Fucosyltransferase 2: A Genetic Risk Factor for Intestinal Diseases

Hu, Mingyang; Zhang, Xiyun; Li, Jinze; Chen, Luotong; He, X. T.; Sui, Tingting

doi:10.3389/fmicb.2022.940196

Cited by 6 publications

(3 citation statements)

References 104 publications

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“…Voraussetzung für diesen Prozess ist allerdings eine vorherige Bindung der Viren an die Zelloberfläche. Diese Bindung ist offensichtlich für Noro-und Rotaviren eng mit der Präsenz bestimmter Blutgruppen-Antigene im Dünndarm verknüpft [6]. Deren intestinale Expression wird über das Enzym Fucosyltransferase 2 (FUT2) vermittelt.…”

Section: Unterschiedliche Empfänglichkeit Der Menschenunclassified

„Zellpiraten“ im Darm – Virusinfektionen des Gastrointestinaltraktes

Rüffer,

Eckert

2024

Zeitschrift für Komplementärmedizin

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SummaryZu den wichtigsten Magen-Darm-Infektionen verursachenden Viren zählen die Adeno-, Astro-, Noro-, Rota- und Sapoviren. Sie verursachen einen Brechdurchfall, der in den meisten Fällen selbstlimitierend ist. Die Therapie bei einem viralen Magen-Darm-Infekt ist nur symptomatisch möglich. Im Fokus steht hierbei insbesondere der Flüssigkeits- und Elektrolytersatz. Laut aktueller Leitlinie werden Probiotika zur Behandlung infektiöser Gastroenteritiden nicht empfohlen. In Hinblick auf die Bedeutung der Darmmikrobiota für den Verlauf von Virusinfektionen erscheint eine zumindest unterstützende probiotische Therapie durchaus sinnvoll. Pflanzliche bzw. mineralische Antidiarrhoika wie Uzara, Apfelpulver, Tannin, Kohle, Heilerde oder Myrrhe werden in der aktuellen Leitlinie aufgrund fehlender kontrollierter Studien nicht empfohlen, können aber durchaus hilfreich sein.

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Section: Unterschiedliche Empfänglichkeit Der Menschenunclassified

„Zellpiraten“ im Darm – Virusinfektionen des Gastrointestinaltraktes

Rüffer,

Eckert

2024

Zeitschrift für Komplementärmedizin

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“…Second, a colocalizing signal (rs516246) near the fucosyltransferase 2 gene (FUT2, chromosome 19) is in near-complete linkage disequilibrium (r2 = 0.99) with a stop-gain mutation in FUT2, and its trans-MR association genetically associates higher intestinal alkaline phosphatase (ALPI, chromosome 2) with a lower risk of inflammatory bowel disease (IBD) (Supplementary Figure 3). A number of studies (including GWAS) have shown that FUT2 non-secretor status is a risk factor for IBD 34 . However, there is, to date, no GWAS evidence supporting the direct association of ALPI with IBD.…”

Section: Trans-colocalizing Target-trait Pairs Are Informative Of Act...mentioning

confidence: 99%

Systematic disease-agnostic identification of therapeutically actionable targets using the genetics of human plasma proteins.

Karim

Ariano

Schwartzentruber

et al. 2023

Preprint

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Proteome-wide Mendelian randomization (MR) has emerged as a promising approach in uncovering novel therapeutic targets. However, genetic colocalization analysis has revealed that a third of MR associations lacked a shared causal signal between the protein and disease outcome, raising questions about the effectiveness of this approach. The impact of proteome-wide MR, stratified by cis-trans status, in the presence or absence of genetic colocalization, on therapeutic target identification remains largely unknown. In this study, we conducted genome-wide MR and cis/trans-genetic colocalization analyses using proteomic and complex trait genome-wide association studies. Using two different gold-standard datasets, we found that the enrichment of target-disease pairs supported by MR increased with more p-value stringent thresholds MR p-value, with the evidence of enrichment limited to colocalizing cis-MR associations. Using a phenome-wide proteogenetic colocalization approach, we identified 235 unique targets associated with 168 binary traits at high confidence (at colocalization posterior probability of shared signal > 0.8 and 5% FDR-corrected MR p-value). The majority of the target-trait pairs did not overlap with existing drug targets, highlighting opportunities to investigate novel therapeutic hypotheses. 42% of these non-overlapping target-trait pairs were supported by GWAS, interacting protein partners, animal models, and Mendelian disease evidence. These high confidence target-trait pairs assisted with causal gene identification and helped uncover translationally informative novel biology, especially from trans-colocalizing signals, such as the association of lower intestinal alkaline phosphatase with a higher risk of inflammatory bowel disease in FUT2 non-secretors. Beyond target identification, we used MR of colocalizing signals to infer therapeutic directions and flag potential safety concerns. For example, we found that most genetically predicted therapeutic targets for inflammatory bowel disease could potentially worsen allergic disease phenotypes, except for TNFRSF6B where we observed directionally consistent associations for both phenotypes. Our results are publicly available (https://mk31.shinyapps.io/mr_app2/), enabling others to use proteogenomic evidence to appraise therapeutic targets.

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“…While mucin Muc2 and Fut1 expression were not altered in Cyba mutant mice, the expression of Fut2 was decreased by 30–40% [ 8 ]. The α1,2-fucosyltransferase FUT2 catalyses the addition of fucose to terminal galactose, and in humans FUT2 nucleotide polymorphisms are associated with changes in the intestinal microbiota composition and predisposition to Crohn’s disease [ 16 ]. Genetic variation in FUT2 determines the ABH secretor status and in cooperation with the α-(1,3/4)-fucosyltransferase FUT3 the Lewis status.…”

Section: Introductionmentioning

confidence: 99%

Characterization of intestinal O-glycome in reactive oxygen species deficiency

Saldova,

Thomsson,

Wilkinson

et al. 2024

PLoS ONE

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Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation resulting from an inappropriate inflammatory response to intestinal microbes in a genetically susceptible host. Reactive oxygen species (ROS) generated by NADPH oxidases (NOX) provide antimicrobial defense, redox signaling and gut barrier maintenance. NADPH oxidase mutations have been identified in IBD patients, and mucus layer disruption, a critical aspect in IBD pathogenesis, was connected to NOX inactivation. To gain insight into ROS-dependent modification of epithelial glycosylation the colonic and ileal mucin O-glycome of mice with genetic NOX inactivation (Cyba mutant) was analyzed. O-glycans were released from purified murine mucins and analyzed by hydrophilic interaction ultra-performance liquid chromatography in combination with exoglycosidase digestion and mass spectrometry. We identified five novel glycans in ileum and found minor changes in O-glycans in the colon and ileum of Cyba mutant mice. Changes included an increase in glycans with terminal HexNAc and in core 2 glycans with Fuc-Gal- on C3 branch, and a decrease in core 3 glycans in the colon, while the ileum showed increased sialylation and a decrease in sulfated glycans. Our data suggest that NADPH oxidase activity alters the intestinal mucin O-glycans that may contribute to intestinal dysbiosis and chronic inflammation.

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Fucosyltransferase 2: A Genetic Risk Factor for Intestinal Diseases

Cited by 6 publications

References 104 publications

„Zellpiraten“ im Darm – Virusinfektionen des Gastrointestinaltraktes

„Zellpiraten“ im Darm – Virusinfektionen des Gastrointestinaltraktes

Systematic disease-agnostic identification of therapeutically actionable targets using the genetics of human plasma proteins.

Characterization of intestinal O-glycome in reactive oxygen species deficiency

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