Unrevealing of dysregulated hub genes linked with immune system and inflammatory signaling pathways in the pathogenesis of irritable bowel syndrome by system biology approaches

Bhuiyan, Piplu; Mahtab, Mamun Al; Akbar, Sheikh Mohammad Fazle

doi:10.1016/j.imu.2023.101241

Cited by 2 publications

(2 citation statements)

References 47 publications

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“…Leptin is recognised for its extensive modulatory roles in in ammatory and autoimmune responses (La Cava 2017), indicating its potential involvement in both T2D and IBD, which have well-established mechanisms related to these responses. Thyroid hormone, interferon, and notch signalling pathways were also signi cantly enriched for genes overlapping T2D and IBS-results that are consistent with a recent study on IBS (Bhuiyan et al 2023). The Notch signalling pathway is crucial in regulating the differentiation and proliferation of the colonic epithelium and has also been linked to IBD (speci cally, ulcerative colitis) (Vooijs et al 2011).…”

Section: Discussionsupporting

confidence: 89%

Genome-wide cross-disease analyses highlight causality and shared biological pathways of type 2 diabetes with gastrointestinal disorders

Adewuyi,

Porter,

O’Brien

et al. 2023

Preprint

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Observational studies suggest links between diabetes and gastrointestinal (GI) traits; however, the question of their underlying biological mechanisms and whether the observed relationship reflects shared genetic aetiology remains unresolved. Here, we comprehensively assess the genetic relationship between type 2 diabetes (T2D) and common GI disorders, leveraging several large-scale genome-wide association studies (GWAS) summary statistics. Our study demonstrates a significant positive global genetic correlation of T2D with peptic ulcer disease (PUD), irritable bowel syndrome (IBS), gastritis-duodenitis, gastroesophageal reflux disease (GERD), and diverticular disease, but not inflammatory bowel disease (IBD). Also, we identify several positive local genetic correlations (negative for T2D – IBD) contributing disproportionately to T2D's relationship with GI disorders. Multivariable Mendelian randomisation analyses suggest causal effects of genetic liability to T2D on PUD and gastritis-duodenitis, and a bidirectional causal association with GERD. Gene-based association analysis reveals gene-level genetic overlap between T2D and GI disorders, identifying several shared genes reaching genome-wide significance (Fisher’s combined P value [FCPgene] < 2.62 × 10− 6). Pathway-based functional enrichment analysis implicates leptin (T2D – IBD), thyroid, interferon, and notch signalling (T2D – IBS), QT interval anomaly and abnormal circulating calcium (T2D – PUD), viral, proinflammatory and (auto)immune-mediated mechanisms in T2D and GI disorders. Current findings provide evidence for a risk-increasing genetic overlap between T2D and GI disorders (except IBD), implicate shared genetically controlled biological pathways, highlight putative causality for certain T2D – GI disorders pairs, and identify important avenues for further exploration.

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Section: Discussionsupporting

confidence: 89%

Genome-wide cross-disease analyses highlight causality and shared biological pathways of type 2 diabetes with gastrointestinal disorders

Adewuyi,

Porter,

O’Brien

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Leptin is recognised for its extensive modulatory roles in inflammatory and autoimmune responses 73 , indicating its potential involvement in T2D and IBD, which have well-established mechanisms related to these responses. Thyroid hormone, interferon, and notch signalling pathways were also significantly enriched for genes overlapping T2D and IBS―results that are consistent with a recent study on IBS 74 —and partly, T2D and IBD. The Notch signalling pathway is crucial in regulating the differentiation and proliferation of the colonic epithelium and has also been linked to IBD (specifically, ulcerative colitis) 75 .…”

Section: Discussionsupporting

confidence: 89%

Genome-wide cross-disease analyses highlight causality and shared biological pathways of type 2 diabetes with gastrointestinal disorders

Adewuyi,

Porter,

O’Brien

et al. 2024

Commun Biol

View full text Add to dashboard Cite

Studies suggest links between diabetes and gastrointestinal (GI) traits; however, their underlying biological mechanisms remain unclear. Here, we comprehensively assess the genetic relationship between type 2 diabetes (T2D) and GI disorders. Our study demonstrates a significant positive global genetic correlation of T2D with peptic ulcer disease (PUD), irritable bowel syndrome (IBS), gastritis-duodenitis, gastroesophageal reflux disease (GERD), and diverticular disease, but not inflammatory bowel disease (IBD). We identify several positive local genetic correlations (negative for T2D – IBD) contributing to T2D’s relationship with GI disorders. Univariable and multivariable Mendelian randomisation analyses suggest causal effects of T2D on PUD and gastritis-duodenitis and bidirectionally with GERD. Gene-based analyses reveal a gene-level genetic overlap between T2D and GI disorders and identify several shared genes reaching genome-wide significance. Pathway-based study implicates leptin (T2D – IBD), thyroid, interferon, and notch signalling (T2D – IBS), abnormal circulating calcium (T2D – PUD), cardiovascular, viral, proinflammatory and (auto)immune-mediated mechanisms in T2D and GI disorders. These findings support a risk-increasing genetic overlap between T2D and GI disorders (except IBD), implicate shared biological pathways with putative causality for certain T2D – GI pairs, and identify targets for further investigation.

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Unrevealing of dysregulated hub genes linked with immune system and inflammatory signaling pathways in the pathogenesis of irritable bowel syndrome by system biology approaches

Cited by 2 publications

References 47 publications

Genome-wide cross-disease analyses highlight causality and shared biological pathways of type 2 diabetes with gastrointestinal disorders

Genome-wide cross-disease analyses highlight causality and shared biological pathways of type 2 diabetes with gastrointestinal disorders

Genome-wide cross-disease analyses highlight causality and shared biological pathways of type 2 diabetes with gastrointestinal disorders

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