [OR] = 2.11, 95% confidence interval [CI] 1.36-3.26) and in never smokers (48.9% versus 36.9%; P = 0.008; OR = 1.64, 95% CI 1.09-2.45); 20.7% underwent colonic resection for severe disease. We confirmed that carriage of the HLA-DRB1*0103 allele is strongly associated with isolated colonic CD (14.9% versus 4.0%; P = 0.000016; OR 4.6, 95% CI 2.25-9.47) and report the novel association of this allele with time to first surgical event (log rank P = 0.001). There was no association with any of the known CD susceptibility loci (NOD2, IBD5, NOD1, IL23R, ATG16L1) and isolated colonic CD. A nonsynonymous polymorphism in MEKK1 (rs832582) was associated with CD susceptibility overall (15% versus 19%; P = 0.0083; OR = 1.28, 95% CI 1.07-1.54). The association was strongest in those patients not carrying a NOD2 mutation and had no effect on disease location. This study describes the clinical features of isolated colonic CD and demonstrates the importance of the HLA region in determining the molecular basis of colonic inflammation.

• Do HLA antigens predict the occurrence of extraintestinal manifestations of IBD?

  Authors: Derek Jewell

  Inflammatory bowel diseases. 10/2008; 14(S2):S28.

• Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease.

  Authors: Jeffrey C Barrett, Sarah Hansoul, Dan L Nicolae, Judy H Cho, Richard H Duerr, John D Rioux, Steven R Brant, Mark S Silverberg, Kent D Taylor, M Michael Barmada [......] Rhian Gwilliam, Mark Tremelling, Panos Deloukas, John Mansfield, Derek Jewell, Jack Satsangi, Christopher G Mathew, Miles Parkes, Michel Georges, Mark J Daly

  Nature genetics. 07/2008;

  Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (aSeveral risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development.

• Cancer in patients with ulcerative colitis, Crohn's disease and coeliac disease: record linkage study.

  Authors: Michael J Goldacre, Clare J Wotton, David Yeates, Valerie Seagroatt, Derek Jewell

  European journal of gastroenterology & hepatology. 05/2008; 20(4):297-304.

  OBJECTIVE: The objective of this study was to determine the risk of cancers in cohorts of patients with ulcerative colitis, Crohn's disease, or coeliac disease, compared with the risk in a controlOBJECTIVE: The objective of this study was to determine the risk of cancers in cohorts of patients with ulcerative colitis, Crohn's disease, or coeliac disease, compared with the risk in a control cohort. METHOD: The method used was the analysis of a linked statistical database of hospital and mortality data in an area in southern England. RESULTS: Rate ratios for cancer (excluding cases occurring within the first year of follow-up), compared with the value of 1 in the control cohort, were 1.25 [95% confidence interval (CI), 1.13-1.39] in patients with ulcerative colitis, 1.27 (95% CI, 1.11-1.45) with Crohn's disease, and 1.16 (95% CI, 0.94-1.43) with coeliac disease. In patients with ulcerative colitis or Crohn's disease, there was a significantly high risk of cancer of the colon [2.22 (95% CI, 1.71-2.83) and 1.64 (95% CI, 1.09-2.39), respectively]. In patients with ulcerative colitis there was a significantly high risk of cancer of the rectum [1.84 (95% CI, 1.27-2.58)]. In patients with ulcerative colitis or Crohn's disease, who did not undergo partial or total colectomy for it, the rate ratios for colon cancer were, respectively, 5.52 (95% CI, 4.39-6.71) and 4.81 (95% CI, 3.52-6.47). In ulcerative colitis, there was an elevated risk of cancer of the rectum, liver and ovary. The rate ratio for lung cancer was low, but of borderline significance [0.72 (95% CI, 0.50-0.98)]. In Crohn's disease, the rate ratio was high for cancer of the cervix [2.63 (95% CI, 1.12-5.29)]. In patients with coeliac disease, the high-risk cancer was non-Hodgkin's lymphoma [rate ratio 3.28 (95% CI, 1.49-6.28)]. CONCLUSION: All three diseases carry an increased risk of cancer overall when the first year cases are included, though fairly modest in scale, and the increased risk seen in coeliac disease reduces when first year cases are excluded. Each has a distinctive pattern of individual high-risk cancers.

• Inflammatory Bowel Disease by Saad Pathan and Derek Jewell in Genomics And Clinical Medicine edited by D. J. Weatherall and Dhavendra Kumar

  Authors: Saad Pathan, Derek Jewell

  01/2008: pages 329;

• A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21.

  Authors: David A van Heel, Lude Franke, Karen A Hunt, Rhian Gwilliam, Alexandra Zhernakova, Mike Inouye, Martin C Wapenaar, Martin C N M Barnardo, Graeme Bethel, Geoffrey K T Holmes [......] Jill Swift, Raymond J Playford, William M McLaren, M Luisa Mearin, Chris J Mulder, Ross McManus, Ralph McGinnis, Lon R Cardon, Panos Deloukas, Cisca Wijmenga

  Nature genetics. 08/2007; 39(7):827-9.

  We tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 x 10(-7)) was in theWe tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 x 10(-7)) was in the KIAA1109-TENR-IL2-IL21 linkage disequilibrium block. We independently confirmed association in two further collections (strongest association at rs6822844, 24 kb 5' of IL21; meta-analysis P = 1.3 x 10(-14), odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease.

• IL23R variation determines susceptibility but not disease phenotype in inflammatory bowel disease.

  Authors: Mark Tremelling, Fraser Cummings, Sheila A Fisher, John Mansfield, Rhian Gwilliam, Andrew Keniry, Elaine R Nimmo, Hazel Drummond, Clive M Onnie, Natalie J Prescott [......] Francesca Bredin, Carlo Berzuini, Alastair Forbes, Cathryn M Lewis, Lon Cardon, Panos Deloukas, Derek Jewell, Christopher G Mathew, Miles Parkes, Jack Satsangi

  Gastroenterology. 06/2007; 132(5):1657-64.

  BACKGROUND & AIMS: Identification of inflammatory bowel disease (IBD) susceptibility genes is key to understanding pathogenic mechanisms. Recently, the North American IBD Genetics Consortium providedBACKGROUND & AIMS: Identification of inflammatory bowel disease (IBD) susceptibility genes is key to understanding pathogenic mechanisms. Recently, the North American IBD Genetics Consortium provided compelling evidence for an association between ileal Crohn's disease (CD) and the IL23R gene using genome-wide association scanning. External replication is a priority, both to confirm this finding in other populations and to validate this new technique. We tested for association between IL23R and IBD in a large independent UK panel to determine the size of the effect and explore subphenotype correlation and interaction with CARD15. METHODS: Eight single nucleotide polymorphism markers in IL23R tested in the North American study were genotyped in 1902 cases of Crohn's disease (CD), 975 cases of ulcerative colitis (UC), and 1345 controls using MassARRAY. Data were analyzed using chi(2) statistics, and subgroup association was sought. RESULTS: A highly significant association with CD was observed, with the strongest signal at coding variant Arg381Gln (allele frequency, 2.5% in CD vs 6.2% in controls [P = 1.1 x 10(-12)]; odds ratio, 0.38; 95% confidence interval, 0.29-0.50). A weaker effect was seen in UC (allele frequency, 4.6%; odds ratio, 0.73; 95% confidence interval, 0.55-0.96). Analysis accounting for Arg381Gln suggested that other loci within IL23R also influence IBD susceptibility. Within CD, there were no subphenotype associations or evidence of interaction with CARD15. CONCLUSIONS: This study shows an association between IL23R and all subphenotypes of CD with a smaller effect on UC. This extends the findings of the North American study, providing clear evidence that genome-wide association scanning can successfully identify true complex disease genes.

• Genetics of inflammatory bowel disease: the role of the HLA complex.

  Authors: Tariq Ahmad, Sara E Marshall, Derek Jewell

  World journal of gastroenterology : WJG. 07/2006; 12(23):3628-35.

  The human leucocyte antigen (HLA) complex on chromosome 6p21.3 is the most extensively studied genetic region in Inflammatory bowel disease (IBD). Consistent evidence of linkage to IBD3 (6p21.1-23),The human leucocyte antigen (HLA) complex on chromosome 6p21.3 is the most extensively studied genetic region in Inflammatory bowel disease (IBD). Consistent evidence of linkage to IBD3 (6p21.1-23), an area which encompasses the HLA complex, has been demonstrated for both Crohn's disease and ulcerative colitis, and a number of replicated associations with disease susceptibility and phenotype have recently emerged. However, despite these efforts the HLA susceptibility gene (s) for IBD remain elusive, a consequence of strong linkage disequilibrium, extensive polymorphism and high gene density across this region. This article reviews current knowledge of the role of HLA complex genes in IBD susceptibility and phenotype, and discusses the factors currently limiting the translation of this knowledge to clinical practice.

• Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease.

  Authors: Keiko Yamazaki, Dermot McGovern, Jiannis Ragoussis, Marta Paolucci, Helen Butler, Derek Jewell, Lon Cardon, Masakazu Takazoe, Torao Tanaka, Toshiki Ichimori, Susumu Saito, Akihiro Sekine, Aritoshi Iida, Atsushi Takahashi, Tatsuhiko Tsunoda, Mark Lathrop, Yusuke Nakamura

  Human molecular genetics. 12/2005; 14(22):3499-506.

  The inflammatory bowel diseases (IBDs), Crohn's disease (CD) and ulcerative colitis, are chronic inflammatory disorders of the digestive tract. The pathogenesis of IBD is complicated, and it isThe inflammatory bowel diseases (IBDs), Crohn's disease (CD) and ulcerative colitis, are chronic inflammatory disorders of the digestive tract. The pathogenesis of IBD is complicated, and it is widely accepted that immunologic, environmental and genetic components contribute to its etiology. To identify genetic susceptibility factors in CD, we performed a genome-wide association study in Japanese patients and controls using nearly 80,000 gene-based single nucleotide polymorphism (SNP) markers and investigated the haplotype structure of the candidate locus in Japanese and European patients. We identified highly significant associations (P = 1.71 x 10(-14) with odds ratio of 2.17) of SNPs and haplotypes within the TNFSF15 (the gene encoding tumor necrosis factor superfamily, member 15) genes in Japanese CD patients. The association was confirmed in the study of two European IBD cohorts. Interestingly, a core TNFSF15 haplotype showing association with increased risk to the disease was common in the two ethnic groups. Our results suggest that the genetic variations in the TNFSF15 gene contribute to the susceptibility to IBD in the Japanese and European populations.

• Ciclosporin use in acute ulcerative colitis: a long-term experience.

  Authors: Simon Campbell, Simon Travis, Derek Jewell

  European journal of gastroenterology & hepatology. 01/2005; 17(1):79-84.

  BACKGROUND: Within a lifetime, approximately 15% of ulcerative colitis (UC) patients will have a severe relapse necessitating admission to hospital. Despite intravenous steroid treatment,BACKGROUND: Within a lifetime, approximately 15% of ulcerative colitis (UC) patients will have a severe relapse necessitating admission to hospital. Despite intravenous steroid treatment, approximately 25% will require either surgery or ciclosporin (CsA) rescue therapy. Initial response rates to CsA have been encouraging, but remission rates have been disappointing. There is a paucity of long-term data on UC patients who have been brought into remission with CsA. OBJECTIVES: To report our 7 year experience on the use of CsA in acute UC and to highlight long-term follow-up data on these patients. PATIENTS AND METHODS: A retrospective database of 76 UC patients requiring CsA between 1996 and 2003 was constructed. CsA was started on the basis of their C-reactive protein (CRP) and/or stool frequency after 3 days or after 5-7 days of i.v. hydrocortisone. The patients (33 female, 43 male, mean age 44.5 years) were followed up for a median 2.9 years (range 0.2-7.0 years). Fifty-four patients received i.v. CsA (4 mg/kg), while 22 received oral CsA (5 mg/kg). Long-term outcome was evaluated by Kaplan-Meier survival analysis: time to first relapse and time to surgery. RESULTS: Median disease duration was 6.6 years. Median CRP and stool frequency at day 3 was 20 mg/l and 6 per day, respectively. Fifty-six patients (74%) achieved initial remission. CsA was discontinued in only four patients due to side effects. Duration of i.v. steroids or the addition of AZA did not improve time to first relapse or time to surgery. Comparison between i.v. CsA and oral CsA revealed a statistically significant difference in time to first relapse (P < 0.01) and time to surgery (P < 0.05) in favour of oral CsA. CONCLUSIONS: These data describe the long-term outcome of the largest series of patients so far reported that have had treatment with CsA for severe refractory UC. If patients achieved initial remission with CsA, after 1 year, 65% had relapsed and after 3 years 90% had relapsed. After 7 years, 58% had come to colectomy. Minor side effects were frequent, but none were life threatening. There was no increase in post-operative complications in those who came to colectomy.

• Clinical relevance of advances in genetics and pharmacogenetics of IBD.

  Authors: Tariq Ahmad, Cyrus Pesi Tamboli, Derek Jewell, Jean-Frédéric Colombel

  Gastroenterology. 06/2004; 126(6):1533-49.

  Crohn's disease and ulcerative colitis result from an inappropriate response of the mucosal immune system to the normal enteric flora in a genetically susceptible individual. During the past decade,Crohn's disease and ulcerative colitis result from an inappropriate response of the mucosal immune system to the normal enteric flora in a genetically susceptible individual. During the past decade, exciting progress has been made in our understanding of the contribution of genetics to inflammatory bowel disease susceptibility and phenotype. This article reviews recent advances in the genetics of inflammatory bowel disease and explores how they might impact on clinical practice. Current knowledge of the genetic basis for disease susceptibility, phenotype, and response to therapy is explored and the factors currently limiting the translation of this knowledge to clinical practice is discussed.

• Genotype-based phenotyping heralds a new taxonomy for inflammatory bowel disease.

  Authors: T Ahmad, Sara Marshall, Derek Jewell

  Current opinion in gastroenterology. 08/2003; 19(4):327-35.

  Inflammatory bowel disease (IBD) has traditionally been categorized as either ulcerative colitis or Crohn disease on the basis of clinical, radiologic, and histologic criteria. Within these diseases,Inflammatory bowel disease (IBD) has traditionally been categorized as either ulcerative colitis or Crohn disease on the basis of clinical, radiologic, and histologic criteria. Within these diseases, however, significant heterogeneity is observed, suggesting the existence of phenotypic subtypes, based on features such as location and behavior of disease. Evidence for a possible genetic basis of these subgroups first emerged in the 1990s from epidemiologic studies in multiply affected families. Recent advances in our understanding of the genetics of IBD, in particular the identification of NOD2/CARD15, have provided the opportunity to explore the genetic basis for this heterogeneity. This article reviews recent studies investigating the contribution of genetics to IBD phenotype. Although many of the genes remain unidentified, the emerging data suggests that IBD comprises a heterogeneous family of oligogenic inflammatory disorders in which the specific clinical manifestations of disease in any individual are determined by the interaction of genetic and environmental factors. These data have validated the approach of classifying patients into accurately defined clinical subgroups, and they raise the possibility that a genetic basis for the observed disease heterogeneity may account for the discrepant findings from earlier genetic studies. A future molecular classification will provide the framework to understanding the different biologic mechanisms that underlie the clinical subgroups of IBD and, by patient stratification, permit the unraveling of the complex interaction between the genetic and environmental causes of disease.

• Management of acute severe colitis.

  Authors: Paul Dunckley, Derek Jewell

  Best practice & research. Clinical gastroenterology. 03/2003; 17(1):89-103.

  Early identification of patients with acute severe colitis is essential so that prompt treatment can be instigated. Corticosteroids have remained the mainstay of treatment since 1955. TheEarly identification of patients with acute severe colitis is essential so that prompt treatment can be instigated. Corticosteroids have remained the mainstay of treatment since 1955. The introduction of ciclosporin into the pharmacological armamentarium has reduced early colectomy rates but even with modern medical management up to 30% of patients will still undergo colectomy on the same admission. The overall mortality is now less than 1% in specialist centres compared to 30% in the pre-steroid era. The future promises further advances in treatment through medications that are targeted directly at the underlying inflammatory process.