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.

Figure 1. Flow diagram of the systematic review.

Figure 2. Histograms on the number of positive studies per P/PI gene (left), the percentage of positive studies per P/PI gene (middle), and the distribution of evidence scores (right) for Crohn's disease (A) and ulcerative colitis (B).

Figure 3. Chromosomal location of top-ranked P/PI genes in Crohn's disease (A) and ulcerative colitis (B).

(A) The top 20 P/PI genes for Crohn's disease clustered on chromosomes 2 (1/20; 5%), 3 (4/20; 20%), 16 (13/20; 65%), and 19 (2/20; 10%). (B) The top 18 P/PI genes for ulcerative colitis were located on chromosomes 2 (1/18; 6%), 3 (5/18; 28%), 6 (2/18; 11%), 12 (8/18; 44%), 15 (1/18; 6%), and 19 (1/18; 6%). The depicted chromosomal banding pattern is according to Ensembl (http://Mar2010.archive.ensembl.org/Homo_sapiens/Location/View?) and has been released by the International System for Human Cytogenetic Nomenclature in 2005.

Figure 4. Visual display of results found in 21 positive studies of the top-ranked gene in Crohn's disease, CYLD.

As a illustrative example for all P/PI genes, the CYLD (cylindromatosis/turban tumor syndrome, chr16q12.1, 49.33–49.39 Mb) gene is shown. CYLD was mapped onto the critical regions shaded in grey. The critical regions of later studies, including genome-wide association scans and replications of genome-wide association scans and some candidate region studies, were more narrow compared with critical regions of earlier studies because of the improved resolution of more recent genotyping platforms.