Inflammation status modulates the effect of host genetic variation on intestinal gene expression in inflammatory bowel disease

Hu, Shixian; Venema, Werna T. Uniken; Westra, Harm-Jan; Vila, Arnau Vich; Barbieri, Ruggero; Voskuil, Michiel; Blokzijl, Tjasso; Jansen, Bernadien H.; Li, Yanni; Daly, Mark J.; Xavier, Ramnik J.; Dijkstra, Gerard; Festen, Eleonora A. M.; Weersma, Rinse K.

doi:10.1038/s41467-021-21458-z

Cited by 25 publications

(21 citation statements)

References 52 publications

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“…To further investigate the roles of these transcription factors in IBD, we modify our previous PECA2 method to infer their trans-regulatory target genes (see the “Inference of trans-regulatory targets” section) in each subpopulation. We download the differential expression genes list from IBD patients versus healthy controls study [ 44 ] for further analysis. First, we find the TF IRF4 is upregulated in IBD patients compared to healthy controls (two samples two-tail t -test, p -value = 7.59E−31).…”

Section: Resultsmentioning

confidence: 99%

Regulatory analysis of single cell multiome gene expression and chromatin accessibility data with scREG

et al. 2022

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Technological development has enabled the profiling of gene expression and chromatin accessibility from the same cell. We develop scREG, a dimension reduction methodology, based on the concept of cis-regulatory potential, for single cell multiome data. This concept is further used for the construction of subpopulation-specific cis-regulatory networks. The capability of inferring useful regulatory network is demonstrated by the two-fold increment on network inference accuracy compared to the Pearson correlation-based method and the 27-fold enrichment of GWAS variants for inflammatory bowel disease in the cis-regulatory elements. The R package scREG provides comprehensive functions for single cell multiome data analysis.

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Section: Resultsmentioning

confidence: 99%

Regulatory analysis of single cell multiome gene expression and chromatin accessibility data with scREG

et al. 2022

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“…Intestinal mucosal bulk RNA sequencing was performed on 299 intestinal biopsies of 171 patients with IBD and has been described before. 20 In brief, 26 million paired-end 150-bp reads were generated per sample. The quality of the raw reads was checked using FastQC with default parameters [v0.11.7].…”

Section: Methodsmentioning

confidence: 99%

The Effect of Phenotype and Genotype on the Plasma Proteome in Patients with Inflammatory Bowel Disease

Bourgonje

Spekhorst

et al. 2021

Journal of Crohn's and Colitis

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Background and Aims Protein profiling in patients with inflammatory bowel diseases (IBD) for diagnostic and therapeutic purposes is underexplored in IBD. This study analysed the association between phenotype, genotype and the plasma proteome in IBD. Methods Ninety-two (92) inflammation-related proteins were quantified in plasma of 1,028 patients with IBD (567 Crohn’s disease [CD]; 461 ulcerative colitis [UC]) and 148 healthy individuals to assess protein-phenotype associations. Corresponding whole-exome sequencing and global screening array data of 919 patients with IBD were included to analyse the effect of genetics on protein levels (protein quantitative trait loci (pQTL) analysis). Intestinal mucosal RNA sequencing and fecal metagenomic data were used for complementary analyses. Results Thirty-two (32) proteins were differentially abundant between IBD and healthy individuals, of which 22 proteins independent of active inflammation. Sixty-nine (69) proteins were associated with 15 demographic and clinical factors. Fibroblast growth factor-19 levels were decreased in CD patients with ileal disease or a history of ileocecal resection. Thirteen novel cis-pQTLs were identified and 10 replicated from previous studies. One trans-pQTL of the fucosyltransferase 2 (FUT2) gene (rs602662) and two independent cis-pQTLs of C-C motif chemokine 25 (CCL25) affected plasma CCL25 levels. Intestinal gene expression data revealed an overlapping cis-expression (e)QTL-variant (rs3745387) of the CCL25 gene. The FUT2 rs602662 trans-pQTL was associated with reduced abundances of fecal butyrate-producing bacteria. Conclusions This study shows that genotype and multiple disease phenotypes strongly associate with the plasma inflammatory proteome in IBD and identifies disease-associated pathways that may help to improve disease management in the future.

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“…More than 240 genetic risk loci are associated with IBD. However, their effects on the disease are poorly understood [ 20 ]. Owing to the complex aetiology and pathogenesis of UC, various modalities are used for its treatment, including the administration of 5-aminosalicylic acid, glucocorticoid, immunosuppressant, and antibiotics, as well as surgery [ 21 – 23 ].…”

Section: Discussionmentioning

confidence: 99%

Active Ingredients and Potential Mechanisms of the Gan Jiang-Huang Qin-Huang Lian-Ren Shen Decoction against Ulcerative Colitis: A Network Pharmacology and Molecular Docking-Based Study

Zhou

Zhang

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Background. Ulcerative colitis (UC), a chronic and nonspecific inflammatory bowel disease, seriously affects the quality of patients’ life. Han Re Bing Yong Fa (treating diseases with both cool- and warm-natured herbs) is a classical therapeutic principle of traditional Chinese medicine (TCM), which is often used to treat chronic diseases, including UC. The Gan Jiang-Huang Qin-Huang Lian-Ren Shen decoction (GJHQHLRSD), a representative of Han Re Bing Yong Fa, is effective in alleviating inflammatory symptoms in UC. However, the pharmacological mechanism underlying its anti-inflammatory effect remains unclear. Methods. A network pharmacology strategy, including the construction and analysis of the drug–disease network, was used to explore the complex mechanism of GJHQHLRSD treatment of UC. In addition, molecular docking technology was used to preliminarily examine the binding ability of the potential active components and core therapeutic targets of GJHQHLRSD. Results. The network pharmacology results revealed 140 targets of GJHQHLRSD which are involved in UC. The PPI network analysis identified seven target genes: BCL2L1, NR3C1, ALOX5, S1PR5, NR1I2, CYP2D6, and LPAR6. The molecular docking results revealed that the following displayed strongest combined effects: EGFR with kaempferol, ERK1 with worenine, STAT3 with Palmidin A, BCL2L1 with diop and VEGFA with ginsenoside Rg3. The KEGG and gene ontology enrichment analyses results indicated that GJHQHLRSD functions by regulating the EGFR signaling pathway in UC treatment. Other effective biological processes involved in UC treatment included cancer-related as well as inflammation and viral infection signaling pathways, such as the “MicroRNAs in cancer,” “TNF signaling pathway,” and “JAK-STAT signaling pathway.” Conclusions. This study reflects the multicomponent, multitarget, and multipathway characteristics of the action mechanism of GJHQHLRSD in treating UC. Furthermore, it helps better understand the TCM therapeutic principle of Han Re Bing Yong Fa and explore novel candidate drug targets for UC treatment.

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Inflammation status modulates the effect of host genetic variation on intestinal gene expression in inflammatory bowel disease

Cited by 25 publications

References 52 publications

Regulatory analysis of single cell multiome gene expression and chromatin accessibility data with scREG

Regulatory analysis of single cell multiome gene expression and chromatin accessibility data with scREG

The Effect of Phenotype and Genotype on the Plasma Proteome in Patients with Inflammatory Bowel Disease

Active Ingredients and Potential Mechanisms of the Gan Jiang-Huang Qin-Huang Lian-Ren Shen Decoction against Ulcerative Colitis: A Network Pharmacology and Molecular Docking-Based Study

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