A cross-ethnic survey of CFB and SLC44A4, Indian ulcerative colitis GWAS hits, underscores their potential role in disease susceptibility

Gupta, Aditi; Juyal, Garima; Sood, Ajit; Midha, Vandana; Yamazaki, Keiko; Vila, Arnau Vich; Esaki, Motohiro; Matsui, Toshiyuki; Takahashi, Atsushi; Kubo, Michiaki; Weersma, Rinse K.; Thelma, B.K.

doi:10.1038/ejhg.2016.131

Cited by 15 publications

(6 citation statements)

References 38 publications

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“…IBD patients exhibit increased levels of circulating CFB ( Nielsen et al, 1978 ; Campbell et al, 1982 ; Adinolfi and Lehner, 1988 ) and a similar increase of serum CFB has been observed in DSS-induced and bisphenol A (BPA)-induced experimental colitis in mice ( Huang et al, 2022 ). More recently, genome-wide association studies (GWAS) have identified one SNP (rs4151657) at the CFB locus, which represents a risk variant for UC susceptibility ( Juyal et al, 2015 ; Gupta et al, 2016 ; Shi et al, 2020 ; Mortlock et al, 2023 ). The presence of the rs4151651 SNP was associated with increased CFB expression, and CFB expression was shown to correlate with disease activity ( Shi et al, 2020 ; Mortlock et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Analysis of the interferon-γ-induced secretome of intestinal endothelial cells: putative impact on epithelial barrier dysfunction in IBD

Naschberger

Flierl

Huang

et al. 2023

Front. Cell Dev. Biol.

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The development of inflammatory bowel diseases (IBD) involves the breakdown of two barriers: the epithelial barrier and the gut-vascular barrier (GVB). The destabilization of each barrier can promote initiation and progression of the disease. Interestingly, first evidence is available that both barriers are communicating through secreted factors that may accordingly serve as targets for therapeutic modulation of barrier functions. Interferon (IFN)-γ is among the major pathogenesis factors in IBD and can severely impair both barriers. In order to identify factors transmitting signals from the GVB to the epithelial cell barrier, we analyzed the secretome of IFN-γ-treated human intestinal endothelial cells (HIEC). To this goal, HIEC were isolated in high purity from normal colon tissues. HIEC were either untreated or stimulated with IFN-γ (10 U/mL). After 48 h, conditioned media (CM) were harvested and subjected to comparative hyper reaction monitoring mass spectrometry (HRM™ MS). In total, 1,084 human proteins were detected in the HIEC-CM. Among these, 43 proteins were present in significantly different concentrations between the CM of IFN-γ- and control-stimulated HIEC. Several of these proteins were also differentially expressed in various murine colitis models as compared to healthy animals supporting the relevance of these proteins secreted by inflammatory activated HIEC in the inter-barrier communication in IBD. The angiocrine pathogenic impact of these differentially secreted HIEC proteins on the epithelial cell barrier and their perspectives as targets to treat IBD by modulation of trans-barrier communication is discussed in detail.

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Section: Discussionmentioning

confidence: 99%

Analysis of the interferon-γ-induced secretome of intestinal endothelial cells: putative impact on epithelial barrier dysfunction in IBD

Naschberger

Flierl

Huang

et al. 2023

Front. Cell Dev. Biol.

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“…These autoimmune diseases responsible genes might be critical for the development of CD. Recently, study found that CXCL5 [454], S100A12 [455], OSM (oncostatin M) [456], LRG1 [457], LCN2 [458], CXCL1 [459], S100A9 [460], IFITM1 [461], XBP1 [462], MMP3 [457], IFITM3 [463], IL1B [464], GBP5 [465], HGF (hepatocyte growth factor) [466], CXCL9 [467], SLC11A1 [468], IL1RN [469], STAT1 [470], CYP27B1 [471], MMP1 [472], SOCS3 [473], TLR8 [474], CD55 [475], CCL28 [476], FCGR2A [477], CCL2 [478], CFB (complement factor B) [479], CD14 [480], GPR84 [481], PCSK9 [482], FOXP3 [483], LPL (lipoprotein lipase) [484], IL1R2 [485], TLR2 [486], MEFV (MEFV innate immuity regulator, pyrin) [487], VWF (von Willebrand factor) [488], NOD2 [489], DMBT1 [490], HSPA6 [491], TIMP1 [492], ICAM1 [493], EGR1 [494], CCL11 [495], IFNG (interferon gamma) [496], APOE (apolipoprotein E) [497] FGR (FGR proto-oncogene, Src family tyrosine kinase) [498], IL6 [499], SPP1 [192], IL11 [500], RNF186 [501], MMP2 [502], CD24 [503], SPHK1 [504], GZMB (granzyme B) [505], MUC5AC [506], SERPINA3 [507], TWIST1 [508], PLAU (plasminogen activator, urokinase) [509], CA2 [510], CA9 [510], CTLA4 [511], PADI4 [512], MMP13 [513], MPO (myeloperoxidase) [244], LEFTY1 [514], CA1 [515], MMP7 [513], ABCG2 [516], CYP2J2 [517], AICDA (activation induced cytidine deaminase) [518], CYP2D6 [519], CYP3A5 [52...…”

Section: Discussionmentioning

confidence: 99%

Identification of hub genes and key pathways in pediatric Crohn’s disease using next generation sequencing and bioinformatics analysis

Vastrad¹,

Vastrad²

2022

Preprint

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Pediatric Crohn's Disease (CD) also known as inflammatory bowel diseases, affects millions of people all over the world. The aim of this investigation is to identify the key genes in CD and uncover their potential functions. We downloaded the next generation sequencing (NGS) dataset GSE73374 from the Gene Expression Omnibus (GEO) database. The NGS dataset GSE73374 was used to screen differentially expressed genes (DEGs) between samples from patients with CD and healthy controls. Gene ontology (GO) and REACTOME pathway enrichment analyses were applied for the DEGs. Subsequently, a protein - protein interaction (PPI) network, modules, miRNA- hub gene regulatory network and TF - hub gene regulatory network were constructed to identify hub genes, miRNAs and TFs. Receiver operating characteristic curve (ROC) analysis was applied to validate the hub genes. A total of 957 DEGs were identified, including 478 up regulated genes and 479 down regulated genes. GO and REACTOME results suggested that several Go terms and pathways are involved in response to stimulus, extracellular region, signaling receptor binding, small molecule metabolic process, membrane, transporter activity, immune system and biological oxidations. The top centrality hub genes MDFI, MNDA, FBXO6, TFRC, STAT1, DPP4, MME, SLC39A4, APOA1 and TMEM25 were screened out as the critical genes among the DEGs from the PPI network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network. This investigation identified key genes and signal pathways, which might help us improve our understanding of the molecular mechanisms of CD and identify some novel therapeutic targets for CD.

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“…The SLC44A4 (solute carrier family 44 member 4) gene located at 6p21.33 encodes human thiamine pyrophosphate transporter (TPPT), which is involved in the uptake of choline by cholinergic neurons. The SLC44A4 gene was reported to be associated with ulcerative colitis (UC) susceptibility in the Indian, Japanese, and Chinese populations ( Gupta and Thelma, 2016 ; Gupta et al, 2016 ; Wu et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Multi-Level Analyses of Genome-Wide Association Study to Reveal Significant Risk Genes and Pathways in Neuromyelitis Optica Spectrum Disorder

et al. 2021

Front. Genet.

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BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system and it is understandable that environmental and genetic factors underlie the etiology of NMOSD. However, the susceptibility genes and associated pathways of NMOSD patients who are AQP4-Ab positive and negative have not been elucidated.MethodsSecondary analysis from a NMOSD Genome-wide association study (GWAS) dataset originally published in 2018 (215 NMOSD cases and 1244 controls) was conducted to identify potential susceptibility genes and associated pathways in AQP4-positive and negative NMOSD patients, respectively (132 AQP4-positive and 83 AQP4-negative).ResultsIn AQP4-positive NMOSD cases, five shared risk genes were obtained at chromosome 6 in AQP4-positive NMOSD cases by using more stringent p-Values in both methods (p < 0.05/16,532), comprising CFB, EHMT2, HLA-DQA1, MSH5, and SLC44A4. Fifty potential susceptibility gene sets were determined and 12 significant KEGG pathways were identified. Sixty-seven biological process pathways, 32 cellular-component pathways, and 29 molecular-function pathways with a p-Value of <0.05 were obtained from the GO annotations of the 128 pathways identified. In the AQP4 negative NMOSD group, no significant genes were obtained by using more stringent p-Values in both methods (p < 0.05/16,485). The 22 potential susceptibility gene sets were determined. There were no shared potential susceptibility genes between the AQP4-positive and negative groups, furthermore, four significant KEGG pathways were also identified. Of the GO annotations of the 165 pathways identified, 99 biological process pathways, 37 cellular-component pathways, and 29 molecular-function pathways with a p-Value of <0.05 were obtained.ConclusionThe potential molecular mechanism underlying NMOSD may be related to proteins encoded by these novel genes in complements, antigen presentation, and immune regulation. The new results may represent an improved comprehension of the genetic and molecular mechanisms underlying NMOSD.

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A cross-ethnic survey of CFB and SLC44A4, Indian ulcerative colitis GWAS hits, underscores their potential role in disease susceptibility

Cited by 15 publications

References 38 publications

Analysis of the interferon-γ-induced secretome of intestinal endothelial cells: putative impact on epithelial barrier dysfunction in IBD

Analysis of the interferon-γ-induced secretome of intestinal endothelial cells: putative impact on epithelial barrier dysfunction in IBD

Identification of hub genes and key pathways in pediatric Crohn’s disease using next generation sequencing and bioinformatics analysis

Multi-Level Analyses of Genome-Wide Association Study to Reveal Significant Risk Genes and Pathways in Neuromyelitis Optica Spectrum Disorder

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