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


CONCLUSIONS
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.
Meijer
Martin J W
MJ
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
Mieremet-Ooms
Marij A C
MA
van Hogezand
Ruud A
RA
Lamers
Cornelis B H W
CB
Hommes
Daniel W
DW
Verspaget
Hein W
HW
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000503:physiopathology; D003424:Crohn Disease / Q000235:genetics* / Q000503:physiopathology; D004247:DNA / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000502:physiology; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000502:physiology
D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D020782:Matrix Metalloproteinases