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Prioritisation and network analysis of Crohn's disease susceptibility genes.

ABSTRACT: Recent Genome-Wide Association Studies (GWAS) have revealed numerous Crohn's disease susceptibility genes and a key challenge now is in understanding how risk polymorphisms in associated genes might contribute to development of this disease. For a gene to contribute to disease phenotype, its risk variant will likely adversely communicate with a variety of other gene products to result in dysregulation of common signaling pathways. A vital challenge is to elucidate pathways of potentially greatest influence on pathological behaviour, in a manner recognizing how multiple relevant genes may yield integrative effect. In this work we apply mathematical analysis of networks involving the list of recently described Crohn's susceptibility genes, to prioritise pathways in relation to their potential development of this disease. Prioritisation was performed by applying a text mining and a diffusion based method (GRAIL, GPEC). Prospective biological significance of the resulting prioritised list of proteins is highlighted by changes in their gene expression levels in Crohn's patients intestinal tissue in comparison with healthy donors.

SUBMITTER: Muraro D

PROVIDER: S-EPMC4182533 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Prioritisation and network analysis of Crohn's disease susceptibility genes.

Muraro Daniele D Lauffenburger Douglas A DA Simmons Alison A

PloS one 20140930 9

Recent Genome-Wide Association Studies (GWAS) have revealed numerous Crohn's disease susceptibility genes and a key challenge now is in understanding how risk polymorphisms in associated genes might contribute to development of this disease. For a gene to contribute to disease phenotype, its risk variant will likely adversely communicate with a variety of other gene products to result in dysregulation of common signaling pathways. A vital challenge is to elucidate pathways of potentially greates ...[more]

PMID: 25268122

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Project description:The aim of the present meta-analysis was to evaluate the correlation between a common polymorphism, rs13361189 C>T in the immunity-related GTPase M (IRGM) gene, and susceptibility to Crohn's disease (CD). The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library and CBM databases were investigated from database inception through to October 1, 2013 without the application of any language restrictions. The meta-analysis was performed using STATA 12.0 software and the relative risk (RR) with a 95% confidence interval (CI) was calculated. Seven case-control studies were included with a total of 3,093 CD patients and 3,227 healthy control subjects. The results of the meta-analysis revealed that the IRGM rs13361189 polymorphism correlates with an increased risk of CD (T allele versus C allele: RR=1.25 with 95% CI, 1.04-1.50; P=0.016 and CT + TT versus CC: RR=1.21 with 95% CI, 1.03-1.42; P=0.018). A subgroup analysis conducted using a genotyping method indicated that the IRGM rs13361189 polymorphism was correlated with an increased risk of CD in the TaqMan® (T allele versus C allele: RR=1.32 with 95% CI, 1.01-1.73; P=0.042) and the polymerase chain reaction-restriction fragment length polymorphism subgroups (T allele versus C allele: RR=1.80 with 95% CI, 1.32-2.45; P<0.001 and CT + TT versus CC: RR=1.61 with 95% CI, 1.19-2.18; P=0.018). However, no correlation was observed in the direct sequencing subgroup (P>0.05). Further subgroup analysis by sample size demonstrated significant correlations between the IRGM rs13361189 polymorphism and an increased risk of CD in the large sample-size subgroup (T allele versus C allele: RR=1.46 with 95% CI, 1.26-1.68; P<0.001 and CT + TT versus CC: RR=1.40 with 95% CI, 1.21-1.62; P<0.001). However, no correlation was identified between the IRGM rs13361189 polymorphism and CD risk in the small sample-size subgroup (P>0.05). The present meta-analysis indicated that the IRGM rs13361189 polymorphism may contribute to susceptibility to CD. Thus, IRGM rs13361189 polymorphism may be a potential biomarker for the early diagnosis of CD.

Project description:Introduction: Crohn's disease (CD) is a disease that manifests mainly as chronic inflammation of the gastrointestinal tract, which is still not well understood in terms of its pathogenesis. The aim of this study was to use bioinformatics analysis to identify differentially expressed genes (DEGs) and miRNAs with diagnostic and therapeutic potential in CD. Materials and methods: Three CD datasets (GSE179285, GSE102133, GSE75214) were downloaded from the Gene Expression Omnibus (GEO) database. DEGs between normal and CD tissues were identified using the GEO2R online tool. The Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the DEGs were conducted using the clusterProfiler function in the R package. Protein-protein interaction network (PPI) analysis and visualization were performed with STRING and Cytoscape. Ten hub genes were identified using cytoHubba's MCC algorithm and validated with datasets GSE6731 and GSE52746. Finally, the miRNA gene regulatory network was constructed by Cytoscape and NetworkAnalyst to predict potential microRNAs (miRNAs) associated with DEGs. Results: A total of 97 DEGs were identified, consisting of 88 downregulated genes and 9 upregulated genes. The enriched functions and pathways of the DEGs include immune system process, response to stress, response to cytokine and extracellular region. KEGG pathway analysis indicates that the genes were significantly enriched in Cytokine-cytokine receptor interaction, IL-17 signaling pathway, Rheumatoid arthritis and TNF signaling pathway. In combination with the results of the protein-protein interaction (PPI) network and CytoHubba, 10 hub genes including IL1B, CXCL8, CXCL10, CXCL1, CXCL2, CXCL5, ICAM1, IL1RN, TIMP1 and MMP3 were selected. Based on the DEG-miRNAs network construction, 5 miRNAs including hsa-mir-21-5p, hsa-mir-93-5p, hsa-mir-98-5p, hsa-mir-1-3p and hsa-mir-335-5p were identified as potential critical miRNAs. Conclusion: In conclusion, a total of 97 DEGs, 10 hub genes and 5 miRNAs that may be involved in the progression or occurrence of CD were identified in this study, which could be regarded as biomarkers of CD.

Dataset Information

Prioritisation and network analysis of Crohn's disease susceptibility genes.

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Prioritisation and network analysis of Crohn's disease susceptibility genes.

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