Matrix metalloproteinases and their tissue inhibitors as prognostic indicators for diagnostic and surgical recurrence in Crohn's disease.
BACKGROUND
Recurrence of disease after surgically induced remission constitutes a major and largely unpredictable problem in Crohn's disease (CD). Matrix metalloproteinases (MMP) and the tissue inhibitors of metalloproteinases (TIMP) are involved in the (etio)pathogenesis of CD and may thereby also affect postsurgical outcome. We studied the predictive value of 1) allelic composition at MMP, TIMP, and TNF-alpha single nucleotide polymorphism loci, and 2) MMP and TIMP intestinal protein levels relative to important clinical variables for recurrence of CD after resection of diseased bowel.


METHODS
From 87 CD patients with a full medical record, surgically resected tissue was homogenized and analyzed for single nucleotide polymorphism (SNP) genotype and MMP-TIMP protein levels. The prognostic value of these parameters was determined using the uni- and multivariate Cox proportional hazards analyses.


RESULTS
The T allele at TIMP-1 SNP +372 T/C was found to be associated with an increased risk for surgical recurrence. Higher levels of TIMP-1, TIMP-2, and MMP-9 in noninflamed CD tissue, but not in inflamed tissue, and negative smoking status independently protected against diagnostic and/or surgical recurrence.


CONCLUSIONS
The TIMP-1 SNP +372 T allele with an increased risk of recurrence is in line with our previous results demonstrating increased CD susceptibility and low TIMP-1 protein expression associated with this allele. High TIMP and MMP-9 levels in noninflamed tissue are predictive of a favorable disease recurrence in CD. The contribution of MMP-9 and TIMPs to disease recurrence appears not to be mediated by smoking status, since no correlation with this parameter could be demonstrated.
Meijer
Martin J
MJ
LUMC, Department of Gastroenterology-Hepatology, Leiden, The Netherlands.
Mieremet-Ooms
Marij A C
MA
Sier
Cornelis F M
CF
van Hogezand
Ruud A
RA
Lamers
Cornelis B H W
CB
Hommes
Daan W
DW
Verspaget
Hein W
HW
D000293:Adolescent; D000483:Alleles; D003424:Crohn Disease / Q000175:diagnosis / Q000235:genetics* / Q000601:surgery; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D008499:Medical Records; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D012008:Recurrence; D012189:Retrospective Studies; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics* / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D019716:Tissue Inhibitor of Metalloproteinase-2; D020780:Matrix Metalloproteinase 9