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Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.
Schafmayer, Clemens; Harrison, James William; Buch, Stephan; Lange, Christina; Reichert, Matthias C; Hofer, Philipp; Cossais, François; Kupcinskas, Juozas; von Schönfels, Witigo; Schniewind, Bodo; Kruis, Wolfgang; Tepel, Jürgen; Zobel, Myrko; Rosendahl, Jonas; Jacobi, Thorsten; Walther-Berends, Andreas; Schroeder, Michael; Vogel, Ilka; Sergeev, Petr; Boedeker, Hans; Hinrichsen, Holger; Volk, Andreas; Erk, Jens-Uwe; Burmeister, Greta; Hendricks, Alexander; Hinz, Sebastian; Wolff, Sebastian; Böttner, Martina; Wood, Andrew R; Tyrrell, Jessica; Beaumont, Robin N; Langheinrich, Melanie; Kucharzik, Torsten; Brezina, Stefanie; Huber-Schönauer, Ursula; Pietsch, Leonora; Noack, Laura Sophie; Brosch, Mario; Herrmann, Alexander; Thangapandi, Raghavan Veera; Schimming, Hans Wolfgang; Zeissig, Sebastian; Palm, Stefan; Focke, Gerd; Andreasson, Anna; Schmidt, Peter T; Weitz, Juergen; Krawczak, Michael; Völzke, Henry; Leeb, Gernot.
Afiliación
  • Schafmayer C; Department of Visceral and Thoracic Surgery, Kiel University, Kiel, Germany.
  • Harrison JW; University of Exeter Medical School, University of Exeter, United Kingdom, Exeter, UK.
  • Buch S; Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
  • Lange C; Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden, Germany.
  • Reichert MC; Institute of Anatomy, Kiel University, Kiel, Germany.
  • Hofer P; Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
  • Cossais F; Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
  • Kupcinskas J; Institute of Anatomy, Kiel University, Kiel, Germany.
  • von Schönfels W; Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
  • Schniewind B; Department of Visceral and Thoracic Surgery, Kiel University, Kiel, Germany.
  • Kruis W; General Hospital Lüneburg, Lüneburg, Germany.
  • Tepel J; Department of Internal Medicine, Gastroenterology and Pulmonology, Evangelic Hospital Köln-Kalk, Cologne, Germany.
  • Zobel M; Department of General and Thoracic Surgery, Hospital Osnabrück, Osnabrück, Germany.
  • Rosendahl J; Department of Gastroenterology, Helios Hospital Weißeritztal, Freital, Germany.
  • Jacobi T; Medical Department 1, University Hospital Halle, Martin-Luther Universität Halle-Wittenberg, Halle, Germany.
  • Walther-Berends A; Diakonissenanstalt, Hospital Dresden, Dresden, Germany.
  • Schroeder M; Gastroenterology Outpatient Center Fördepraxis, Kiel, Germany.
  • Vogel I; Center for Gastroenterology and Hepatology, Kiel, Germany.
  • Sergeev P; Department of Surgery, Community Hospital Kiel, Kiel, Germany.
  • Boedeker H; Department of Internal Medicine II, Hospital Riesa, Kiel, Germany.
  • Hinrichsen H; Department of Internal Medicine, Hospital Freiberg, Freiberg, Germany.
  • Volk A; Center for Gastroenterology and Hepatology, Kiel, Germany.
  • Erk JU; Department of Visceral, Thoracic and Vascular Surgery, Technische Universität Dresden (TU Dresden), Dresden, Germany.
  • Burmeister G; Medical Department 1, University Hospital Halle, Martin-Luther Universität Halle-Wittenberg, Halle, Germany.
  • Hendricks A; Department of Visceral and Thoracic Surgery, Kiel University, Kiel, Germany.
  • Hinz S; Department of Visceral and Thoracic Surgery, Kiel University, Kiel, Germany.
  • Wolff S; Department of Visceral and Thoracic Surgery, Kiel University, Kiel, Germany.
  • Böttner M; Department of Internal Medicine, Gastroenterology and Pulmonology, Evangelic Hospital Köln-Kalk, Cologne, Germany.
  • Wood AR; Institute of Anatomy, Kiel University, Kiel, Germany.
  • Tyrrell J; University of Exeter Medical School, University of Exeter, United Kingdom, Exeter, UK.
  • Beaumont RN; University of Exeter Medical School, University of Exeter, United Kingdom, Exeter, UK.
  • Langheinrich M; University of Exeter Medical School, University of Exeter, United Kingdom, Exeter, UK.
  • Kucharzik T; Department of Surgery, University Hospital Erlangen, Erlangen, Germany.
  • Brezina S; General Hospital Lüneburg, Lüneburg, Germany.
  • Huber-Schönauer U; Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
  • Pietsch L; Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private Medical University of Salzburg, Oberndorf, Austria.
  • Noack LS; Medical Department 1, University Hospital Halle, Martin-Luther Universität Halle-Wittenberg, Halle, Germany.
  • Brosch M; Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
  • Herrmann A; Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
  • Thangapandi RV; Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden, Germany.
  • Schimming HW; Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
  • Zeissig S; Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
  • Palm S; Department of Gastroenterology, Helios Hospital Weißeritztal, Freital, Germany.
  • Focke G; Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
  • Andreasson A; Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden, Germany.
  • Schmidt PT; Outpatient Center for Gastroenterology, Dippoldiswalde, Germany.
  • Weitz J; Outpatient Center for Gastroenterology Dresden-Blasewitz, Dresden, Germany.
  • Krawczak M; Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
  • Völzke H; Stress Research Institute, Stockholm University, Stockholm, Sweden.
  • Leeb G; Department of Medicine Solna and Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Gut ; 68(5): 854-865, 2019 05.
Article en En | MEDLINE | ID: mdl-30661054
OBJECTIVE: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. DESIGN: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. RESULTS: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10-10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). CONCLUSION: In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades del Colon / Tejido Conectivo / Epitelio / Estudio de Asociación del Genoma Completo / Enfermedades Diverticulares / Unión Neuromuscular Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Adult / Aged / Female / Humans / Male / Middle aged País/Región como asunto: Europa Idioma: En Revista: Gut Año: 2019 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades del Colon / Tejido Conectivo / Epitelio / Estudio de Asociación del Genoma Completo / Enfermedades Diverticulares / Unión Neuromuscular Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Adult / Aged / Female / Humans / Male / Middle aged País/Región como asunto: Europa Idioma: En Revista: Gut Año: 2019 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido