Ulcerative Colitis: Satsangi J

Hare NC, Arnott ID, Satsangi J. · Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK. · Expert Rev Gastroenterol Hepatol. · Pubmed #19072385 No free full text.

Abstract: Ulcerative colitis is a relapsing-remitting inflammatory disease affecting the colon and is associated with considerable morbidity. In acute severe attacks, there continues to be an associated mortality rate of 1-2%, even in specialist units. During an acute severe exacerbation, approximately two-thirds of patients will respond to intravenous corticosteroid therapy, the accepted first-line therapy in such cases. For steroid-refractory patients, options are limited to surgery (colectomy) or second-line agents, such as ciclosporin or infliximab, used in an attempt to salvage the colon. Considerable debate exists over the optimal management of such patients. During the last decade, an increased understanding of the pathogenesis of inflammatory bowel disease has led to the rapid development of other biological agents, such as basiliximab and visilizumab. Novel methods, such as leucopheresis, have been studied and other established immunomodulatory agents, such as tacrolimus, have also been suggested. The purpose of this review is to highlight some of the areas of recent development in the treatment of acute severe ulcerative colitis and review important safety data, with a particular emphasis on biological agents.

Satsangi J. · Edinburgh University, Edinburgh, UK. · J Pediatr Gastroenterol Nutr. · Pubmed #18354311 No free full text.

This publication has no abstract.

Gaya DR, Russell RK, Nimmo ER, Satsangi J. · Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. · Lancet. · Pubmed #16631883 No free full text.

Abstract: The chronic inflammatory bowel diseases Crohn's disease and ulcerative colitis are common causes of gastrointestinal disease in northern Europe, affecting as many as one in 250 people. Although mortality is low, morbidity associated with these diseases is substantial. We review the recent advances in the genetics of inflammatory bowel disease, with particular emphasis on the data that have been generated since the discovery of the CARD15 (NOD2) gene in 2001.

Noble C, Nimmo E, Gaya D, Russell RK, Satsangi J. · Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, EH4 2XU, United Kindgom. · World J Gastroenterol. · Pubmed #16610046 links to  free full text

Abstract: The inflammatory bowel disease, Crohn's disease and ulcerative colitis, are polygenic disorders with important environmental interactions. To date, the most widely adopted approach to identifying susceptibility genes in complex diseases has involved genome wide linkage studies followed by studies of positional candidate genes in loci of interest. This review encompasses data from studies into novel candidate genes implicated in the pathogenesis of inflammatory bowel disease. Novel techniques to identify candidate genes-genome wide association studies, yeast-two hybrid screening, microarray gene expression studies and proteomic profiling, are also reviewed and their potential role in unravelling the pathogenesis of inflammatory bowel disease are discussed.

Russell RK, Satsangi J. · Department of Medical Sciences, Gastrointestinal Unit, University of Edinburgh, Edinburgh EH4 2XU, UK. · Best Pract Res Clin Gastroenterol. · Pubmed #15157825 No free full text.

Abstract: The recent molecular advances in the understanding of the genetics of inflammatory bowel disease (IBD) have their grounding in studies examining IBD within different family groups and populations. The risk of IBD is highest in first-degree relatives of an IBD proband but more distant relatives are also at increased risk. The risk is higher for relatives of a CD proband. The risks of developing IBD for 'high-risk' relatives might be as great as 1 in 3 but in general first-degree relatives have a 1 in 10-20 risk. Three recent systematic studies have identified a total of 326 European twin pairs to examine disease concordance rates. The derived heritability in Crohn's disease is greater than for many complex diseases and is currently under detailed examination. Strong concordance has been shown, in particular for disease type and disease location, in multiplex families and twin studies. More than 75% children are diagnosed with IBD at a younger age than their parents but true genetic anticipation appears unlikely.

Ho GT, Moodie FM, Satsangi J. · University Department of Medical Sciences, Western General Hospital, Edinburgh, UK. · Gut. · Pubmed #12692067 links to  free full text

Abstract: The interface between luminal contents and intestinal epithelium constitutes the largest area of interaction between the host and the environment. There is now strong evidence that the gene product of the multidrug resistant pump (MDR) plays a critical role in host-bacterial interactions in the gastrointestinal tract and maintenance of intestinal homeostasis. This review highlights the efflux mechanism in the intestinal epithelium which is mediated by the multidrug resistant pump, also known as P-glycoprotein 170. Current studies promise to provide further insights into the contribution of the MDR1 gene in the pathogenesis of inflammatory and malignant disorders of the gastrointestinal tract.

Satsangi J, Morecroft J, Shah NB, Nimmo E. · Gastrointestinal Unit, Western General Hospital, Edinburgh, EH4 2XU, UK. · Best Pract Res Clin Gastroenterol. · Pubmed #12617879 No free full text.

Abstract: Considerable progress has been made in the last decade in studies of the genetics of the inflammatory bowel diseases, Crohn's disease and ulcerative colitis. Epidemiological data, notably concordance rates in twin pairs and sibling pairs, have provided strong evidence for the importance of the genetic contribution, particularly in Crohn's disease. These observations provided the catalyst for laboratory-based studies of the molecular genetics of Crohn's disease and ulcerative colitis around the world. The complementary strategies of genome-wide scanning and candidate gene-directed studies have led to the identification of a number of genetic markers which appear to predict disease susceptibility and behaviour. The identification of the IBD1 gene on chromosome 16 as NOD-2 is unquestionably an important scientific discovery. Although many issues with respect to gene function and expression remain to be resolved there is great optimism that important clinical applications will directly result.

Watts DA, Satsangi J. · Gastrointestinal Unit, The University of Edinburgh, Western General Hospital, Edinburgh, UK. · Gut. · Pubmed #11953330 links to  free full text

Abstract: Following a prolonged period of relative inertia, real progress has been made in the past few years in understanding the pathogenesis of the chronic inflammatory bowel diseases, Crohn's disease and ulcerative colitis. Clinical experience, epidemiological studies, and molecular genetics have provided strong evidence that both genetic and environmental factors are important in disease pathogenesis, and gene-environmental interaction determines disease susceptibility and behaviour.

Satsangi J. · Western General Hospital, University of Edinburgh, UK. · Acta Odontol Scand. · Pubmed #11501890 No free full text.

Abstract: Epidemiological data, particularly concordance rates in twin pairs and in multiply affected families, provide strong evidence that both genetic and environmental influences are important in the development of the chronic intestinal inflammation characteristic of Crohn disease and ulcerative colitis. Furthermore, supplementary data now suggest that not only susceptibility, but also disease behavior and response to therapy may have a strong genetic influence. The model of disease susceptibility most pertinent to the inflammatory bowel diseases is that Crohn disease and ulcerative colitis are related polygenic disorders. Recently, this model has received strong support from the results of genome-wide scanning and candidate gene studies carried out in European, North American and Australian populations. In spite of all potential difficulties related to disease and ethnic heterogeneity, consistent replication of linkage has been found with distinct regions on chromosomes 16, 12, 6 (the major histocompatibility complex) and most recently chromosome 14. Whereas the linkages on chromosome 16 and 14 appear strongest in Crohn disease, the chromosome 12 locus appears most pertinent to ulcerative colitis, and the HLA region appears more pertinent in all forms of inflammatory bowel disease. The current challenge is to narrow these regions of linkage and identify the susceptibility genes within the regions. The task may be greatly benefited by the recent successful sequence data available from the human genome project. Compelling data have emerged to suggest genetic markers that may allow prediction of disease severity, and efficacy and tolerability of immuno-suppressants commonly used in inflammatory bowel disease.

Ahmad T, Satsangi J, McGovern D, Bunce M, Jewell DP. · Gastroenterology Unit, Radcliffe Infirmary, Oxford, UK. · Aliment Pharmacol Ther. · Pubmed #11380312 links to  free full text

Abstract: Recent epidemiological, clinical and molecular studies have provided strong evidence that inherited predisposition is important in the pathogenesis of chronic inflammatory bowel diseases. The model most consistent with the epidemiological data suggests that Crohn's disease and ulcerative colitis are related polygenic diseases, sharing some but not all susceptibility genes. Investigators throughout the world have applied the complementary techniques of genome-wide scanning and candidate gene analysis. Four areas of linkage have been widely replicated on chromosomes 16 (IBD1), 12 (IBD2), 6 (IBD3-the HLA region), and most recently on chromosome 14. Fine mapping of these regions is underway. Of the 'positional' candidate genes, most attention has centred on the genes of the major histocompatibility complex. Genes within this region may determine disease susceptibility, behaviour, complications and response to therapy. Hope continues that studies of inflammatory bowel disease genetics will provide fresh insight into disease pathogenesis and soon deliver clinical applications.

Jayaram H, Satsangi J, Chapman RW. · Gastroenterology Unit, Radcliffe Infirmary Oxford OX2 6HG, UK. · Gut. · Pubmed #11171838 links to  free full text

This publication has no abstract.

van Heel DA, Satsangi J, Carey AH, Jewell DP. · Wellcome Trust Centre for Human Genetics, University of Oxford, United Kingdom. · Can J Gastroenterol. · Pubmed #10758418 links to  free full text

Abstract: The pathogenesis of ulcerative colitis (UC) and Crohn's disease (CD) is still unknown, but the importance of genetic susceptibility has been clearly shown by epidemiological data from family and twin studies. Linkage studies have identified two susceptibility loci for inflammatory bowel disease (IBD) on chromosomes 12 and 16. Importantly, these linkages have been replicated by independent investigators, and studies of positional candidates within these regions continue, together with fine mapping strategies. Regions of 'suggestive' linkage on chromosomes 1, 3, 4, 6, 7, 10, 22 and X have also been reported in individual studies. Other important candidate genes investigated include the interleukin-1 receptor antagonist, MUC3 and genes of the human leukocyte antigen (HLA) system. The apparently conflicting data in different studies from around the world may be explained by ethnic differences, case mix and genetic heterogeneity. Replicated class II HLA associations include HLA DRB1*0103 and DR2 (DRB1*1502), involved in UC susceptibility, and HLA DRB1*03 and DR4 as resistance alleles for CD and UC respectively. Animal studies have provided insights from targeted mutations and quantitative trait locus analysis. The goals of continuing research include narrowing the regions of linkages and analysis of candidate genes, and possibly the application of newly developed methods using single nucleotide polymorphisms. Advances in IBD genetics hold the potential to provide knowledge about the disease pathogenesis at the molecular level, with ensuing benefits for clinical practice.

Noble CL, McCullough J, Ho W, Lees CW, Nimmo E, Drummond H, Bear S, Hannan J, Millar C, Ralston SH, Satsangi J. · Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK. · Aliment Pharmacol Ther. · Pubmed #18194505 No free full text.

Abstract: BACKGROUND: Osteoporosis is a recognized complication of inflammatory bowel disease (IBD). Aim To investigate the role of environmental factors and vitamin D receptor (VDR) variants on the prevalence of osteoporosis. METHODS: DEXA scans and case note review were performed on 440 IBD patients from 1997 to 2006. All the IBD patients and 240 healthy controls were genotyped for VDR variants Taq-1 and Apa-1 using PCR-RFLP. RESULTS: Osteoporosis and osteopenia rates were 15% and 18% for IBD, 16% and 18% for Crohn's disease (CD) and 13% and 19% for ulcerative colitis, respectively. On univariate analysis of the CD patients, low body mass index (BMI, <18.5) and smoking status (P = 0.008 and 0.005 respectively) were associated with osteoporosis and osteopenia. Low BMI was also associated with osteoporosis on multivariate analysis in CD (P = 0.021, OR 5.83, CI 1.31-25.94). No difference was observed between Taq-1 and Apa-1 VDR polymorphisms in IBD, CD, ulcerative colitis and healthy controls. However, CD males were more likely to carry the variant Taq-1 polymorphism than healthy controls males (P = 0.0018, OR 1.94, CI 1.28-2.92) and female CD patients (P = 0.0061, OR 1.60, CI 1.17-2.44). CONCLUSIONS: In this well-phenotyped cohort of IBD patients, a relatively low prevalence of osteoporosis was observed. Low BMI was the only independent risk factor identified to be associated with osteoporosis.

Aldhous MC, Noble CL, Satsangi J. · Gastrointestinal Unit, School of Clinical and Molecular Medicine, University of Edinburgh, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland, UK. · PLoS One. · Pubmed #19617917 links to  free full text

Abstract: BACKGROUND: Human beta-defensin-2 (HBD2) is an antimicrobial peptide implicated in the pathogenesis of inflammatory bowel disease (IBD). Low copy number and concomitant low mRNA expression of the HBD2 gene have been implicated in susceptibility to colonic Crohn's Disease (CD). We investigated the colonic distribution of HBD2 mRNA expression, and the contributions of genetic and environmental factors on HBD2 protein production. METHODOLOGY/PRINCIPAL FINDINGS: We examined HBD2 mRNA expression at three colonic locations by microarray analysis of biopsies from 151 patients (53 CD, 67 ulcerative colitis [UC], 31 controls). We investigated environmental and genetic influences on HBD2 protein production using ex vivo cultured sigmoid colon biopsies from 69 patients (22 CD, 26 UC, 21 controls) stimulated with lipopolysaccharide (LPS) and/or nicotine for 24 hours. HBD2 and cytokines were measured in culture supernatants. Using DNA samples from these patients, regions in the HBD2 gene promoter were sequenced for NF-kappaB binding-sites and HBD2 gene copy number was determined. HBD2 mRNA expression was highest in inflamed (vs. uninflamed p = 0.0122) ascending colon in CD and in inflamed (vs. uninflamed p<0.0001) sigmoid colon in UC. HBD2 protein production was increased in inflamed UC biopsies (p = 0.0078). There was no difference in HBD2 protein production from unstimulated biopsies of CD, UC and controls. LPS-induced HBD2 production was significantly increased in CD (p = 0.0375) but not UC (p = 0.2017); this LPS-induced response was augmented by nicotine in UC (p = 0.0308) but not CD (p = 0.6872). Nicotine alone did not affect HBD2 production. HBD2 production correlated with IL8 production in UC (p<0.001) and with IL10 in CD (p<0.05). Variations in the HBD2 promoter and HBD2 gene copy number did not affect HBD2 production. SIGNIFICANCE/CONCLUSIONS: Colonic HBD2 was dysregulated at mRNA and protein level in IBD. Inflammatory status and stimulus but not germline variations influenced these changes.

Ho GT, Lee HM, Brydon G, Ting T, Hare N, Drummond H, Shand AG, Bartolo DC, Wilson RG, Dunlop MG, Arnott ID, Satsangi J. · Western General Hospital, University of Edinburgh, UK. · Am J Gastroenterol. · Pubmed #19262524 No free full text.

Abstract: OBJECTIVES: Calprotectin is a granulocyte neutrophil-predominant cytosolic protein. Fecal concentrations are elevated in intestinal inflammation and may predict relapse in quiescent inflammatory bowel disease. We aim to investigate fecal calprotectin (FC) as a biomarker in predicting the clinical course of acute severe ulcerative colitis (ASUC). METHODS: In 90 patients with ASUC requiring intensive in-patient medical therapy (January 2005-September 2007), we investigated the discriminant ability of FC to predict colectomy and corticosteroid and infliximab nonresponse. All patients received parenteral corticosteroids as first-line treatment; 21 (23.3%) were also treated with infliximab (5 mg/kg), after failure of corticosteroid therapy. RESULTS: Of 90 patients, 31 (34.4%) required colectomy, including 11 (52.4%) of those treated with infliximab. Overall FC was high (1,020.0 microg/g interquartile range: 601.5-1,617.5). FC was significantly higher in patients requiring colectomy (1,200.0 vs. 887.0; P=0.04), with a trend toward significance when comparing corticosteroid nonresponders and responders (1,100.0 vs. 863.5; P=0.08), as well as between infliximab nonresponders and responders (1,795.0 vs. 920.5; P=0.06). Receiver-operator characteristic curve analysis yielded an area under the curve of 0.65 to predict colectomy (P=0.04), with a maximum likelihood ratio of 9.23, specificity 97.4%, and sensitivity 24.0% at a cutoff point of 1,922.5 microg/g. Kaplan-Meier analyses showed that using 1,922.5 microg/g over a median follow-up of 1.10 years, 87% of patients will need subsequent colectomy. CONCLUSIONS: This is the first data set to demonstrate that FC levels are dramatically elevated in severe UC. These data raise the possibility that this biomarker can predict response to first or second-line medical therapy in this setting.

Russell RK, Ip B, Aldhous MC, MacDougall M, Drummond HE, Arnott ID, Gillett PM, McGrogan P, Weaver LT, Bisset WM, Mahdi G, Wilson DC, Satsangi J. · Department of Paediatric Gastroenterology, Yorkhill Hospital, UK. · J Pediatr Gastroenterol Nutr. · Pubmed #19179877 No free full text.

Abstract: OBJECTIVES: To determine anti-Saccharomyces cerevisiae antibodies (ASCA) status and its relation to disease phenotype in patients with inflammatory bowel disease (IBD). PATIENTS AND METHODS: A total of 301 Scottish patients with early-onset IBD-197 Crohn disease (CD), 76 ulcerative colitis (UC), 28 indeterminate colitis (IC)-and 78 healthy control individuals were studied. ASCA status (IgA, IgG) was determined by enzyme-linked immunosorbent assay. ASCA status was then analyzed in relation to CD phenotype. RESULTS: Patients with CD had a higher prevalence of ASCA than patients with UC and healthy controls: 82/197 versus 12/76, odds ratio (OR) 3.80 (1.93-7.50) and 82/197 versus 6/78, OR 8.56 (3.55-20.62), respectively. Univariate analysis showed that positive ASCA status was associated with oral CD (17/25 vs 59/153, OR 3.39 [1.38-8.34]), perianal CD (39/77 vs 38/108, OR 1.89 [1.04-3.44]) and the presence of granulomata (63/132 vs 15/52, OR 2.25 [1.13-4.48]) and also with markers of disease severity: raised C-reactive protein (44/90 vs 12/49, OR 2.95[1.36-6.37]), hypoalbuminemia (44/85 vs 20/74, OR 2.28[1.19-4.37]), and surgery (27/49 vs 54/147, OR 2.11 [1.10-4.06]). From multivariate analysis, the presence of oral disease (adjusted P = 0.001, OR 22.22 [3.41-142.86]) and hypoalbuminemia (adjusted P = 0.01, OR 4.78 [1.40-16.39]) was found to be independently associated with ASCA status. No association was demonstrated between ASCA and IBD candidate genes. CONCLUSIONS: Patients with CD had a higher prevalence of ASCA than did other patients with IBD. ASCA status described patients with CD who had a specific phenotype, showing an association with markers of disease severity and oral CD involvement.

Lees CW, Ali AI, Thompson AI, Ho GT, Forsythe RO, Marquez L, Cochrane CJ, Aitken S, Fennell J, Rogers P, Shand AG, Penman ID, Palmer KR, Wilson DC, Arnott ID, Satsangi J. · Gastrointestinal Unit, Western General Hospital, Edinburgh, UK. · Aliment Pharmacol Ther. · Pubmed #19132970 No free full text.

Abstract: BACKGROUND: Anti-TNF agents are now widely used in Crohn's disease (CD), and in ulcerative colitis (UC). AIM: To review the safety profile of anti-TNF agents in all patients treated with infliximab in Edinburgh from 1999 to 2007. METHODS: Complete data were available on 202/207 patients comprising 157 CD, 42 UC and three coeliac disease. Median follow-up was 2.4 years (1.0-4.9) with a total of 620 patient-years follow-up. About 19.1% of CD patients were subsequently treated with adalimumab. RESULTS: Seven deaths (3.3%) occurred in follow-up; only one death was <1 year post-infliximab (at day 72, from lung cancer). A total of six malignancies (three haematological, three bronchogenic) and six cases of suspected demyelination (three with confirmed neurological disease) were reported. In the 90 days following infliximab, 95 adverse events (36 serious) occurred in 58/202 (28.7%) patients. In all, 42/202 (20.8%) had an infectious event (22 serious) and 27/202 (13.4%) of patients had an infusion reaction: 19 acute (four serious) and eight delayed (three serious). CONCLUSIONS: Serious infections, malignancies and neurological disease complicate anti-TNF use in clinical practice. Although evidence for causality is unclear, potential mechanisms and predisposing factors need to be explored. In individual patients, the risk/benefit analysis needs to be carefully assessed and discussed prior to commencement of therapy.

Lees CW, Zacharias WJ, Tremelling M, Noble CL, Nimmo ER, Tenesa A, Cornelius J, Torkvist L, Kao J, Farrington S, Drummond HE, Ho GT, Arnott ID, Appelman HD, Diehl L, Campbell H, Dunlop MG, Parkes M, Howie SE, Gumucio DL, Satsangi J. · Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Edinburgh, United Kingdom. · PLoS Med. · Pubmed #19071955 links to  free full text

Abstract: BACKGROUND: Ulcerative colitis (UC) and Crohn's disease (CD) are polygenic chronic inflammatory bowel diseases (IBD) of high prevalence that are associated with considerable morbidity. The hedgehog (HH) signalling pathway, which includes the transcription factor glioma-associated oncogene homolog 1 (GLI1), plays vital roles in gastrointestinal tract development, homeostasis, and malignancy. We identified a germline variation in GLI1 (within the IBD2 linkage region, 12q13) in patients with IBD. Since this IBD-associated variant encodes a GLI1 protein with reduced function and our expression studies demonstrated down-regulation of the HH response in IBD, we tested whether mice with reduced Gli1 activity demonstrate increased susceptibility to chemically induced colitis. METHODS AND FINDINGS: Using a gene-wide haplotype-tagging approach, germline GLI1 variation was examined in three independent populations of IBD patients and healthy controls from Northern Europe (Scotland, England, and Sweden) totalling over 5,000 individuals. On log-likelihood analysis, GLI1 was associated with IBD, predominantly UC, in Scotland and England (p < 0.0001). A nonsynonymous SNP (rs2228226C-->G), in exon 12 of GLI1 (Q1100E) was strongly implicated, with pooled odds ratio of 1.194 (confidence interval = 1.09-1.31, p = 0.0002). GLI1 variants were tested in vitro for transcriptional activity in luciferase assays. Q1100E falls within a conserved motif near the C terminus of GLI1; the variant GLI protein exhibited reduced transactivation function in vitro. In complementary expression studies, we noted the colonic HH response, including GLI1, patched (PTCH), and hedgehog-interacting protein (HHIP), to be down-regulated in patients with UC. Finally, Gli1(+/lacZ) mice were tested for susceptibility to dextran sodium sulphate (DSS)-induced colitis. Clinical response, histology, and expression of inflammatory cytokines and chemokines were recorded. Gli1(+/lacZ) mice rapidly developed severe intestinal inflammation, with considerable morbidity and mortality compared with wild type. Local myeloid cells were shown to be direct targets of HH signals and cytokine expression studies revealed robust up-regulation of IL-12, IL-17, and IL-23 in this model. CONCLUSIONS: HH signalling through GLI1 is required for appropriate modulation of the intestinal response to acute inflammatory challenge. Reduced GLI1 function predisposes to a heightened myeloid response to inflammatory stimuli, potentially leading to IBD.

Anderson CA, Massey DC, Barrett JC, Prescott NJ, Tremelling M, Fisher SA, Gwilliam R, Jacob J, Nimmo ER, Drummond H, Lees CW, Onnie CM, Hanson C, Blaszczyk K, Ravindrarajah R, Hunt S, Varma D, Hammond N, Lewis G, Attlesey H, Watkins N, Ouwehand W, Strachan D, McArdle W, Lewis CM, Anonymous00026, Lobo A, Sanderson J, Jewell DP, Deloukas P, Mansfield JC, Mathew CG, Satsangi J, Parkes M. · Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK. · Gastroenterology. · Pubmed #19068216 links to  free full text

Abstract: BACKGROUND & AIMS: Identifying shared and disease-specific susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC) would help define the biologic relationship between the inflammatory bowel diseases. More than 30 CD susceptibility loci have been identified. These represent important candidate susceptibility loci for UC. Loci discovered by the index genome scans in CD have previously been tested for association with UC, but those identified in the recent meta-analysis await such investigation. Furthermore, the recently identified UC locus at ECM1 requires formal testing for association with CD. METHODS: We analyzed 45 single nucleotide polymorphisms, tagging 29 of the loci recently associated with CD in 2527 UC cases and 4070 population controls. We also genotyped the UC-associated ECM1 variant rs11205387 in 1560 CD patients and 3028 controls. RESULTS: Nine regions showed association with UC at a threshold corrected for the 29 loci tested (P < .0017). The strongest association (P = 4.13 x 10(-8); odds ratio = 1.27) was identified with a 170-kilobase region on chromosome 1q32 that contains 3 genes. We also found association with JAK2 and replicated a recently reported association with STAT3, further implicating the role of this signaling pathway in inflammatory bowel disease. Additional novel UC susceptibility genes were LYRM4 and CDKAL1. Twenty of the loci were not associated with UC, and several appear to be specific to CD. ECM1 variation was not associated with CD. CONCLUSIONS: Collectively, these data help define the genetic relationship between CD and UC and characterize common, as well as disease-specific mechanisms of pathogenesis.

Van Limbergen J, Russell RK, Drummond HE, Aldhous MC, Round NK, Nimmo ER, Smith L, Gillett PM, McGrogan P, Weaver LT, Bisset WM, Mahdi G, Arnott ID, Satsangi J, Wilson DC. · Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom. · Gastroenterology. · Pubmed #18725221 No free full text.

Abstract: BACKGROUND & AIMS: Childhood-onset inflammatory bowel disease (IBD) might be etiologically different from adult-onset IBD. We analyzed disease phenotypes and progression of childhood-onset disease and compared them with characteristics of adult-onset disease in patients in Scotland. METHODS: Anatomic locations and behaviors were assessed in 416 patients with childhood-onset (276 Crohn's disease [CD], 99 ulcerative colitis [UC], 41 IBD type unclassified [IBDU] diagnosed before seventeenth birthday) and 1297 patients with adult-onset (596 CD, 701 UC) IBD using the Montreal classification. RESULTS: At the time of diagnosis in children, CD involved small bowel and colon (L3) in 51% (138/273), colon (L2) in 36%, and ileum (L1) in 6%; the upper gastrointestinal (GI) tract (L4) was also affected in 51%. In 39%, the anatomic extent increased within 2 years. Behavioral characteristics progressed; 24% of children developed stricturing or penetrating complications within 4 years (vs 9% at diagnosis; P < .0001; odds ratio [OR], 3.32; 95% confidence interval [CI], 1.86-5.92). Compared with adults, childhood-onset disease was characterized by a "panenteric" phenotype (ileocolonic plus upper GI [L3+L4]; 43% vs 3%; P < .0001; OR, 23.36; 95% CI, 13.45-40.59) with less isolated ileal (L1; 2% vs 31%; P < .0001; OR, 0.06; 95% CI, 0.03-0.12) or colonic disease (L2; 15% vs 36%; P < .0001; OR, 0.31; 95% CI, 0.21-0.46). UC was extensive in 82% of the children at diagnosis, versus 48% of adults (P < .0001; OR, 5.08; 95% CI, 2.73-9.45); 46% of the children progressed to develop extensive colitis during follow-up. Forty-six percent of children with CD and 35% with UC required immunomodulatory therapy within 12 months of diagnosis. The median time to first surgery was longer in childhood-onset than adult-onset patients with CD (13.7 vs 7.8 years; P < .001); the reverse was true for UC. CONCLUSIONS: Childhood-onset IBD is characterized by extensive intestinal involvement and rapid early progression.

Aldhous MC, Prescott RJ, Roberts S, Samuel K, Waterfall M, Satsangi J. · Gastrointestinal Unit, School of Clinical and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland, UK. · Inflamm Bowel Dis. · Pubmed #18618634 No free full text.

Abstract: BACKGROUND: Smoking differentially influences susceptibility to the inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis (UC). We investigated the effects of nicotine on cytokine, cell cycle, and apoptotic responses in peripheral blood mononuclear cells (PBMCs) from IBD patients and healthy controls (HCs). METHODS: PBMCs from IBD patients and HC were stimulated with lipopolysaccharide (LPS; 1 microg/mL) or phytohemagglutinin (PHA, 5 or 0.5 microg/mL), +/- nicotine (1, 10, 100 microg/mL). Cytokines (IL1beta, IL2, IL10, IL12/IL23p40, TGFbeta, TNFalpha) were measured in supernatants at 24 hours. After 72 hours cells were analyzed by flow cytometry for cell cycle and apoptosis. Statistical modeling was used to identify interactions between cytokines and cell cycle / apoptosis and minimize confounding effects. RESULTS: Stimulation by LPS and PHA (5 microg/mL) increased IL12/IL23p40 production from CD and UC versus HC (P < 0.05); PHA (0.5 microg/mL) increased IL1beta in UC and decreased TGFbeta from CD and UC (P < 0.01). In all groups, nicotine reduced LPS- and PHA (0.5 microg/mL)-stimulated production of IL1beta, IL10, TGFbeta, and TNFalpha (P < 0.001). Cell cycle analysis showed that PHA, but not LPS, induced proliferation and decreased G(0)/G(1) resting cells in CD and UC versus HC (P < 0.001). Nicotine decreased PHA-stimulated S-phase proliferation and increased G(0)/G(1) resting cells (P < 0.01). Modeling showed independent associations between IL12/IL23p40 and apoptosis (P = 0.01), IL1beta and resting cells (P = 0.006), TNFalpha and proliferating cells (P < 0.001). Disease activity and smoking habit had no effect. CONCLUSIONS: Dysregulated cytokine profiles in UC and CD are associated with specific alterations in cell cycle responses; these effects may be modified by nicotine, and potentially by anticytokine therapies.

Russell RK, Drummond HE, Wilson DC, Anderson NH, Arnott ID, Van Limbergen JE, Satsangi J, Nimmo ER. · Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, UK. · Genes Immun. · Pubmed #18563169 No free full text.

Abstract: The high incidence of Scottish Crohn's disease (CD) is not explained by the common three NOD2/CARD15 variants. We aimed to identify population-specific NOD2/CARD15 coding variants. A total of 1478 (320 inflammatory bowel disease patients <16 years, 343 adult CD patients, 542 parents and 273 controls). All NOD2/CARD15 exons were sequenced in 24 CD patients. Sequencing identified 18 single-nucleotide polymorphisms (SNPs) including 4 non-synonymous coding SNPs altering the structure of the Leucine-rich region--two were well established (1007-/C and 908G/R). Two other variants, valine955isoleucine (955V/I) and methionine863valine (863M/V), were genotyped in all subjects. 863M/V carriage was not significantly higher in CD patients vs controls (1.35 vs 0.37%, P=0.27). 955V/I carriage was no higher in CD or ulcerative colitis patients (12.8 and 15.8%, respectively) compared to controls (16.2%). Transmission disequilibrium test analysis was negative. 955V/I carriage was higher in indeterminate colitis patients (n=29) compared to controls (41.4 vs 16.2%, P=0.001, OR=3.6 (1.6-8.2)). Population-specific NOD2/CARD15 exonic variants do not account for the high-CD prevalence in Scotland.

Noble CL, Abbas AR, Cornelius J, Lees CW, Ho GT, Toy K, Modrusan Z, Pal N, Zhong F, Chalasani S, Clark H, Arnott ID, Penman ID, Satsangi J, Diehl L. · Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, EH4 2XU, UK. · Gut. · Pubmed #18523026 No free full text.

Abstract: OBJECTIVE: To investigate differential intestinal gene expression in patients with ulcerative colitis and in controls. DESIGN: Genome-wide expression study (41,058 expression sequence tags, 215 biopsies). SETTING: Western General Hospital, Edinburgh, UK, and Genentech, San Francisco, USA. PATIENTS: 67 patients with ulcerative colitis and 31 control subjects (23 normal subjects and 8 patients with inflamed non-inflammatory bowel disease biopsies). INTERVENTIONS: Paired endoscopic biopsies were taken from 5 specific anatomical locations for RNA extraction and histology. The Agilent microarray platform was used and confirmation of results was undertaken by real time polymerase chain reaction and immunohistochemistry. RESULTS: In healthy control biopsies, cluster analysis showed differences in gene expression between the right and left colon. (chi(2) = 25.1, p<0.0001). Developmental genes, homeobox protein A13 (HOXA13), (p = 2.3x10(-16)), HOXB13 (p<1x10(-45)), glioma-associated oncogene 1 (GLI1) (p = 4.0x10(-24)), and GLI3 (p = 2.1x10(-28)) primarily drove this separation. When all ulcerative colitis biopsies and control biopsies were compared, 143 sequences had a fold change of >1.5 in the ulcerative colitis biopsies (0.01>p>10(-45)) and 54 sequences had a fold change of <-1.5 (0.01>p>10(-20)). Differentially upregulated genes in ulcerative colitis included serum amyloid A1 (SAA1) (p<10(-45)) the alpha defensins 5 and 6 (DEFA5 and 6) (p = 0.00003 and p = 6.95x10(-7), respectively), matrix metalloproteinase 3 (MMP3) (p = 5.6x10(-10)) and MMP7 (p = 2.3x10(-7)). Increased DEFA5 and 6 expression was further characterised to Paneth cell metaplasia by immunohistochemistry and in situ hybridisation. Sub-analysis of the inflammatory bowel disease 2 (IBD2) and IBD5 loci, and the ATP-binding cassette (ABC) transporter genes revealed a number of differentially regulated genes in the ulcerative colitis biopsies. CONCLUSIONS: Key findings are the expression gradient in the healthy adult colon and the involvement of novel gene families, as well as established candidate genes in the pathogenesis of ulcerative colitis.

Fisher SA, Tremelling M, Anderson CA, Gwilliam R, Bumpstead S, Prescott NJ, Nimmo ER, Massey D, Berzuini C, Johnson C, Barrett JC, Cummings FR, Drummond H, Lees CW, Onnie CM, Hanson CE, Blaszczyk K, Inouye M, Ewels P, Ravindrarajah R, Keniry A, Hunt S, Carter M, Watkins N, Ouwehand W, Lewis CM, Cardon L, Anonymous00021, Lobo A, Forbes A, Sanderson J, Jewell DP, Mansfield JC, Deloukas P, Mathew CG, Parkes M, Satsangi J. · Department of Medical and Molecular Genetics, King's College London School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK. · Nat Genet. · Pubmed #18438406 links to  free full text

Abstract: We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously unknown susceptibility locus at ECM1. We also show that several risk loci are common to ulcerative colitis and Crohn's disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohn's disease. These data provide the first detailed illustration of the genetic relationship between these common inflammatory bowel diseases.

Lees CW, Maan AK, Hansoti B, Satsangi J, Arnott ID. · GI Unit, University of Edinburgh, Edinburgh, UK. · Aliment Pharmacol Ther. · Pubmed #17988235 No free full text.

Abstract: BACKGROUND: Azathioprine intolerance is a common clinical problem, requiring drug withdrawal in up to 30% of patients. The successful use of mercaptopurine is described, but data to support this strategy are needed. AIMS: To assess the tolerability of mercaptopurine in inflammatory bowel disease patients previously intolerant of azathioprine, and identify predictive factors. METHODS: Sixty-one azathioprine-intolerant patients (31 males, median age at diagnosis 32 years, 31 with Crohn's disease, 30 with ulcerative colitis) who had been treated with mercaptopurine were identified. Intolerances included nausea and vomiting, flu-like illness, neutropenia, hepatotoxicity and pancreatitis. RESULTS: Mercaptopurine was tolerated by 59% (36 of 61) of azathioprine-intolerant patients (median dose 1.0 mg/kg), 61% (17 of 28) in patients with azathioprine-related nausea and vomiting, 61% (11 of 18) with flu-like illness, 33% (three of nine) with hepatotoxicity, 100% (one of one) with neutropenia, 100% (three of three) with rash and 0% (zero of one) with pancreatitis. Mercaptopurine intolerance was frequently for a different adverse event. Those intolerant of mercaptopurine were younger (28.4 years vs. 37.0 years; P = 0.014) and more frequently female (14/30 vs. 2/29, P = 0.027). Mercaptopurine tolerability was not affected by diagnosis, location, behaviour, surgery, smoking, family history or extra-intestinal manifestations. CONCLUSION: Mercaptopurine may be tolerated in up to 60% of azathioprine-intolerant patients, and treatment should be considered, particularly if intolerance was due to nausea, vomiting, flu-like illness or rash.