Genetic evidence supporting the association of protease and protease inhibitor genes with inflammatory bowel disease: a systematic review

• Published in: PloS one Vol. 6; no. 9; p. e24106
• Main Authors: Cleynen, Isabelle, Jüni, Peter, Bekkering, Geertruida E, Nüesch, Eveline, Mendes, Camila T, Schmied, Stefanie, Wyder, Stefan, Kellen, Eliane, Villiger, Peter M, Rutgeerts, Paul, Vermeire, Séverine, Lottaz, Daniel
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.09.2011; Public Library of Science (PLoS)
• Subjects: Acids; Acylaminoacyl-peptidase; Analysis; Biology; Chromosome 16; Chromosome 3; Clinical trials; Consortia; Crohn's disease; Crohns disease; Databases, Protein; Deubiquitinating Enzyme CYLD; Dystroglycan; Dystroglycans - genetics; Gastroenterology; Gastrointestinal system; Gastrointestinal tract; Genes; Genetic Predisposition to Disease - genetics; Genome-Wide Association Study; Genomes; Haplotypes; Hepatocyte Growth Factor - genetics; Humans; Immunology; In vivo methods and tests; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory Bowel Diseases - genetics; Intestine; Macrophage-stimulating protein; Macrophages; Medical research; Medicine; Meta-analysis; Mucosa; Pathogenesis; Pediatrics; Peptidase; Peptidases; Peptide Hydrolases - genetics; Population genetics; Population studies; Preventive medicine; Protease; Protease Inhibitors; Proteases; Proteinase inhibitors; Proto-Oncogene Proteins - genetics; Rankings; Reviews; Rheumatology; Studies; Tumor Suppressor Proteins - genetics; Ubiquitin; Ubiquitin Thiolesterase - genetics; Ubiquitin-Specific Proteases; Ulcerative colitis; Belgium; Switzerland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0024106

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.