Genetic variations in matrix metalloproteinases may be associated with increased risk of ulcerative colitis

Morgan, Angharad R.; Han, Dawei; Lam, Wen-Jiun; Triggs, Christopher M.; Fraser, Alan G.; Barclay, Murray L.; Gearry, Richard B.; Meisner, Sander; Stokkers, Pieter; Boeckxstaens, Guy E.; Ferguson, Lynnette R.

doi:10.1016/j.humimm.2011.08.011

Cited by 19 publications

(22 citation statements)

References 45 publications

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“…The activity of MMP1, 3 and 9 is controlled by tissue inhibitor of metalloproteinase (TIMP-1), the expression of which is also increased in colitis [45]. Increased production of MMPs has a role in tissue damage in IBD and some studies show that genetic variation in MMP genes may play a role in inter-individual differences in UC susceptibility and clinical outcome [46]. The results of this study indicate that increased expression levels of gene transcripts for MMP and TIMP1 proteins in IBD occurs in the epithelium.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Changes in the Colon Epithelium Are Similar to Those of Intact Colon during Late Inflammation in Interleukin-10 Gene Deficient Mice

et al. 2013

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In addition to their role in absorption and secretion, epithelial cells play an important role in the protection of the colon mucosa from the resident microbiota and are important for the maintenance of homeostasis. Microarray analysis of intact colon samples is widely used to gain an overview of the cellular pathways and processes that are active in the colon during inflammation. Laser microdissection of colon epithelial cells allows a more targeted analysis of molecular pathways in the mucosa, preceding and during inflammation, with potentially increased sensitivity to changes in specific cell populations. The aim of this study was to investigate the molecular changes that occur in early and late inflammation stages in colon epithelium of a mouse model of inflammatory bowel diseases. Microarray analysis of intact colon samples and microdissected colon epithelial cell samples from interleukin-10 gene deficient and control mice at 6 and 12 weeks of age was undertaken. Results of gene set enrichment analysis showed that more immune-related pathways were identified between interleukin-10 gene deficient and control mice at 6 weeks of age in epithelial cells than intact colon. This suggests that targeting epithelial cells could increase sensitivity for detecting immune changes that occur early in the inflammatory process. However, in the later stages of inflammation, microarray analyses of intact colon and epithelium both provide a similar overview of gene expression changes in the colon mucosa at the pathway level.

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Section: Discussionmentioning

confidence: 99%

Gene Expression Changes in the Colon Epithelium Are Similar to Those of Intact Colon during Late Inflammation in Interleukin-10 Gene Deficient Mice

et al. 2013

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“…Interestingly, the five most significant DEGs were the same, namely, SLC6A14, DUOX2, MMP1, MMP3, and MMP10. Increased levels of MMPs have been previously described in inflammatory bowel diseases and their pathogenic relevance to UC supported by association with genetic variants [23,24].…”

Section: Resultsmentioning

confidence: 87%

“…On the one hand, they can have a protective role in maintaining the balance between extracellular matrix deposition and degradation. On the other hand, increased expression of MMPs may contribute to tissue damage in IBD [23,24,39]. Interestingly, we found a group of potential biomarkers that had not been described as biomarkers in UC, namely, COL6A3, CTHRC1, EGFL6, FBN1, GLIPR1, GREM1, VCAN, MZB1, and PNLIPRP2 (Table 4).…”

Section: Positive Canonical Pathwaymentioning

confidence: 84%

Meta-Analysis of Expression Profiling Data Indicates Need for Combinatorial Biomarkers in Pediatric Ulcerative Colitis

Lee

Gawel

et al. 2020

Journal of Immunology Research

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Background. Unbiased studies using different genome-wide methods have identified a great number of candidate biomarkers for diagnosis and treatment response in pediatric ulcerative colitis (UC). However, clinical translation has been proven difficult. Here, we hypothesized that one reason could be differences between inflammatory responses in an inflamed gut and in peripheral blood cells. Methods. We performed meta-analysis of gene expression microarray data from intestinal biopsies and whole blood cells (WBC) from pediatric patients with UC and healthy controls in order to identify overlapping pathways, predicted upstream regulators, and potential biomarkers. Results. Analyses of profiling datasets from colonic biopsies showed good agreement between different studies regarding pathways and predicted upstream regulators. The most activated predicted upstream regulators included TNF, which is known to have a key pathogenic and therapeutic role in pediatric UC. Despite this, the expression levels of TNF were increased in neither colonic biopsies nor WBC. A potential explanation was increased expression of TNFR2, one of the membrane-bound receptors of TNF in the inflamed colon. Further analyses showed a similar pattern of complex relations between the expression levels of the regulators and their receptors. We also found limited overlap between pathways and predicted upstream regulators in colonic biopsies and WBC. An extended search including all differentially expressed genes that overlapped between colonic biopsies and WBC only resulted in identification of three potential biomarkers involved in the regulation of intestinal inflammation. However, two had been previously proposed in adult inflammatory bowel diseases (IBD), namely, MMP9 and PROK2. Conclusions. Our findings indicate that biomarker identification in pediatric UC is complicated by the involvement of multiple pathways, each of which includes many different types of genes in the blood or inflamed intestine. Therefore, further studies for identification of combinatorial biomarkers are warranted. Our study may provide candidate biomarkers for such studies.

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“…Morgan et al . [30] has demonstrated that rs11225394 is associated with increased risk of ulcerative colitis. In addition, rs11225394 has been associated with the refractive error [31].…”

Section: Discussionmentioning

confidence: 99%

MMP8polymorphism is associated with susceptibility to osteonecrosis of the femoral head in a Chinese Han population

Cao

et al. 2017

Oncotarget

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Osteonecrosis of the femoral head (ONFH) is an orthopedic refractory disease that adversely affects quality of life. Matrix metalloproteinase-8 (MMP-8) produced by the bone marrow has been implicated in the degradation of collagen during bone development. We assessed whether MMP8 polymorphisms are associated with ONFH. In a case-control study, using χ2 tests and genetic model analyses, we genotyped 5 MMP8 single-nucleotide polymorphisms (SNPs) in 585 ONFH patients and 507 healthy control subjects in a Chinese Han population. The MMP8 rs11225394 SNP was associated with an increased risk of ONFH in an allele model (OR=1.34; 95% CI, 1.003-1.786, P=0.047). In addition, rs11225394 was associated with an increased risk of ONFH in a dominant model (OR =1.39, 95% CI, 1.02–1.89, P=0.036), over-dominant model (OR=1.39, 95% CI, 1.02–1.89, P=0.038), and log-additive model (OR =1.36, 95% CI, 1.01–1.84, P=0.039). After adjusting for age and gender, rs11225394 was associated with ONFH in a dominant (OR =1.44, 95% CI, 1.05–1.96, P=0.023), over-dominant (OR =1.44, 95% CI, 1.05–1.98, P=0.022), and log-additive model (OR =1.40, 95% CI, 1.04–1.90, P=0.027). These results provide the first evidence that MMP8 SNP at the rs11225394 locus is associated with the increased risk of ONFH in Chinese Han population.

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Genetic variations in matrix metalloproteinases may be associated with increased risk of ulcerative colitis

Cited by 19 publications

References 45 publications

Gene Expression Changes in the Colon Epithelium Are Similar to Those of Intact Colon during Late Inflammation in Interleukin-10 Gene Deficient Mice

Gene Expression Changes in the Colon Epithelium Are Similar to Those of Intact Colon during Late Inflammation in Interleukin-10 Gene Deficient Mice

Meta-Analysis of Expression Profiling Data Indicates Need for Combinatorial Biomarkers in Pediatric Ulcerative Colitis

MMP8polymorphism is associated with susceptibility to osteonecrosis of the femoral head in a Chinese Han population

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