Ulcerative Colitis: Belaiche J

Belaiche J, Chapelier N, Wertz S, Louis E. · Service d'Hépato-Gastroentérologie, CHU Sart Tilman, Liège, Belgique. · Rev Med Liege. · Pubmed #18214363 No free full text.

Abstract: Inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis are frequent illnesses in western countries. They have a dramatic impact on the health-related quality of life. The new biological treatments developed for these diseases are potentially very effective, but are also expensive and may have significant side effects. In the present paper, the authors describe new biological therapies used during the past 10 years at the CHU. More than 20 therapeutic protocols were implemented. These protocols have given the patients the opportunity to gain very rapid access to new efficient therapies, to benefit from promising techniques for the evaluation of their pathology and to be submitted to a close follow-up that frequently called their treatment into question in the light of the most innovative options.

Louis E, Belaiche J. · Service de Gastroentérologie, CHU de Liège, Belgium. · Acta Gastroenterol Belg. · Pubmed #10692777 No free full text.

Abstract: Azathioprine and 6-mercaptopurine are effective drugs in the management of steroid dependent and chronic active inflammatory bowel diseases. They are also well tolerated on the long term. However, their use is still hampered by some drawbacks including delay before efficacy, 20-35% of non responders, relapse at withdrawal of the drugs, possible bone marrow toxicity and other side effects. During the last few years, these drawbacks have been challenged by important studies showing that a better knowledge of the metabolism of these drugs may help to improve their use.

Dideberg V, Kristjansdottir G, Milani L, Libioulle C, Sigurdsson S, Louis E, Wiman AC, Vermeire S, Rutgeerts P, Belaiche J, Franchimont D, Van Gossum A, Bours V, Syvänen AC. · Department of Human Genetics, CHU de Liège, Belgium. · Hum Mol Genet. · Pubmed #17881657 links to  free full text

Abstract: The interferon regulatory factor 5 (IRF5) gene encodes a transcription factor that plays an important role in the innate as well as in the cell-mediated immune responses. The IRF5 gene has been shown to be associated with systemic lupus erythematosus and rheumatoid arthritis. We studied whether the IRF5 gene is also associated with inflammatory bowel diseases (IBD), Crohn disease (CD) and ulcerative colitis (UC). Twelve polymorphisms in the IRF5 gene were genotyped in a cohort of 1007 IBD patients (748 CD and 254 UC) and 241 controls from Wallonia, Belgium. The same polymorphisms were genotyped in a confirmatory cohort of 311 controls and 687 IBD patients (488 CD and 192 UC) from Leuven, Belgium. A strong signal of association [P = 1.9 x 10(-5), odds ratio (OR) 1.81 (1.37-2.39)] with IBD was observed for a 5 bp indel (CGGGG) polymorphism in the promoter region of the IRF5 gene. The association was detectable also in CD patients (P = 6.8 x 10(-4)) and was particularly strong among the UC patients [P = 5.3 x 10(-8), OR = 2.42 (1.76-3.34)]. The association of the CGGGG indel was confirmed in the second cohort [P = 3.2 x 10(-5), OR = 1.59 (1.28-1.98)]. The insertion of one CGGGG unit is predicted to create an additional binding site for the transcription factor SP1. Using an electrophoretic mobility shift assay, we show allele-specific differences in protein binding to this repetitive DNA-stretch, which suggest a potential function role for the CGGGG indel.

De Jager PL, Franchimont D, Waliszewska A, Bitton A, Cohen A, Langelier D, Belaiche J, Vermeire S, Farwell L, Goris A, Libioulle C, Jani N, Dassopoulos T, Bromfield GP, Dubois B, Cho JH, Brant SR, Duerr RH, Yang H, Rotter JI, Silverberg MS, Steinhart AH, Daly MJ, Podolsky DK, Louis E, Hafler DA, Rioux JD, Anonymous00242, Anonymous00243. · Department of Neurology, Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. · Genes Immun. · Pubmed #17538633 No free full text.

Abstract: The intestinal flora has long been thought to play a role either in initiating or in exacerbating the inflammatory bowel diseases (IBD). Host defenses, such as those mediated by the Toll-like receptors (TLR), are critical to the host/pathogen interaction and have been implicated in IBD pathophysiology. To explore the association of genetic variation in TLR pathways with susceptibility to IBD, we performed a replication study and pooled analyses of the putative IBD risk alleles in NFKB1 and TLR4, and we performed a haplotype-based screen for association to IBD in the TLR genes and a selection of their adaptor and signaling molecules. Our genotyping of 1539 cases of IBD and pooled analysis of 4805 cases of IBD validates the published association of a TLR4 allele with risk of IBD (odds ratio (OR): 1.30, 95% confidence interval (CI): 1.15-1.48; P=0.00017) and Crohn's disease (OR: 1.33, 95% CI: 1.16-1.54; P=0.000035) but not ulcerative colitis. We also describe novel suggestive evidence that TIRAP (OR: 1.16, 95% CI: 1.04-1.30; P=0.007) has a modest effect on risk of IBD. Our analysis, therefore, offers additional evidence that the TLR4 pathway - in this case, TLR4 and its signaling molecule TIRAP - plays a role in susceptibility to IBD.

Meuwis MA, Fillet M, Geurts P, de Seny D, Lutteri L, Chapelle JP, Bours V, Wehenkel L, Belaiche J, Malaise M, Louis E, Merville MP. · Laboratory of Clinical Chemistry, GIGA Research, CHU, University of Liège, B34, 4000 Liège, Belgium. · Biochem Pharmacol. · Pubmed #17258689 No free full text.

Abstract: Crohn's disease and ulcerative colitis known as inflammatory bowel diseases (IBD) are chronic immuno-inflammatory pathologies of the gastrointestinal tract. These diseases are multifactorial, polygenic and of unknown etiology. Clinical presentation is non-specific and diagnosis is based on clinical, endoscopic, radiological and histological criteria. Novel markers are needed to improve early diagnosis and classification of these pathologies. We performed a study with 120 serum samples collected from patients classified in 4 groups (30 Crohn, 30 ulcerative colitis, 30 inflammatory controls and 30 healthy controls) according to accredited criteria. We compared protein sera profiles obtained with a Surface Enhanced Laser Desorption Ionization-Time of Flight-Mass Spectrometer (SELDI-TOF-MS). Data analysis with univariate process and a multivariate statistical method based on multiple decision trees algorithms allowed us to select some potential biomarkers. Four of them were identified by mass spectrometry and antibody based methods. Multivariate analysis generated models that could classify samples with good sensitivity and specificity (minimum 80%) discriminating groups of patients. This analysis was used as a tool to classify peaks according to differences in level on spectra through the four categories of patients. Four biomarkers showing important diagnostic value were purified, identified (PF4, MRP8, FIBA and Hpalpha2) and two of these: PF4 and Hpalpha2 were detected in sera by classical methods. SELDI-TOF-MS technology and use of the multiple decision trees method led to protein biomarker patterns analysis and allowed the selection of potential individual biomarkers. Their downstream identification may reveal to be helpful for IBD classification and etiology understanding.

Lebas E, Gielen S, Nguyen M, Ghaye B, Bartsch P, Belaiche J. · Service d'Hépato-Gastro-Entérologie, CHU Sart-Tilman, Liège. · Rev Med Liege. · Pubmed #16681002 No free full text.

Abstract: We report the case of a 52 year old man who was hospitalized within a context of a persistent deterioration of his general condition. He was suspected of having a chronic inflammatory colitis. A pulmonary radiography revealed the presence of voluminous bilateral excavated masses with hydro-aerical levels. After having refuted among others a suspicion of tuberculosis, the results of a thoracic percutaneous transpleural lung aspiration by needle under tomodensitometric control steered our diagnosis towards a vascularitis of the Wegener disease type. A treatment with corticotherapy in large doses completed with cyclophosphamid allowed for clinical, biological and radiological improvement. Wegener's granulomatosis usually starts in an insidious manner with febrile episodes and an impairment of the general condition associated with inflammatory biological signs, as observed in our patient. After these warning symptoms, come ORL and/or pulmonary and/or renal impairment, which represent the classical triad of diffused GW. However a certain number of particularities unusual for that diagnosis characterized our patient and prompted the discussion of this case.

Vijverman A, Piront P, Belaiche J, Louis E. · Department of gastroenterology, CHU of Liège, Belgium. · Acta Gastroenterol Belg. · Pubmed #16673554 No free full text.

Abstract: INTRODUCTION: Anemia has been considered as an overlooked complication of inflammatory bowel disease. Studies dating back to the 80ties and the 90ties have shown 30% of anemia among inflammatory bowel disease (IBD) patients. More recently, the broader use of immunosuppressive drug and infliximab allowing better mucosal healing as well as a more aggressive treatment of anemia, including the use of safer form of IV iron, may have influenced the prevalence of anemia among IBD patients. Our aim was to asses the prevalence and characteristics of anemia among two cohorts of IBD patients at 10 years interval and to look for associated clinical or demographic factors. METHODS: Using the IBD patients register of one senior gastroenterologist, we identified IBD patients he had consecutively seen and who had blood test at the outpatient clinic during the years 1993 and 2003. Demographic and clinical characteristics, treatment for Crohn's disease, blood test results and treatment of anemia were recorded and compared between these two cohorts. Anemia was defined as an hemoglobin level lower than the normal value of the laboratory of our hospital. RESULTS: 80 and 90 patients were identified in 1993 and 2003, respectively. There was no significant difference between the two cohorts, according to age, gender, disease type, duration or location. There were 27/80 (33.8%) and 15/90 (16.7%) anemic patients in 1993 and 2003, respectively (P = 0.013). The prevalence of severe anemia (hemoglobin level < 10.5 g/100 ml) was similar in the two cohorts (6.3% and 5.6%). Characteristics of the anemia were similar in the two cohorts with a majority of iron deficiency anemia and inflammatory anemia. Ferritin and CRP levels were not significantly different in the two cohorts. The only significant difference was a more frequent use of immunosuppressive treatment and infliximab in 2003 than in 1993 (33.3% vs. 13.8% ; P = 0.0038, RR: 0.41, 0.22-0.77) CONCLUSIONS: Prevalence of mild to moderate anemia has significantly decreased in our population over the last 10 years. The only difference detected between the two cohorts was the increased use of immunosuppressive drug (mainly azathioprine).

Laurent S, Reenaers C, Detroz B, Detry O, Delvenne P, Belaiche J, Meurisse M. · Dept of Abdominal Surgery, CHU Sart Tilman B35, B-4000 Liège, Belgium. · Acta Gastroenterol Belg. · Pubmed #16013652 No free full text.

Abstract: The authors report the case of a patient aged 60-year-old who survived ulcerative colitis complicated by toxic megacolon and disseminated intravascular coagulation. This patient was not known for this ulcerative colitis and was first hospitalised for a suspicion of diverticulitis. The admission symptoms were fever, abdominal pain and bloody diarrhoea. The evolution was defavorable under antibiotics and sulfasalazine. The patient was readmitted 5 days after he left hospital, and the diagnosis of UC was based on colon biopsy made during the first hospitalisation. A treatment with methylprednisolone was started and the patient worsened day by day with apparition of toxic megacolon and disseminated intravascular coagulation. Subtotal colectomy was performed for degradation of general status and coagulation factors. Pathological findings confirmed ulcerative colitis with toxic megacolon. Cytomegalovirus inclusions were demonstrated on the colonic specimen and confirmed by PCR. In this report the authors discuss the etiology of toxic megacolon and disseminated intravascular coagulation in ulcerative colitis surinfected by cytomegalovirus. Mortality of these pathologies is high necessitating rapid diagnosis of cytomegalovirus infection by sigmoid biopsy. Management requires immunosupression interruption and ganciclovir therapy, or surgery in unsuccessful medical treatment.

Gustot T, Lemmers A, Louis E, Nicaise C, Quertinmont E, Belaiche J, Roland S, Van Gossum A, Devière J, Franchimont D. · Division of Gastroenterology, Erasme University Hospital, Free University of Brussels, 808 Lennik St, 1070 Brussels, Belgium. · Gut. · Pubmed #15753533 links to  free full text

Abstract: INTRODUCTION: Soluble cytokine receptors (sCRs) modulate the in vivo activity of cytokines. Deficient sCR production could participate in the pathogenesis and course of Crohn's disease (CD). The aim of the study was to examine the profile of sCRs in CD patients and their modulation by infliximab and corticosteroids. METHODS: We prospectively examined active CD patients (aCD) treated with either infliximab (n = 21) or corticosteroids (n = 9), CD patients in clinical remission (rCD, n = 20), ulcerative colitis patients (UC, n = 24), and healthy subjects (HS, n = 15). Cultures of colonic biopsies were also examined from CD inflamed (n = 8), CD non-inflamed (n = 7), and healthy mucosa (n = 8). Levels of tumour necrosis factor alpha (TNF-alpha), soluble TNF receptor I (sTNFRI), soluble TNF receptor II (sTNFRII), interleukin 1beta (IL-1beta), soluble IL-1 receptor I (sIL-1RI), soluble IL-1 receptor II (sIL-1RII), IL-6, soluble IL-6 receptor (sIL-6R), and sgp130 were measured using ELISA. RESULTS: Higher levels of sTNFRI (p<0.05, p<0.01), sTNFRII (p<0.01, p<0.01), sIL-1RI (p<0.05, NS), IL-6 (p<0.01, p<0.01), and sIL-6R (p<0.05, NS) were observed in aCD compared with rCD and HS. Interestingly, sIL-1RII (p<0.05, p<0.01) and sgp130 (p<0.01, p<0.01) were profoundly decreased in aCD compared with rCD and HS, and were negatively correlated with CRP. Deficient production of sIL-1RII was specific to CD (not observed in ulcerative colitis), and was further confirmed at the mucosal level. Infliximab decreased sTNFRII at one and four weeks (p<0.05) and enhanced sIL-6R levels at one week (p<0.05). Corticosteroids increased sIL-1RII levels at one week (p<0.05). CONCLUSION: CD is associated with dysregulated production of sCRs. Deficiency in sIL-1RII and sgp130 may be essential to CD pathogenesis. Their replacement through the use of fusion proteins could represent future alternative therapeutic strategies for CD.

El Yafi F, Winkler R, Delvenne P, Boussif N, Belaiche J, Louis E. · Department of Gastroenterology, CHU of Liège, Liège, Belgium. · Clin Exp Immunol. · Pubmed #15730399 links to  free full text

Abstract: The fibrotic and antiapoptotic effects of insulin-like growth factors (IGF) are mediated by type I IGF receptor (IGF-1R). IGFs could play a role in intestinal stricturing and in the maintenance of inflammation in Crohn's disease (CD). We aimed to describe IGF-1R expression in CD intestinal lesions, to compare it to other intestinal inflammatory diseases and to correlate it with fibrosis and apoptosis. IGF-1R expression and apoptosis (active caspase-3) were studied by immunohistochemistry. Surgical intestinal specimens [17 CD, nine controls, six diverticulitis and four ulcerative colitis (UC)] were used. IGF-1R was expressed transmurally mainly by inflammatory cells (IC) and smooth muscle cells, both in diseased intestine and controls. IGF-1R positive IC were increased in the mucosa and the submucosa of CD (P < 0.007), and in involved areas compared to uninvolved areas (P = 0.03). In UC, the number of IGF-1R positive IC was only increased in the mucosa, and was not different from controls in the submucosa. In diverticulitis, the number of IGF-1R positive IC did not differ from controls. In CD submucosa, IGF-1R expression in IC was inversely correlated with apoptosis in uninvolved areas (P = 0.01). Expression of IGF-1R in submucosal fibroblast-like cells, subserosal adipocytes and hypertrophic nervous plexi was specific for CD. We have shown a transmural altered expression of IGF-1R in CD. This may suggest a role for IGF-1R in the maintenance of chronic inflammation and stricture formation in CD.

Zouali H, Lesage S, Merlin F, Cézard JP, Colombel JF, Belaiche J, Almer S, Tysk C, O'Morain C, Gassull M, Christensen S, Finkel Y, Modigliani R, Gower-Rousseau C, Macry J, Chamaillard M, Thomas G, Hugot JP, Anonymous00017, Anonymous00018. · Fondation Jean Dausset-CEPH, Paris, France. · Gut. · Pubmed #12477763 links to  free full text

Abstract: BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex genetic disorders. CARD15/NOD2, a member of the Ced4 superfamily which includes Apaf-1 and CARD4/NOD1, has recently been associated with genetic predisposition to CD but additional genetic factors remain to be identified. Because CARD4/NOD1 shares many structural and functional similarities with CARD15, we tested its putative role in IBD. PATIENTS AND METHODS: The 11 exons of CARD4 were screened for the presence of variants in 63 unrelated IBD patients. The only non-private genetic variation encoding for a substitution in the peptidic chain was genotyped in 381 IBD families (235 CD, 58 UC, 81 mixed, and seven indeterminate colitis families) using a polymerase chain reaction-restriction fragment length polymorphism procedure. Genotyping data were analysed by the transmission disequilibrium test. RESULTS: Five of nine sequence variations identified in the coding sequence of the gene encoded for non-conservative changes (E266K, D372N, R705Q, T787M, and T787K). Four were present in only one family. The remaining variant (E266K), which exhibited an allele frequency of 0.28, was not associated with CD, UC, or IBD. Furthermore, IBD patients carrying sequence variations in their CARD4 gene had a similar phenotype to those with a normal sequence. CONCLUSION: Our results suggest that CARD4 does not play a major role in genetic susceptibility to IBD.

Piront P, Louis E, Latour P, Plomteux O, Belaiche J. · Service de Gastroentérologie, CHU of Liège, Belgique. · Gastroenterol Clin Biol. · Pubmed #11938067 links to  free full text

Abstract: OBJECTIVE: Inflammatory bowel diseases (IBD) are heterogeneous diseases which affect preferentially young adults. The late onset could represent a particular form of expression of these diseases. The aim of our prospective study was to describe the incidence of IBD in patients older than 60 years as well as their clinical pattern in comparison with a population younger than 60.METHODS: A standardized questionnaire for each new case diagnosed in the province of Liège between 01/06/1993 and 31/05/1996 was completed.RESULTS: During the three years, 270 patients were enrolled. In group IBD > 60 years old, there were 60 new cases, including 23 cases with Crohn's disease (CD) (38%), 30 with ulcerative colitis (UC) (50%), and 7 with undetermined colitis (IC) (12%). The proportion of CD was significantly lower in the group IBD > 60 years old than in the group<60 (114 CD (54%), 81 UC (39%) and 15 IC (7%); P=0.04).The annual incidence tended to be higher for UC than for CD in group IBD > 60 (4.5 and 3.5 per 100,000, respectively) while it was the contrary in younger patients (3.4 and 4.8 per 100,000, respectively). There was no striking difference in the clinical features for both diseases in the two groups, except more frequent diarrhea, weight loss and extraintestinal symptoms in CD patients<60 years old.CONCLUSIONS: In the province of Liège, the incidence of IBD in people older than 60 years is high. IBD in the elderly is characterized by a lower proportion of CD than in the younger population. Clinical features tend to be the same whatever the age at diagnosis for each disease.

Lesage S, Zouali H, Cézard JP, Colombel JF, Belaiche J, Almer S, Tysk C, O'Morain C, Gassull M, Binder V, Finkel Y, Modigliani R, Gower-Rousseau C, Macry J, Merlin F, Chamaillard M, Jannot AS, Thomas G, Hugot JP, Anonymous00210, Anonymous00211, Anonymous00212. · Fondation Jean Dausset-CEPH, 27 rue Juliette Dodu, 75010 Paris, France. · Am J Hum Genet. · Pubmed #11875755 links to  free full text

Abstract: CARD15/NOD2 encodes a protein involved in bacterial recognition by monocytes. Mutations in CARD15 have recently been found in patients with Crohn disease (CD), a chronic inflammatory condition of the digestive tract. Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects. Of 67 sequence variations identified, 9 had an allele frequency >5% in patients with CD. Six of them were considered to be polymorphisms, and three (R702W, G908R, and 1007fs) were confirmed to be independently associated with susceptibility to CD. Also considered as potential disease-causing mutations (DCMs) were 27 rare additional mutations. The three main variants (R702W, G908R, and 1007fs) represented 32%, 18%, and 31%, respectively, of the total CD mutations, whereas the total of the 27 rare mutations represented 19% of DCMs. Altogether, 93% of the mutations were located in the distal third of the gene. No mutations were found to be associated with UC. In contrast, 50% of patients with CD carried at least one DCM, including 17% who had a double mutation. This observation confirmed the gene-dosage effect in CD. The patients with double-dose mutations were characterized by a younger age at onset (16.9 years vs. 19.8 years; P=.01), a more frequent stricturing phenotype (53% vs. 28%; P=.00003; odds ratio 2.92), and a less frequent colonic involvement (43% vs. 62%; P=.003; odds ratio 0.44) than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of patients with CD with or without mutation. These findings provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel disease.

Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G. · Fondation Jean Dausset CEPH, 27 rue J. Dodu 75010 Paris, France. · Nature. · Pubmed #11385576 No free full text.

Abstract: Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.

Belaiche J, Louis E. · Department of gastroenterology, CHU Sart-Tilman, 4000 Liège, Belgium. · Acta Gastroenterol Belg. · Pubmed #11189987 No free full text.

Abstract: Severe colitis is life-threatening complication of ulcerative colitis. Early recognition of the severity of the colitis, intensive medical therapy and prompt surgery when necessary have all contributed to improved outcome. Initial medical treatment should be instituted as soon as the diagnosis is made with an intravenous corticosteroid associated with supportive treatment. If the patient fails to response to this intensive treatment after 5-7 days, cyclosporin should be initiated. If cyclosporin is not used then colectomy should be performed immediately. Moreover, significant deterioration at any point during medical therapy is an indication for colectomy. The gravity of the patient's condition require close interaction between physician an surgeon.

Lesage S, Zouali H, Colombel JF, Belaiche J, Cézard JP, Tysk C, Almer S, Gassull M, Binder V, Chamaillard M, Le Gall I, Thomas G, Hugot JP. · Fondation Jean Dausset/CEPH and Unité INSERM 434, 27 rue Juliette Dodu, 75010 Paris, France. · Gut. · Pubmed #11076876 links to  free full text

Abstract: BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn's disease, both of which are multifactorial diseases involving the interaction of genetic and environmental factors. A region on chromosome 12 centred around the marker locus D12S83 has previously been associated with IBD predisposition. The aim of the study was to investigate this genetic region in an independent panel of European families affected by Crohn's disease. METHODS: A sample of 95 families with two or more affected relatives and 75 simplex nuclear families were genotyped for 19 microsatellite loci located on chromosome 12. A search for linkage and linkage disequilibrium was performed using non-parametric two point and multipoint analyses with the Analyze and Genehunter packages. RESULTS: No evidence of linkage or linkage disequilibrium was observed for any of the marker loci, including D12S83 (p=0.35 for the two point linkage test). Multipoint linkage analysis also failed to reveal positive linkage on chromosome 12. Power calculations allowed us to reject the hypothesis that the genetic region of chromosome 12 centred on D12S83 contains a susceptibility locus with a relative risk (lambda(s)) equal to or greater than 2.0 in these families. CONCLUSION: Failure to detect linkage or linkage disequilibrium in these families suggests that the chromosome 12 locus previously reported to be associated with genetic predisposition to IBD does not play a role in all European family samples. This observation is compatible with heterogeneity in the genetic basis of susceptibility to the disease and/or exposure to various environmental factors among Caucasian families.

Louis E, Ribbens C, Godon A, Franchimont D, De Groote D, Hardy N, Boniver J, Belaiche J, Malaise M. · Department of Gastroenterology, Inflammatory Diseases Research Group, and Department of Pathology, CHU, Liège, Belgium. · Clin Exp Immunol. · Pubmed #10792371 links to  free full text

Abstract: Inflammatory bowel diseases (IBD) are characterized by a sustained inflammatory cascade that gives rise to the release of mediators capable of degrading and modifying bowel wall structure. Our aims were (i) to measure the production of matrix metalloproteinase-3 (MMP-3), and its tissue inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), by inflamed and uninflamed colonic mucosa in IBD, and (ii) to correlate their production with that of proinflammatory cytokines and the anti-inflammatory cytokine, IL-10. Thirty-eight patients with IBD, including 25 with Crohn's disease and 13 with ulcerative colitis, were included. Ten controls were also studied. Biopsies were taken from inflamed and uninflamed regions and inflammation was graded both macroscopically and histologically. Organ cultures were performed for 18 h. Tumour necrosis factor-alpha (TNF-alpha), IL-6, IL-1beta, IL-10, MMP-3 and TIMP-1 concentrations were measured using specific immunoassays. The production of both MMP-3 and the TIMP-1 were either undetectable or below the sensitivity of our immunoassay in the vast majority of uninflamed samples either from controls or from those with Crohn's disease or ulcerative colitis. In inflamed mucosa, the production of these mediators increased significantly both in Crohn's disease (P < 0.01 and 0.001, respectively) and ulcerative colitis (P < 0.001 and 0.001, respectively). Mediator production in both cases was significantly correlated with the production of proinflammatory cytokines and IL-10, as well as with the degree of macroscopic and microscopic inflammation. Inflamed mucosa of both Crohn's disease and ulcerative colitis show increased production of both MMP-3 and its tissue inhibitor, which correlates very well with production of IL-1beta, IL-6, TNF-alpha and IL-10.