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An ileal Crohn's disease gene signature based on whole human genome expression profiles of disease unaffected ileal mucosal biopsies.

Zhang T, Song B, Zhu W, Xu X, Gong QQ, Morando C, Dassopoulos T, Newberry RD, Hunt SR, Li E - PLoS ONE (2012)

Bottom Line: This gene is an established biomarker for prostate cancer, but has not previously been associated with Crohn's disease.Immunohistochemical staining confirmed increased expression of FOLH1 in the ileal epithelium.These results provide evidence for convergent molecular abnormalities in the macroscopically disease unaffected proximal margin of resected ileum from ileal CD subjects.

View Article: PubMed Central - PubMed

Affiliation: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York, United States of America.

ABSTRACT
Previous genome-wide expression studies have highlighted distinct gene expression patterns in inflammatory bowel disease (IBD) compared to control samples, but the interpretation of these studies has been limited by sample heterogeneity with respect to disease phenotype, disease activity, and anatomic sites. To further improve molecular classification of inflammatory bowel disease phenotypes we focused on a single anatomic site, the disease unaffected proximal ileal margin of resected ileum, and three phenotypes that were unlikely to overlap: ileal Crohn's disease (ileal CD), ulcerative colitis (UC), and control patients without IBD. Whole human genome (Agilent) expression profiling was conducted on two independent sets of disease-unaffected ileal samples collected from the proximal margin of resected ileum. Set 1 (47 ileal CD, 27 UC, and 25 Control non-IBD patients) was used as the training set and Set 2 was subsequently collected as an independent test set (10 ileal CD, 10 UC, and 10 control non-IBD patients). We compared the 17 gene signatures selected by four different feature-selection methods to distinguish ileal CD phenotype with non-CD phenotype. The four methods yielded different but overlapping solutions that were highly discriminating. All four of these methods selected FOLH1 as a common feature. This gene is an established biomarker for prostate cancer, but has not previously been associated with Crohn's disease. Immunohistochemical staining confirmed increased expression of FOLH1 in the ileal epithelium. These results provide evidence for convergent molecular abnormalities in the macroscopically disease unaffected proximal margin of resected ileum from ileal CD subjects.

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Partial correlation network among the 17 selected genes.FOLH1 is linked to multiple genes and serves as a hub gene. A red line between genes indicates a positive non-zero partial correlation and a blue line indicates a negative non-zero partial correlation.
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pone-0037139-g003: Partial correlation network among the 17 selected genes.FOLH1 is linked to multiple genes and serves as a hub gene. A red line between genes indicates a positive non-zero partial correlation and a blue line indicates a negative non-zero partial correlation.

Mentions: Partial correlation network analysis was conducted on the union of the features selected by the four methods using all 129 microarrays in both the training and test set to assess the coregulation of these 42 genes. As shown in Figure 3, the folate hydrolase 1 (FOLH1) gene was identified as a “hub” gene that has significantly non-zero partial correlations to 12 of the other 16 gene biomarkers (see Figure 3). The FOLH1 gene was originally identified as a prostate specific membrane antigen detected as upregulated in prostate carcinoma [33], however expression of FOLH1 has since been observed in other tissues including the small intestine, particularly in the duodenal mucosa, the nervous system and the kidney [34]. Because FOLH1 expression has been observed in neoplastic and nonneoplastic neovasculature [35], immunochemical localization of FOLH1 was performed on the disease unaffected proximal margin of resected ileum from ileal CD and control non-IBD subjects. A representative micrograph is shown in Figure 4, which demonstrates that the more prominent staining in ileal CD samples was localized to the villous epithelium.


An ileal Crohn's disease gene signature based on whole human genome expression profiles of disease unaffected ileal mucosal biopsies.

Zhang T, Song B, Zhu W, Xu X, Gong QQ, Morando C, Dassopoulos T, Newberry RD, Hunt SR, Li E - PLoS ONE (2012)

Partial correlation network among the 17 selected genes.FOLH1 is linked to multiple genes and serves as a hub gene. A red line between genes indicates a positive non-zero partial correlation and a blue line indicates a negative non-zero partial correlation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351422&req=5

pone-0037139-g003: Partial correlation network among the 17 selected genes.FOLH1 is linked to multiple genes and serves as a hub gene. A red line between genes indicates a positive non-zero partial correlation and a blue line indicates a negative non-zero partial correlation.
Mentions: Partial correlation network analysis was conducted on the union of the features selected by the four methods using all 129 microarrays in both the training and test set to assess the coregulation of these 42 genes. As shown in Figure 3, the folate hydrolase 1 (FOLH1) gene was identified as a “hub” gene that has significantly non-zero partial correlations to 12 of the other 16 gene biomarkers (see Figure 3). The FOLH1 gene was originally identified as a prostate specific membrane antigen detected as upregulated in prostate carcinoma [33], however expression of FOLH1 has since been observed in other tissues including the small intestine, particularly in the duodenal mucosa, the nervous system and the kidney [34]. Because FOLH1 expression has been observed in neoplastic and nonneoplastic neovasculature [35], immunochemical localization of FOLH1 was performed on the disease unaffected proximal margin of resected ileum from ileal CD and control non-IBD subjects. A representative micrograph is shown in Figure 4, which demonstrates that the more prominent staining in ileal CD samples was localized to the villous epithelium.

Bottom Line: This gene is an established biomarker for prostate cancer, but has not previously been associated with Crohn's disease.Immunohistochemical staining confirmed increased expression of FOLH1 in the ileal epithelium.These results provide evidence for convergent molecular abnormalities in the macroscopically disease unaffected proximal margin of resected ileum from ileal CD subjects.

View Article: PubMed Central - PubMed

Affiliation: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York, United States of America.

ABSTRACT
Previous genome-wide expression studies have highlighted distinct gene expression patterns in inflammatory bowel disease (IBD) compared to control samples, but the interpretation of these studies has been limited by sample heterogeneity with respect to disease phenotype, disease activity, and anatomic sites. To further improve molecular classification of inflammatory bowel disease phenotypes we focused on a single anatomic site, the disease unaffected proximal ileal margin of resected ileum, and three phenotypes that were unlikely to overlap: ileal Crohn's disease (ileal CD), ulcerative colitis (UC), and control patients without IBD. Whole human genome (Agilent) expression profiling was conducted on two independent sets of disease-unaffected ileal samples collected from the proximal margin of resected ileum. Set 1 (47 ileal CD, 27 UC, and 25 Control non-IBD patients) was used as the training set and Set 2 was subsequently collected as an independent test set (10 ileal CD, 10 UC, and 10 control non-IBD patients). We compared the 17 gene signatures selected by four different feature-selection methods to distinguish ileal CD phenotype with non-CD phenotype. The four methods yielded different but overlapping solutions that were highly discriminating. All four of these methods selected FOLH1 as a common feature. This gene is an established biomarker for prostate cancer, but has not previously been associated with Crohn's disease. Immunohistochemical staining confirmed increased expression of FOLH1 in the ileal epithelium. These results provide evidence for convergent molecular abnormalities in the macroscopically disease unaffected proximal margin of resected ileum from ileal CD subjects.

Show MeSH
Related in: MedlinePlus