title: Genetic evidence supporting the association of protease and protease inhibitor genes with inflammatory bowel disease: a systematic review.
abstract: As part of the European research consortium IBDase, we addressed the role of proteases and protease inhibitors (P/PIs) in inflammatory bowel disease (IBD), characterized by chronic mucosal inflammation of the gastrointestinal tract, which affects 2.2 million people in Europe and 1.4 million people in North America. We systematically reviewed all published genetic studies on populations of European ancestry (67 studies on Crohn's disease [CD] and 37 studies on ulcerative colitis [UC]) to identify critical genomic regions associated with IBD. We developed a computer algorithm to map the 807 P/PI genes with exact genomic locations listed in the MEROPS database of peptidases onto these critical regions and to rank P/PI genes according to the accumulated evidence for their association with CD and UC. 82 P/PI genes (75 coding for proteases and 7 coding for protease inhibitors) were retained for CD based on the accumulated evidence. The cylindromatosis/turban tumor syndrome gene (CYLD) on chromosome 16 ranked highest, followed by acylaminoacyl-peptidase (APEH), dystroglycan (DAG1), macrophage-stimulating protein (MST1) and ubiquitin-specific peptidase 4 (USP4), all located on chromosome 3. For UC, 18 P/PI genes were retained (14 proteases and 4 protease inhibitors), with a considerably lower amount of accumulated evidence. The ranking of P/PI genes as established in this systematic review is currently used to guide validation studies of candidate P/PI genes, and their functional characterization in interdisciplinary mechanistic studies in vitro and in vivo as part of IBDase. The approach used here overcomes some of the problems encountered when subjectively selecting genes for further evaluation and could be applied to any complex disease and gene family.
authors.affiliation: Department of Gastroenterology, Catholic University Leuven, Leuven, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cleynen
authors.forename: Peter
authors.initials: P
authors.lastname: Jüni
authors.forename: Geertruida E
authors.initials: GE
authors.lastname: Bekkering
authors.forename: Eveline
authors.initials: E
authors.lastname: Nüesch
authors.forename: Camila T
authors.initials: CT
authors.lastname: Mendes
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schmied
authors.forename: Stefan
authors.initials: S
authors.lastname: Wyder
authors.forename: Eliane
authors.initials: E
authors.lastname: Kellen
authors.forename: Peter M
authors.initials: PM
authors.lastname: Villiger
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
authors.forename: Séverine
authors.initials: S
authors.lastname: Vermeire
authors.forename: Daniel
authors.initials: D
authors.lastname: Lottaz
mesh_terms: D030562:Databases, Protein; D000074749:Deubiquitinating Enzyme CYLD; D049030:Dystroglycans / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D017228:Hepatocyte Growth Factor / Q000235:genetics; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D010447:Peptide Hydrolases / Q000235:genetics*; D011480:Protease Inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics; D064570:Ubiquitin-Specific Proteases
chemical_list: D011480:Protease Inhibitors; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; C486203:USP4 protein, human; C082332:macrophage stimulating protein; D049030:Dystroglycans; D017228:Hepatocyte Growth Factor; D010447:Peptide Hydrolases; C038220:acylaminoacyl-peptidase; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases