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

Martin Meijer

Marij Mieremet-Ooms

Ruud van Hogezand

Cornelis Lamers

Daniel Hommes

Hein Verspaget

Martin JW Meijer, Marij AC Mieremet-Ooms, Ruud A van Hogezand, Cornelis BHW Lamers, Daniel W Hommes, Hein W Verspaget, Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands

Author contributions: All authors contributed equally to the work.

Correspondence to: Dr. Hein W Verspaget, Associate Professor, LUMC, Department of Gastroenterology-Hepatology, C4-P, PO Box 9600, 2300 RC Leiden, The Netherlands. ln.cmul@tegapsrev.w.h

Telephone: +31-71-5262680 Fax: +31-71-5248115

Author contributions: All authors contributed equally to the work.

Correspondence to: Dr. Hein W Verspaget, Associate Professor, LUMC, Department of Gastroenterology-Hepatology, C4-P, PO Box 9600, 2300 RC Leiden, The Netherlands. ln.cmul@tegapsrev.w.h

Telephone: +31-71-5262680 Fax: +31-71-5248115

Received 2007 Mar 28; Revised 2007 Apr 3; Accepted 2007 Apr 18.

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)-α 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.

Keywords: Crohn’s disease, Ulcerative colitis, Matrix metalloproteinases, Inhibitors of matrix metalloproteinases, Single nucleotide gene polymorphisms

Abstract

n = 239-240/245 IBD patients vs n = 244/248 controls with successful genotype determinations.

♂: n = 53/54 vs 93/96; ♀: n = 77/80 vs 151/152 successful genotype determinations, respectively. ^P-value, Chi-Square test.

Footnotes

Supported by grant WS98-17 from the Netherlands Digestive Diseases Foundation

S- Editor Liu Y L- Editor Alpini GD E- Editor Lu W

Footnotes

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