Ulcerative Colitis: Witt H

Baumgart DC, Buning C, Geerdts L, Schmidt HH, Genschel J, Fiedler T, Gentz E, Molnar T, Nagy F, Lonovics J, Lochs H, Wiedenmann B, Nickel R, Witt H, Dignass A. · Division of Gastroenterology and Hepatology, Department of Medicine, Charité Medical School, Humboldt University of Berlin, Berlin, Germany. · Digestion. · Pubmed #18174680 No free full text.

Abstract: BACKGROUND: Inflammatory bowel disease (IBD) results from an aberrant immune response to the indigenous intestinal flora in genetically susceptible hosts. Therefore, the study of candidate genes involved in host pathogen interactions is of key interest. METHODS: In this two-center, retrospective German and Hungarian cohort study, patients with Crohn's disease (CD) (n = 379; German n = 235, Hungarian n = 144) and ulcerative colitis (UC) (n = 263; German n = 145, Hungarian n = 118) and healthy controls (n = 605; German n = 403, Hungarian n = 202) were genotyped for the presence of the CD14 c.1-260C>T promoter variant and the TLR4 c.896A>G (p.D299G) variant by melting curve analysis using fluorescence resonance energy transfer probes. Data were stratified according to the presence of NOD2 (CARD15) mutations and a detailed genotype-phenotype analysis was performed. RESULTS: In the German cohort the CD14 single-nucleotide polymorphism was associated with UC, but not CD (UC p = 0.016 vs. CD p = 0.190), while the opposite was found in the Hungarian cohort (UC p = 0.083 vs. CD p = 0.019). No association of IBD with the TLR4 single-nucleotide polymorphism was found in either cohort (UC p = 0.430, CD p = 0.783 vs. UC p = 0.745, CD p = 0.383). CONCLUSION: IBD appears to be associated with the CD14 c.1-260C>T promoter variant in Germans and Hungarians, but not with the TLR4 c.896A>G (p.D299G) variant.

Büning C, Schmidt HH, Molnár T, Drenth JP, Fiedler T, Gentz E, Todorov T, Baumgart DC, Sturm A, Nagy F, Lonovics J, de Jong DJ, Landt O, Kage A, Nickel R, Büttner J, Lochs H, Witt H. · Department of Gastroenterology, Hepatology & Endocrinology, Charité, Campus Mitte, Universitätsmedizin Berlin, Germany. · Inflamm Bowel Dis. · Pubmed #18092344 links to  free full text

Abstract: BACKGROUND: A recent study reported that the c.30T>A (p.Cys10Ter; rs2043211) variant, in the CARD8 (TUCAN) gene, is associated with Crohn's disease (CD). The aim of this study was to analyze the frequency of p.C10X in 3 independent European (IBD) cohorts from Germany, Hungary, and the Netherlands. METHODS: We included a European IBD cohort of 921 patients and compared the p.C10X genotype frequency to 832 healthy controls. The 3 study populations analyzed were: (1) Germany [CD, n = 317; ulcerative colitis (UC), n = 180], (2) Hungary (CD, n = 149; UC, n = 119), and (3) the Netherlands (CD, n = 156). Subtyping analysis was performed in respect to NOD2 variants (p.Arg702Trp, p.Gly908Arg, c.3020insC) and to clinical characteristics. Ethnically matched controls were included (German, n = 413; Hungarian, n = 202; Dutch, n = 217). RESULTS: We observed no significant difference in p.C10X genotype frequency in either patients with CD or patients with UC compared with controls in all 3 cohorts. Conversely to the initial association study, we found a trend toward lower frequencies of the suggestive risk wild type in CD from the Netherlands compared with controls (P = 0.14). We found neither evidence for genetic interactions between p.C10X and NOD2 nor the C10X variant to be associated with a CD or UC phenotype. CONCLUSIONS: Analyzing 3 independent European IBD cohorts, we found no evidence that the C10X variant in CARD8 confers susceptibility for CD.

Büning C, Schmidt HH, Molnar T, De Jong DJ, Fiedler T, Bühner S, Sturm A, Baumgart DC, Nagy F, Lonovics J, Drenth JP, Landt O, Nickel R, Büttner J, Lochs H, Witt H. · Department of Gastroenterology, Hepatology and Endocrinology, Charité, Campus Mitte, Universitätsmedizin Berlin, Berlin, Germany. · Aliment Pharmacol Ther. · Pubmed #17877509 No free full text.

Abstract: BACKGROUND: A recent study reported that a non-synonymous single nucleotide polymorphism (rs11209026, p.Arg381Gln) located in the IL23R gene is a protective marker for inflammatory bowel disease. AIM: To analyse the frequency of p.Arg381Gln in three independent European inflammatory bowel disease cohorts and to evaluate how this variant influences disease behaviour. METHODS: We assessed a European cohort of 919 inflammatory bowel disease patients and compared the IL23R p.Arg381Gln genotype frequency with 845 healthy controls. Inflammatory bowel disease patients originated from Germany [Crohn's disease (CD): n = 318; ulcerative colitis (UC): n = 178], Hungary (CD: n = 148; UC: n = 118) and the Netherlands (CD: n = 157). Ethnically matched controls were included. We performed subtyping analysis in respect to CARD15 alterations and clinical characteristics. RESULTS: The frequency of the glutamine allele of p.Arg381Gln was significantly lower in inflammatory bowel disease patients compared with controls in a pooled analysis of all three cohorts (P < 0.000001) as well as in the individual cohorts (Germany: P = 0.001, Hungary: P = 0.02 and the Netherlands: P = 0.0002). The p.Arg381Gln genotype distribution was similar between CD and UC. We did not observe either statistical interactions between p.Arg381Gln and CARD15 variants or any significant associations between p.Arg381Gln genotype and subphenotypes. CONCLUSIONS: The p.Arg381Gln IL23R variant confers a protective effect against both CD and UC, but does not determine disease phenotype.

Büning C, Geerdts L, Fiedler T, Gentz E, Pitre G, Reuter W, Luck W, Buhner S, Molnar T, Nagy F, Lonovics J, Dignass A, Landt O, Nickel R, Genschel J, Lochs H, Schmidt HH, Witt H. · Department of Gastroenterology, Hepatology & Endocrinology, Charité, Campus Mitte, Universitätsmedizin Berlin, Berlin, Germany. · Am J Gastroenterol. · Pubmed #16494592 No free full text.

Abstract: OBJECTIVES: Genetic variants within DLG5 were recently reported to be associated with inflammatory bowel disease (IBD). The aim of our study was to test for allelic and haplotype associations of six DLG5 variants in 668 IBD patients from two European populations. Furthermore, we evaluated whether DLG5 variants alter gastrointestinal permeability in Crohn's disease (CD). METHODS: Six DLG5 variants (p.R30Q, p.P1371Q, p.G1066G, rs2289308, DLG_e26, p.D1507D) were genotyped in two study populations: (1) German IBD patients (CD n = 250; ulcerative colitis (UC) n = 150) and German healthy controls (n = 422); (2) Hungarian IBD patients (CD n = 144; UC n = 124) and Hungarian healthy controls (n = 205). Subtyping analysis was performed in respect of CARD15 mutations and clinical characteristics. We also tested for differences within DLG5 genotypes in German CD patients with respect to gastroduodenal and intestinal permeability measured by triple-sugar-test. RESULTS: Allele as well as genotype frequencies of DLG5 variants did not differ between IBD patients and controls in either study population. Indeed, the p.R30Q polymorphism was found more frequently in controls than in patients. The distribution of DLG5 genotypes in German and Hungarian CD patients with CARD15 mutations was not different from patients without mutated CARD15. We did also not observe any association between DLG5 variants and clinical parameters. Importantly, DLG5 variants were not associated with gastroduodenal or intestinal permeability. CONCLUSIONS: We could not replicate that DLG5 is a relevant disease susceptibility gene for IBD in German or Hungarian subjects. In addition, we have no evidence that DLG5 variants are involved in altered gastrointestinal permeability in CD.

Büning C, Halangk J, Dignass A, Ockenga J, Deindl P, Nickel R, Genschel J, Landt O, Lochs H, Schmidt H, Witt H. · Department of Gastroenterology, Hepatology and Endocrinology, Universitätsmedizin Berlin, Charité, Campus Mitte, Schumannstrasse 20/21, D-10117 Berlin, Germany. · Dig Liver Dis. · Pubmed #15248378 No free full text.

Abstract: BACKGROUND: Keratin 8 is a major component of intermediate filaments in single-layered epithelia of the gastrointestinal tract. Keratin 8 deficient mice display signs of colitis and diarrhoea characteristic for inflammatory bowel disease. Very recently, two keratin 8 mutations, Y54H and G62C, were identified. AIMS: We investigated if these keratin 8 missense mutations were associated with inflammatory bowel disease. PATIENTS: In total, 217 German patients with Crohn' s disease, 131 German patients with ulcerative colitis, and 560 German control subjects were enrolled in this study. METHODS: Samples were analysed by PCR amplification and subsequent melting curve analysis using fluorescence resonance energy transfer probes. RESULTS: The G62C mutation was detected in five (2.3%) patients presenting with Crohn's disease and in three (2.3%) with ulcerative colitis. In comparison, 9 (1.6%) out of 560 controls were heterozygous for this mutation. No patient or control was homozygous for this mutation. Patients carrying one mutant allele did not show any noticeable characteristics in their corresponding phenotype. In contrast, the Y54H mutation was observed in neither any of the 348 patients with inflammatory bowel disease nor in any control subject. CONCLUSIONS: Our data indicate that both keratin 8 mutations, G62C and Y54H, do not play a relevant pathogenic role in inflammatory bowel disease.