Genomic and Expression Analyses Identify a Disease-Modifying Variant for Fibrostenotic Crohn’s Disease

Visschedijk, Marijn C.; Spekhorst, Lieke M.; Cheng, Shih-Chin; Loo, Ellen S. van; Jansen, Bernadien H.; Blokzijl, Tjasso; Kil, Hyunsuk; Jong, Dirk J. de; Pierik, Marieke; Maljaars, Jeroen; Woude, C. Janneke van der; Bodegraven, Adriaan A. van; Oldenburg, Bas; Löwenberg, Mark; Nieuwenhuijs, Vincent B.; Imhann, Floris; Sommeren, Suzanne van; Alberts, Rudi; Xavier, Ramnik J.; Dijkstra, Gerard; Faber, Klaas Nico; Aldaz, C. Marcelo; Weersma, Rinse K.; Festen, Eleonora A. M.

doi:10.1093/ecco-jcc/jjy001

Cited by 20 publications

(19 citation statements)

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“…In agreement with this observation, evidence from studies in various inflammatory pathologies strongly suggests that Wwox has a relevant function in inflammation in general. Furthermore, a direct association between WWOX and the NF-kB inflammation signaling pathway has been demonstrated [24][25][26][27]. observation, evidence from studies in various inflammatory pathologies strongly suggests that Wwox has a relevant function in inflammation in general.…”

Section: Wwox Expression In Cnsmentioning

confidence: 95%

WWOX Loss of Function in Neurodevelopmental and Neurodegenerative Disorders

Aldaz

Hussain

2020

IJMS

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The WWOX gene was initially discovered as a putative tumor suppressor. More recently, its association with multiple central nervous system (CNS) pathologies has been recognized. WWOX biallelic germline pathogenic variants have been implicated in spinocerebellar ataxia type 12 (SCAR12; MIM:614322) and in early infantile epileptic encephalopathy (EIEE28; MIM:616211). WWOX germline copy number variants have also been associated with autism spectrum disorder (ASD). All identified germline genomic variants lead to partial or complete loss of WWOX function. Importantly, large-scale genome-wide association studies have also identified WWOX as a risk gene for common neurodegenerative conditions such as Alzheimer’s disease (AD) and multiple sclerosis (MS). Thus, the spectrum of CNS disorders associated with WWOX is broad and heterogeneous, and there is little understanding of potential mechanisms at play. Exploration of gene expression databases indicates that WWOX expression is comparatively higher in the human cerebellar cortex than in other CNS structures. However, RNA in-situ hybridization data from the Allen Mouse Brain Atlas show that specific regions of the basolateral amygdala (BLA), the medial entorhinal cortex (EC), and deep layers of the isocortex can be singled out as brain regions with specific higher levels of Wwox expression. These observations are in close agreement with single-cell RNA-seq data which indicate that neurons from the medial entorhinal cortex, Layer 5 from the frontal cortex as well as GABAergic basket cells and granule cells from cerebellar cortex are the specific neuronal subtypes that display the highest Wwox expression levels. Importantly, the brain regions and cell types in which WWOX is most abundantly expressed, such as the EC and BLA, are intimately linked to pathologies and syndromic conditions in turn associated with this gene, such as epilepsy, intellectual disability, ASD, and AD. Higher Wwox expression in interneurons and granule cells from cerebellum points to a direct link to the described cerebellar ataxia in cases of WWOX loss of function. We now know that total or partial impairment of WWOX function results in a wide and heterogeneous variety of neurodegenerative conditions for which the specific molecular mechanisms remain to be deciphered. Nevertheless, these observations indicate an important functional role for WWOX in normal development and function of the CNS. Evidence also indicates that disruption of WWOX expression at the gene or protein level in CNS has significant deleterious consequences.

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Section: Wwox Expression In Cnsmentioning

confidence: 95%

WWOX Loss of Function in Neurodevelopmental and Neurodegenerative Disorders

Aldaz

Hussain

2020

IJMS

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“…Microbial DNA profiles and RNA-sequencing profiles from the intestinal biopsies of the RISK cohort have uncovered RNA-microbe interactions and shown that biopsies taken from the distal colon can predict the IBD disease location higher up in the intestine [7, 14]. In addition, stool samples from the PRISM cohort have also been used to discover microbial profiles that can predict the efficacy of vedolizumab, a biological drug regulating T-cell homing to the gut [15], while a genetic variant in the WWOX gene discovered using genotypes of IBD patients treated in our hospital can be used to assess the risk of stricturing and penetrating Crohn’s disease behavior [16].…”

Section: Introductionmentioning

confidence: 99%

The 1000IBD project: multi-omics data of 1000 inflammatory bowel disease patients; data release 1

et al. 2019

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BackgroundInflammatory bowel disease (IBD) is a chronic complex disease of the gastrointestinal tract. Patients with IBD can experience a wide range of symptoms, but the pathophysiological mechanisms that cause these individual differences in clinical presentation remain largely unknown. In consequence, IBD is currently classified into subtypes using clinical characteristics. If we are to develop a more targeted treatment approach, molecular subtypes of IBD need to be discovered that can be used as new drug targets. To achieve this, we need multiple layers of molecular data generated from the same IBD patients.Construction and contentWe initiated the 1000IBD project (https://1000ibd.org) to prospectively follow more than 1000 IBD patients from the Northern provinces of the Netherlands. For these patients, we have collected a uniquely large number of phenotypes and generated multi-omics profiles. To date, 1215 participants have been enrolled in the project and enrolment is on-going. Phenotype data collected for these participants includes information on dietary and environmental factors, drug responses and adverse drug events. Genome information has been generated using genotyping (ImmunoChip, Global Screening Array and HumanExomeChip) and sequencing (whole exome sequencing and targeted resequencing of IBD susceptibility loci), transcriptome information generated using RNA-sequencing of intestinal biopsies and microbiome information generated using both sequencing of the 16S rRNA gene and whole genome shotgun metagenomic sequencing.Utility and discussionAll molecular data generated within the 1000IBD project will be shared on the European Genome-Phenome Archive (https://ega-archive.org, accession no: EGAS00001002702). The first data release, detailed in this announcement and released simultaneously with this publication, will contain basic phenotypes for 1215 participants, genotypes of 314 participants and gut microbiome data from stool samples (315 participants) and biopsies (107 participants) generated by tag sequencing the 16S gene. Future releases will comprise many more additional phenotypes and -omics data layers. 1000IBD data can be used by other researchers as a replication cohort, a dataset to test new software tools, or a dataset for applying new statistical models.ConclusionsWe report on the establishment and future development of the 1000IBD project: the first comprehensive multi-omics dataset aimed at discovering IBD biomarker profiles and treatment targets.Electronic supplementary materialThe online version of this article (10.1186/s12876-018-0917-5) contains supplementary material, which is available to authorized users.

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“…is might be explained by differences in disease duration, the development of fibrosis prior to medication, or genotypic and phenotypic differences between patients. An allele that could lead to overexpression of the main profibrotic mediator, TGF-β, has been identified [8], which could lead to more rapid development of fibrosis and strictures. Another explanation could be that inflammation and fibrosis are initially linked in the pathogenesis, but later become two independent processes [9].…”

Section: Discussionmentioning

confidence: 99%

Levels of Intestinal Inflammation and Fibrosis in Resection Specimens after Preoperative Anti-Tumor Necrosis Factor Alpha Treatment in Patients with Crohn’s Disease: A Comparative Pilot Study

Torle

Dabir

Korsgaard

et al. 2020

Surgery Research and Practice

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Background. Strictures are a common complication in Crohn’s disease (CD), found in more than 50% of patients. They are characterized by the excessive deposition of extracellular proteins in the tissue as a result of the chronic inflammatory process. The effect of anti-tumor necrosis factor alpha (TNF-α) therapy on the development of fibrosis is not yet fully understood. Aim. To investigate whether the degree of intestinal inflammation and fibrosis is correlated with preoperative anti-TNF-α therapy in patients with CD who are undergoing bowel resection. Methods. This unblinded, prospective, single tertiary center, pilot cohort study included all adult patients with CD who underwent elective, laparoscopic, or open intestinal resection. Preoperative investigations included measurement of blood TNF-α concentration, specific antidrug antibodies, and the concentration of selected inflammatory cytokines. Three pathologists independently examined the specimens and assessed the degree of inflammation and fibrosis. Results. Histopathological specimens from 10 patients with CD who underwent ileocecal or ileocolic resections were retrieved. Four of those patients were on anti-TNF-α treatment prior to surgery. The last dose of the anti-TNF-α agent was administered 1–9 weeks prior to bowel resection. Patients on anti-TNF-α treatment had a higher fibrosis score than controls (p=0.01). Anti-TNF-α treatment was not associated with an increase in CD68- or CD163-positive macrophages. There was no significant relationship between the time from the final preoperative anti-TNF-α dose to surgery and the fibrosis score. No significant association was found between the concentration of major inflammatory cytokines, including TNF-α, and the fibrosis score or degree of inflammation. Conclusions. Patients who underwent preoperative anti-TNF-α treatment had a higher fibrosis score than controls.

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Genomic and Expression Analyses Identify a Disease-Modifying Variant for Fibrostenotic Crohn’s Disease

Cited by 20 publications

References 29 publications

WWOX Loss of Function in Neurodevelopmental and Neurodegenerative Disorders

WWOX Loss of Function in Neurodevelopmental and Neurodegenerative Disorders

The 1000IBD project: multi-omics data of 1000 inflammatory bowel disease patients; data release 1

Levels of Intestinal Inflammation and Fibrosis in Resection Specimens after Preoperative Anti-Tumor Necrosis Factor Alpha Treatment in Patients with Crohn’s Disease: A Comparative Pilot Study

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