Ulcerative Colitis: Finkel Y

Thiébaut R, Kotti S, Jung C, Merlin F, Colombel JF, Lemann M, Almer S, Tysk C, O'Morain M, Gassull M, Binder V, Finkel Y, Pascoe L, Hugot JP. · INSERM, U843, Hôpital Robert Debré, Université Paris Diderot, Paris, France. · Am J Gastroenterol. · Pubmed #19174806 No free full text.

Abstract: OBJECTIVES: Inflammatory bowel disease (IBD), e.g., Crohn's disease (CD) and ulcerative colitis (UC), is a complex genetic disorder. Tumor necrosis factor (ligand) superfamily, member 15 (TNFSF15) has been previously identified as a susceptibility gene for CD in Japanese and UK cohorts. This replication study was designed in order to confirm and further validate the role of TNFSF15 in IBD. METHODS: A total of 666 IBD families (corresponding to 2,982 relatives) with European ancestry were genotyped for the rs6478108 and rs7869487 polymorphisms, which define the main TNFSF15 haplotypes previously associated with CD. An association between the main haplotypes and CD, UC and IBD was tested using the Genehunter TDT and Unphased statistics. Caspase recruitment domain 15 (CARD15)/TNFSF15 interaction and genotype/phenotype correlations were also studied. RESULTS: The previously reported "high-risk" haplotype (A) was associated with IBD (P=0.001) (OR=1.25 (1.05-1.50)) and CD (P=0.02) (OR=1.31 (1.03-1.67)) whereas the "protective" (B) haplotype was significantly less transmitted to IBD and CD patients. No interaction between CARD15 and TNFSF15 was detected. We also failed to define a clinical subgroup of CD patients specifically associated with TNFSF15 haplotype A. CONCLUSIONS: This study confirms that TNFSF15 or a closely linked gene is involved in the genetic predisposition to CD.

Hildebrand H, Finkel Y, Grahnquist L, Lindholm J, Ekbom A, Askling J. · Department of Women and Child Health, Astrid Lindgren Children's Hospital, Stockholm, Sweden. · Gut. · Pubmed #12970135 links to  free full text

Abstract: BACKGROUND: An increased incidence of paediatric Crohn's disease was reported recently by our group. AIMS: To assess the incidence and characteristics of inflammatory bowel disease (IBD) in northern Stockholm between 1990 and 2001. METHODS: All records of individuals 0-15 years of age with suspected IBD in the population based catchment area of 180000 individuals were scrutinised using defined diagnostic criteria. Patient files were searched for relatives with IBD, and for concomitant autoimmune diseases. RESULTS: A total of 152 children were diagnosed with IBD, corresponding to an overall incidence (per 100000) of IBD of 7.4. The incidence of Crohn's disease (CD) was 4.9, ulcerative colitis (UC) 2.2, and indeterminate colitis 0.2. Between 1990 and 2001, there was a marked increase in the incidence of CD while the incidence of UC was almost unchanged, leading to a net increase in the overall occurrence of IBD. There was a male dominance of CD. Fourteen per cent and 11% of patients with CD and UC, respectively, had a first or second degree relative with IBD. Eighteen per cent and 10% of patients with CD and UC, respectively, had a concomitant autoimmune disease. Ten patients with CD (10%) underwent surgery. CONCLUSIONS: The incidence of CD has increased in northern Stockholm. The current incidence is higher than that reported from other areas. Our results suggest a shift in presentation and diagnosis from UC towards CD, but also a net increase in IBD. Concomitant autoimmune disorders and family history are common in paediatric IBD.

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.

Ljung T, Beijer E, Herulf M, Weitzberg E, Lundberg JO, Finkel Y, Hellström PM. · Departments of Gastroenterology and Hepatology, Karolinska Hospital, Stockholm, Sweden. · J Pediatr Gastroenterol Nutr. · Pubmed #11964958 No free full text.

Abstract: BACKGROUND: Luminal nitric oxide increases in ulcerative colitis and Crohn disease. The authors have previously used a minimally invasive method to demonstrate increased luminal nitric oxide in ulcerative colitis and Crohn disease of the colon. The aim of the current study was to determine whether this method could be applied to identify inflammatory activity in ulcerative colitis and Crohn disease in children. METHODS: Thirty-six children (18 of whom had active disease) with inflammatory bowel disease localized to the colon were studied. The control group comprised 12 healthy children. To measure nitric oxide, a silicon catheter with an inflatable balloon was inserted into the rectum and inflated with 10 mL of nitric oxide-free air. After a 10-minute incubation time, the air was withdrawn and nitric oxide concentrations were immediately analyzed using a chemiluminescence technique. RESULTS: Children with active ulcerative colitis and Crohn disease of the colon had greatly increased luminal nitric oxide concentrations in the rectum (8,840 +/- 5,120 and 15,170 +/- 4,757 parts per billion [ppb], respectively) compared with controls (77 +/- 17 ppb) (P < 0.001). Children with nonactive ulcerative colitis or Crohn disease displayed low concentrations of rectal nitric oxide (356 +/- 110 and 188 +/- 55 ppb, respectively), which was not different from that of healthy controls. CONCLUSION: Rectal nitric oxide measurement is a feasible and useful method for monitoring disease activity in inflammatory bowel disease, especially in children.

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.

Ljung T, Herulf M, Beijer E, Jacobsson H, Lundberg J, Finkel Y, Hellström PM. · Dept. of Gastroenterology, Karolinska Hospital, Stockholm, Sweden. · Scand J Gastroenterol. · Pubmed #11589381 No free full text.

Abstract: BACKGROUND: Nitric oxide (NO) production is increased in inflammatory bowel disease (IBD). Measurements of luminal NO in Crohn disease and ulcerative colitis have revealed that levels are increased during active disease. We aim to evaluate whether rectal measurements of NO can reveal active disease of the colon as well as ileum. METHODS: Sixteen children with active Crohn disease in the ileocaecal or colorectal regions of the gut and 6 children with active ulcerative colitis were compared to a group of 14 healthy children. Gaseous samples for analysis of luminal NO were collected using a Foley catheter inserted into rectum. The balloon of the catheter was filled with NO-free air and incubated for 10 min. After aspiration, samples were analysed using chemiluminescence. Values are expressed as median and range. RESULTS: In healthy children, rectal NO values were 60 (0-275) ppb. In children with Crohn disease of the colorectal region, NO concentrations were 5,675 (300-49,350) ppb (P < 0.001), while those with Crohn disease of the ileocaecal region had NO levels of 2,625 (300-15,000) ppb (P < 0.01). In children with ulcerative colitis, NO values of 5,500 (950-34,000) ppb were found (P < 0.001). CONCLUSION: Rectal NO levels are greatly increased in children with IBD. Highest values were found in patients with colorectal engagement, but rectal NO was increased also in ileocaecal disease. Rectal sampling of luminal NO is a simple and minimally invasive method and should be considered a diagnostic tool for intestinal inflammatory activity in children regardless of primary disease location.

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.

Askling J, Grahnquist L, Ekbom A, Finkel Y. · No affiliation provided · Lancet. · Pubmed #10513717 No free full text.

Abstract: We report an increase in the incidence of Crohn's disease in northern Stockholm, Sweden.