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 4protease 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.

Structural investigation of the cold-adapted acylaminoacyl peptidase from Sporosarcina psychrophila by atomistic simulations and biophysical methods

“…A cold-adapted variant from Sporosarcina psychrophila AAP (SpAAP) [19,20] and another thermophilic AAP [21] have been recently isolated and characterized. AAPs not only represent an intriguing model for the study of structure-function-dynamics relationships, but also are of marked pharmacological interest [22][23][24].…”

Seasonal variations in the onset of ulcerative colitis in Japan

“…UC is the result of a complex interaction between genetic susceptibility [1] , stimulation by bacterial antigens [2] in the lumen and occasional environmental triggers [3] that damage the mucosal barrier. Although the incidence and prevalence of UC is lower in Asia than in the West, recent population-based and referral center cohorts have shown a rising incidence and prevalence of UC in Asia [3] .…”

Brooke-Spiegler Syndrome Associated with Ulcerative Rectosigmoiditis

“…In CYLD-nuW mice an increased predisposition to inducible colitis has been observed (11). Another study investigated the genes that have the role of proteases and protease inhibitors (P/PIs) in inflammatory bowel disease in populations of European ancestry, and pointed out that CYLD gene is the highest ranked P/PI gene associated with inflammatory bowel diseases (14). Also, in an expression microarray study, CFLD was one of the most significantly down-regulated genes in the intestine of patients with inflammatory bowel disease (12).…”

“…To confirm the diagnosis of BSS, mutation analysis of the CYLD gene was performed by sequence analysis of all coding exons [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], exon/intron boundaries and Q-PCR analysis (laboratory of the Department of Clinical Genetics of Erasmus MC, Rotterdam, The Netherlands). A splice-site mutation, 2350+5G>A in the exon 17 of the CYLD gene was found.…”