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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.
Gut; 68(5): 854-865, 2019 05.
Artigo em Inglês | 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.
Selo DaSilva