Dataset Information

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

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.

SUBMITTER: Suzuki S

PROVIDER: S-EPMC3368714 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Suzuki Satoru S Takai-Igarashi Takako T Fukuoka Yutaka Y Wall Dennis P DP Tanaka Hiroshi H Tonellato Peter J PJ

BMC medical genetics 20120405

<h4>Background</h4>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 a ...[more]

PMID: 22480395

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Project description:BACKGROUND: IL12B encodes the p40 subunit of IL-12, which is also part of IL-23. Recent genome-wide association studies identified IL12B and IL23R as susceptibility genes for inflammatory bowel disease (IBD). However, the phenotypic effects and potential gene-gene interactions of IL12B variants are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed IL12B gene variants regarding association with Crohn's disease (CD) and ulcerative colitis (UC). Genomic DNA from 2196 individuals including 913 CD patients, 318 UC patients and 965 healthy, unrelated controls was analyzed for four SNPs in the IL12B gene region (rs3212227, rs17860508, rs10045431, rs6887695). Our analysis revealed an association of the IL12B SNP rs6887695 with susceptibility to IBD (p?=?0.035; OR 1.15 [95% CI 1.01-1.31] including a trend for rs6887695 for association with CD (OR 1.41; [0.99-1.31], p?=?0.066) and UC (OR 1.18 [0.97-1.43], p?=?0.092). CD patients, who were homozygous C/C carriers of this SNP, had significantly more often non-stricturing, non-penetrating disease than carriers of the G allele (p?=?6.8×10(-5); OR?=?2.84, 95% CI 1.66-4.84), while C/C homozygous UC patients had less often extensive colitis than G allele carriers (p?=?0.029; OR?=?0.36, 95% CI 0.14-0.92). In silico analysis predicted stronger binding of the minor C allele of rs6887695 to the transcription factor ROR? which is involved in Th17 differentiation. Differences regarding the binding to the major and minor allele sequence of rs6887695 were also predicted for the transcription factors HSF1, HSF2, MZF1 and Oct-1. Epistasis analysis revealed weak epistasis of the IL12B SNP rs6887695 with several SNPs (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694) in the STAT4 gene which encodes the major IL-12 downstream transcription factor STAT4 (p<0.05) but there was no epistasis between IL23R and IL12B variants. CONCLUSIONS/SIGNIFICANCE: The IL12B SNP rs6887695 modulates the susceptibility and the phenotype of IBD, although the effect on IBD susceptibilty is less pronounced than that of IL23R gene variants.

Project description:ObjectivesInflammatory bowel disease (IBD) is a heterogeneous group of chronic inflammatory gastrointestinal conditions with variable disease courses often requiring significant healthcare expenditures. We aimed to identify disease trajectory patterns based on longitudinal financial expenditures and to assess the association of classic disease activity parameters with financial charges.MethodsThis was an analysis of a consented, prospective, natural history IBD registry (2009-2013) from a tertiary IBD center of 2,203 patients and their associated medical charges excluding pharmacy expenses. We applied group-based trajectory modeling to longitudinal healthcare financial charges to determine patterns of charges. We assessed the association between charge patterns and disease activity, quality of life, healthcare utilization, and medication requirement.ResultsThe final model included 1,600 IBD patients with 5-year charges. We identified six distinct trajectories over the study period. Consistently High charges were associated with Crohn's disease (66.0% Consistently High patients, P<0.01), perianal involvement (22.6%, P<0.01), ulcerative colitis extent (89.7% extensive, P=0.01), prior IBD surgery (52.5%, P<0.01), and depression/anxiety (36.2%, P<0.01). Compared with other trajectories, Consistently High charges had higher 5-year disease activity indices (Harvey-Bradshaw P<0.01; ulcerative colitis activity index P<0.01), elevated C-reactive protein rates (72.3%, P<0.01), IBD surgery (64.5%, P<0.01), hospitalization (97.2%, P<0.01), corticosteroid (70.9%, P<0.01) and antitumor necrosis factor requirement (50.4%, P<0.01), and worse quality of life (P<0.01). Annual trends in parameters were reflected in temporal changes in financial charges. The majority of financial burden stemmed from inpatient care.ConclusionsHealthcare financial charges represent a novel phenotype in IBD that reflect trends in classic disease activity parameters and allow for subgroup identification of temporal disease trajectories.

Dataset Information

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

Background

Methods and results

Conclusions

Publications

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

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