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

World J Gastroenterol. 2007 Jun 7;13(21):2960-6. doi: 10.3748/wjg.v13.i21.2960.

Abstract

Aim: 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.

Methods: 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.

Results: 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).

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Risk Factors
  • Tissue Inhibitor of Metalloproteinases / genetics*
  • Tissue Inhibitor of Metalloproteinases / physiology
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • Tissue Inhibitor of Metalloproteinases
  • Tumor Necrosis Factor-alpha
  • DNA
  • Matrix Metalloproteinases