Role of matrix metalloproteinase, tissue inhibitor of metalloproteinase and tumor necrosis factor-alpha single nucleotide gene polymorphisms in inflammatory bowel disease

• Published in: World journal of gastroenterology : WJG 2007-06, Vol.13 (21), p.2960-2966
• Main Authors: Meijer, Martin J W, Mieremet-Ooms, Marij A C, van Hogezand, Ruud A, Lamers, Cornelis B H W, Hommes, Daniel W, Verspaget, Hein W
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Case-Control Studies; Child; Colitis, Ulcerative - genetics; Colitis, Ulcerative - physiopathology; Crohn Disease - genetics; Crohn Disease - physiopathology; DNA - genetics; Female; Genetic Predisposition to Disease; Genotype; Humans; Intestinal Mucosa - pathology; Intestinal Mucosa - physiopathology; Male; Matrix Metalloproteinases - genetics; Matrix Metalloproteinases - physiology; Middle Aged; Polymorphism, Single Nucleotide; Rapid Communication; Risk Factors; Tissue Inhibitor of Metalloproteinases - genetics; Tissue Inhibitor of Metalloproteinases - physiology; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - physiology
• ISSN: 1007-9327; 2219-2840
• DOI: 10.3748/wjg.v13.i21.2960

To study the (functional) relevance of single nucleotide polymorphisms (SNPs) in genes encoding matrix metalloproteinases (MMP)-1, -2, -3, -9, tissue inhibitors of metalloproteinases (TIMP)-1, -2 and tumor necrosis factor (TNF)-alpha in the etiopathogenesis of inflammatory bowel diseases (IBD), that may enhance susceptibility and/or disease severity. Genomic DNA from 134 Crohn' s disease (CD), 111 ulcerative colitis (UC) patients and 248 control subjects was isolated from resected intestinal tissue or blood. Allelic composition at SNP loci was determined by PCR-RFLP or tetra primer ARMS PCR. The TIMP-1 genotype TT in women and T in men at SNP +372 T/C was found to increase CD susceptibility (39% vs 23.8%, P = 0.018 and 67.9% vs 51.6%, P = 0.055, respectively), while women with this genotype were less prone to development of fistulae during follow-up (41.4% vs 68.3%, P = 0.025). Male IBD or CD patients carrying the TIMP-1 +372 T-allele expressed lower levels of TIMP-1 in surgically resected macroscopically inflamed tissue (0.065 < P < 0.01). The 5T5T genotype at MMP-3 SNP -1613 5T/6T increased the chance of stenotic complications in CD during follow-up (91.2% vs 71.8%, P = 0.022) but seemed to protect against colonic involvement of this disease at first endoscopic/radiologic examination (35.3% vs 59.5%, P = 0.017). Allelic composition at the examined SNPs in genes coding for TIMP-1 and MMP-3 affect CD susceptibility and/or phenotype, i.e., fistulizing disease, stricture pathogenesis and first disease localisation. These findings reinforce the important role of these proteins in IBD.