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Systems analysis of inflammatory bowel disease based on comprehensive gene information.

Suzuki S, Takai-Igarashi T, Fukuoka Y, Wall DP, Tanaka H, Tonellato PJ - BMC Med. Genet. (2012)

Bottom Line: Approximately 1,000 genes associated with the sibling diseases were retrieved from four databases.After ranking the genes by the frequency of records in the databases, we obtained 250 and 253 genes highly associated with the mild and severe IBD states, respectively.The results demonstrate that this knowledge-based systems approach, predicated on functionally similar genes important to sibling diseases is an effective method to identify important components of the IBD human disease network.

View Article: PubMed Central - HTML - PubMed

Affiliation: Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.

ABSTRACT

Background: The rise of systems biology and availability of highly curated gene and molecular information resources has promoted a comprehensive approach to study disease as the cumulative deleterious function of a collection of individual genes and networks of molecules acting in concert. These "human disease networks" (HDN) have revealed novel candidate genes and pharmaceutical targets for many diseases and identified fundamental HDN features conserved across diseases. A network-based analysis is particularly vital for a study on polygenic diseases where many interactions between molecules should be simultaneously examined and elucidated. We employ a new knowledge driven HDN gene and molecular database systems approach to analyze Inflammatory Bowel Disease (IBD), whose pathogenesis remains largely unknown.

Methods and results: Based on drug indications for IBD, we determined sibling diseases of mild and severe states of IBD. Approximately 1,000 genes associated with the sibling diseases were retrieved from four databases. After ranking the genes by the frequency of records in the databases, we obtained 250 and 253 genes highly associated with the mild and severe IBD states, respectively. We then calculated functional similarities of these genes with known drug targets and examined and presented their interactions as PPI networks.

Conclusions: The results demonstrate that this knowledge-based systems approach, predicated on functionally similar genes important to sibling diseases is an effective method to identify important components of the IBD human disease network. Our approach elucidates a previously unknown biological distinction between mild and severe IBD states.

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Related in: MedlinePlus

Protein-protein interactions among the genes with high functional similarities to the drug targets. (A) A network composed of functionally similar genes to prostaglandin G/H synthetase 1 and 2, arachidonate 5-lipoxygenase, and PPARG, all of which are drug targets for IBDmild. (B) A network composed of functionally similar genes to TNF receptor 1A and 1B, which are drug targets for IBDsevere. In each network, a triangle node indicates a gene common to the HDNs of IBDmild and IBDsevere, a circle node indicates a gene specific either the HDN of IBDmild or IBDsevere. A node bordered with an orange line indicates a gene detected by GWAS. An edge connecting the GWAS genes is also highlighted in pale orange. A node marked with an arrow indicates a differentially expressed gene in GSE6731. A blue arrow indicates an up-regulated gene in IBMmild, while a red arrow indicates an up-regulated gene in IBMsevere. Both networks are divided into three portions by colored areas. The blue area indicates genes relate to tissue remodeling. The green area indicates genes relate to inflammation and immunoregulation. The rose area indicates genes relate to tumorigenesis and apoptosis.
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Figure 2: Protein-protein interactions among the genes with high functional similarities to the drug targets. (A) A network composed of functionally similar genes to prostaglandin G/H synthetase 1 and 2, arachidonate 5-lipoxygenase, and PPARG, all of which are drug targets for IBDmild. (B) A network composed of functionally similar genes to TNF receptor 1A and 1B, which are drug targets for IBDsevere. In each network, a triangle node indicates a gene common to the HDNs of IBDmild and IBDsevere, a circle node indicates a gene specific either the HDN of IBDmild or IBDsevere. A node bordered with an orange line indicates a gene detected by GWAS. An edge connecting the GWAS genes is also highlighted in pale orange. A node marked with an arrow indicates a differentially expressed gene in GSE6731. A blue arrow indicates an up-regulated gene in IBMmild, while a red arrow indicates an up-regulated gene in IBMsevere. Both networks are divided into three portions by colored areas. The blue area indicates genes relate to tissue remodeling. The green area indicates genes relate to inflammation and immunoregulation. The rose area indicates genes relate to tumorigenesis and apoptosis.

Mentions: Figure 2 shows the HDNs whose nodes were selected by the functional similarity of a gene to the drug targets. A node scored less than 0.5 (upper quartile of the random distribution of SSM) were eliminated from the HDNs. A triangular node indicates a gene belongs to both HDNs of IBDmild and IBDsevere, while a circular node represents a gene belongs to either HDN of IBDmild or IBDsevere. Additional file 3: Table S2 lists the genes consist of the HDNs. The similarity score in this study showed a mean score of 0.40050, with a standard deviation of 0.13942, a maximum score of 0.86640, a minimum score of 0.02972, and a upper quartile of 0.50760 against IBDmild drug targets, and a mean score of 0.37570, with a standard deviation of 0.17189, a maximum score of 0.91200, and a minimum score of 0.02417, and a upper quartile of 0.50940 against IBDsevere drug targets.


Systems analysis of inflammatory bowel disease based on comprehensive gene information.

Suzuki S, Takai-Igarashi T, Fukuoka Y, Wall DP, Tanaka H, Tonellato PJ - BMC Med. Genet. (2012)

Protein-protein interactions among the genes with high functional similarities to the drug targets. (A) A network composed of functionally similar genes to prostaglandin G/H synthetase 1 and 2, arachidonate 5-lipoxygenase, and PPARG, all of which are drug targets for IBDmild. (B) A network composed of functionally similar genes to TNF receptor 1A and 1B, which are drug targets for IBDsevere. In each network, a triangle node indicates a gene common to the HDNs of IBDmild and IBDsevere, a circle node indicates a gene specific either the HDN of IBDmild or IBDsevere. A node bordered with an orange line indicates a gene detected by GWAS. An edge connecting the GWAS genes is also highlighted in pale orange. A node marked with an arrow indicates a differentially expressed gene in GSE6731. A blue arrow indicates an up-regulated gene in IBMmild, while a red arrow indicates an up-regulated gene in IBMsevere. Both networks are divided into three portions by colored areas. The blue area indicates genes relate to tissue remodeling. The green area indicates genes relate to inflammation and immunoregulation. The rose area indicates genes relate to tumorigenesis and apoptosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368714&req=5

Figure 2: Protein-protein interactions among the genes with high functional similarities to the drug targets. (A) A network composed of functionally similar genes to prostaglandin G/H synthetase 1 and 2, arachidonate 5-lipoxygenase, and PPARG, all of which are drug targets for IBDmild. (B) A network composed of functionally similar genes to TNF receptor 1A and 1B, which are drug targets for IBDsevere. In each network, a triangle node indicates a gene common to the HDNs of IBDmild and IBDsevere, a circle node indicates a gene specific either the HDN of IBDmild or IBDsevere. A node bordered with an orange line indicates a gene detected by GWAS. An edge connecting the GWAS genes is also highlighted in pale orange. A node marked with an arrow indicates a differentially expressed gene in GSE6731. A blue arrow indicates an up-regulated gene in IBMmild, while a red arrow indicates an up-regulated gene in IBMsevere. Both networks are divided into three portions by colored areas. The blue area indicates genes relate to tissue remodeling. The green area indicates genes relate to inflammation and immunoregulation. The rose area indicates genes relate to tumorigenesis and apoptosis.
Mentions: Figure 2 shows the HDNs whose nodes were selected by the functional similarity of a gene to the drug targets. A node scored less than 0.5 (upper quartile of the random distribution of SSM) were eliminated from the HDNs. A triangular node indicates a gene belongs to both HDNs of IBDmild and IBDsevere, while a circular node represents a gene belongs to either HDN of IBDmild or IBDsevere. Additional file 3: Table S2 lists the genes consist of the HDNs. The similarity score in this study showed a mean score of 0.40050, with a standard deviation of 0.13942, a maximum score of 0.86640, a minimum score of 0.02972, and a upper quartile of 0.50760 against IBDmild drug targets, and a mean score of 0.37570, with a standard deviation of 0.17189, a maximum score of 0.91200, and a minimum score of 0.02417, and a upper quartile of 0.50940 against IBDsevere drug targets.

Bottom Line: Approximately 1,000 genes associated with the sibling diseases were retrieved from four databases.After ranking the genes by the frequency of records in the databases, we obtained 250 and 253 genes highly associated with the mild and severe IBD states, respectively.The results demonstrate that this knowledge-based systems approach, predicated on functionally similar genes important to sibling diseases is an effective method to identify important components of the IBD human disease network.

View Article: PubMed Central - HTML - PubMed

Affiliation: Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.

ABSTRACT

Background: The rise of systems biology and availability of highly curated gene and molecular information resources has promoted a comprehensive approach to study disease as the cumulative deleterious function of a collection of individual genes and networks of molecules acting in concert. These "human disease networks" (HDN) have revealed novel candidate genes and pharmaceutical targets for many diseases and identified fundamental HDN features conserved across diseases. A network-based analysis is particularly vital for a study on polygenic diseases where many interactions between molecules should be simultaneously examined and elucidated. We employ a new knowledge driven HDN gene and molecular database systems approach to analyze Inflammatory Bowel Disease (IBD), whose pathogenesis remains largely unknown.

Methods and results: Based on drug indications for IBD, we determined sibling diseases of mild and severe states of IBD. Approximately 1,000 genes associated with the sibling diseases were retrieved from four databases. After ranking the genes by the frequency of records in the databases, we obtained 250 and 253 genes highly associated with the mild and severe IBD states, respectively. We then calculated functional similarities of these genes with known drug targets and examined and presented their interactions as PPI networks.

Conclusions: The results demonstrate that this knowledge-based systems approach, predicated on functionally similar genes important to sibling diseases is an effective method to identify important components of the IBD human disease network. Our approach elucidates a previously unknown biological distinction between mild and severe IBD states.

Show MeSH
Related in: MedlinePlus