18 results on '"Festen, Eleonora A. M."'
Search Results
2. Genetic Analysis in A Dutch Study Sample Identifies More Ulcerative Colitis Susceptibility Loci and Shows Their Additive Role in Disease Risk.
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Festen, Eleonora A. M., Stokkers, Pieter C. F., van Diemen, Cleo C., van Bodegraven, Adriaan A., Boezen, H. Marieke, Crusius, Bart J. A., Hommes, Daniel W., van der Woude, Janneke C., Balschun, Tobias, Verspaget, Hein W., Schreiber, Stephan, de Jong, Dirk J., Franke, Andre, Dijkstra, Gerard, Wijmenga, Cisca, and Weersma, Rinse K.
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GENETIC polymorphisms , *COLON diseases , *ULCERATIVE colitis , *INFLAMMATORY bowel diseases , *CONFIDENCE intervals , *LOCUS (Genetics) - Abstract
OBJECTIVES:Genetic susceptibility is known to make a major contribution to the pathogenesis of ulcerative colitis (UC). Recently, three studies, including a genome-wide association study (GWAS), reported novel UC risk loci.METHODS:The top-20 single-nucleotide polymorphisms (SNPs) from the first UC-GWAS were genotyped, as part of the study's replication phase, in 561 UC cases and 728 controls from our Dutch UC study sample. We genotyped eight SNPs identified in two more studies, in these individuals, and replicated all significantly associated SNPs in an additional 894 UC cases and 1,174 controls from our Dutch UC study sample. A combined analysis for all patients (n=1,455) and controls (n=1,902) was performed. Dose–response models were constructed with the associated risk alleles.RESULTS:We found 12 SNPs tagging ten loci, including HLA-DRA, IL10, IL23R, JAK2, S100Z, ARPC2, and ECM1, to be associated with UC. We identified 10q26, flagged by the UC-GWAS but not confirmed in its replication phase, as a UC locus and found a trend toward association for GAS7. No association with disease localization or severity was found. The dose–response models show that individuals carrying 11 or more risk alleles have an odds ratio of 8.2 (confidence interval 3.0–22.8) for UC susceptibility.CONCLUSIONS:We confirmed the association of multiple loci with UC in the Dutch population and found evidence for association of 10q26 and a trend suggesting association for GAS7. Genetic models show that multiple risk loci in an individual increase the risk for developing UC. [ABSTRACT FROM AUTHOR]
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- 2010
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3. Corrigendum: Genetic Analysis in A Dutch Study Sample Identifies More Ulcerative Colitis Susceptibility Loci and Shows Their Additive Role in Disease Risk.
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Festen, Eleonora A. M., Stokkers, Pieter C. F., van Diemen, Cleo C., van Bodegraven, Adriaan A., Boezen, H. Marieke, Crusius, Bart J. A., Hommes, Daniel W., van der Woude, Janneke C., Balschun, Tobias, Verspaget, Hein W., Schreiber, Stephan, de Jong, Dirk J., Franke, Andre, Dijkstra, Gerard, Wijmenga, Cisca, and Weersma, Rinse K.
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INFLAMMATORY bowel diseases , *DISEASE risk factors - Abstract
A correction to the article "Genetic Analysis in A Dutch Study Sample Identifi es More Ulcerative Colitis Susceptibility Loci and Shows Their Additive Role in Disease Risk" that was published in the previous issue is presented.
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- 2010
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4. Proteomic analyses do not reveal subclinical inflammation in fatigued patients with clinically quiescent inflammatory bowel disease.
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Bourgonje, Arno R., Wichers, Sietse J., Hu, Shixian, van Dullemen, Hendrik M., Visschedijk, Marijn C., Faber, Klaas Nico, Festen, Eleonora A. M., Dijkstra, Gerard, Samsom, Janneke N., Weersma, Rinse K., and Spekhorst, Lieke M.
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INFLAMMATORY bowel diseases , *LEUKEMIA inhibitory factor , *PROTEOMICS , *FATIGUE (Physiology) , *C-reactive protein - Abstract
Fatigue is a common and clinically challenging symptom in patients with inflammatory bowel diseases (IBD), occurring in ~ 50% of patients with quiescent disease. In this study, we aimed to investigate whether fatigue in patients with clinically quiescent IBD is reflected by circulating inflammatory proteins, which might reflect ongoing subclinical inflammation. Ninety-two (92) different inflammation-related proteins were measured in plasma of 350 patients with clinically quiescent IBD. Quiescent IBD was defined as clinical (Harvey-Bradshaw Index < 5 or Simple Clinical Colitis Activity Index < 2.5) and biochemical remission (C-reactive protein < 5 mg/L and absence of anemia) at time of fatigue assessment. Leukemia inhibitory factor receptor (LIF-R) concentrations were inversely associated with severe fatigue, also after adjustment for confounding factors (nominal P < 0.05). Although solely LIF-R showed weak ability to discriminate between mild and severe fatigue (area under the curve [AUC] = 0.61, 95%CI: 0.53–0.69, P < 0.05), a combined set of the top seven (7) fatigue-associated proteins (all P < 0.10) was observed to have reasonable discriminative performance (AUC = 0.82 [95%CI: 0.74–0.91], P < 0.01). Fatigue in patients with IBD is not clearly reflected by distinct protein signatures, suggesting there is no subclinical inflammation defined by the studied inflammatory proteins. Future studies are warranted to investigate other proteomic markers that may reflect fatigue in clinically quiescent IBD. [ABSTRACT FROM AUTHOR]
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- 2022
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5. Serological biomarkers of type I, III and IV collagen turnover are associated with the presence and future progression of stricturing and penetrating Crohnʼs disease.
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Bourgonje, Arno R., Alexdottir, Marta S., Otten, Antonius T., Loveikyte, Roberta, Bay‐Jensen, Anne‐Christine, Pehrsson, Martin, van Dullemen, Hendrik M., Visschedijk, Marijn C., Festen, Eleonora A. M., Weersma, Rinse K., Karsdal, Morten A., Faber, Klaas Nico, Mortensen, Joachim H., and Dijkstra, Gerard
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COLLAGEN , *CROHN'S disease , *PEPTIDE mass fingerprinting , *INFLAMMATORY bowel diseases , *INTESTINAL fistula , *MATRIX metalloproteinases , *BIOMARKERS - Abstract
Summary: Background: Increased collagen remodelling is a key pathophysiological component underlying intestinal stricture and fistula development in Crohn's disease (CD). Aims: To investigate associations between serological biomarkers of collagen turnover and disease behaviour according to the Montreal classification in patients with CD. Methods: Serological biomarkers of type III/IV collagen formation (PRO‐C3, PRO‐C4) and matrix metalloproteinase (MMP) or granzyme‐B (GrzB)‐mediated type I, III, IV and VI collagen degradation (C1M, C3M, C4M, C4G, C6Ma3) were measured using neo‐epitope protein fingerprint assays in 101 patients with CD (Montreal B1: n = 37; B2: n = 27; B3: n = 37) and 96 controls. Patients were followed up until their last outpatient visit to monitor stricturing/penetrating disease progression and recurrence and the occurrence of surgical interventions. Results: C1M, C3M and C4M were significantly reduced in patients with stricturing disease (Montreal B2) and accurately differentiated them from patients with either non‐stricturing, non‐penetrating (B1) or penetrating (B3) disease (all p < 0.001, multivariable analysis). Similarly, the type IV collagen formation/degradation (PRO‐C4/C4M) ratio demonstrated high discriminative capacity (B1/B2: AUC = 0.90; B1/B3: AUC = 0.87, both p < 0.001, multivariable analysis). Prospectively, higher baseline levels of C1M and C4G were associated with an increased risk of penetrating disease progression (C4G: hazard ratio [HR] 1.71 [1.05–2.81], p < 0.05). Conclusions: Elevated degradation of type I, III and IV collagen and excessive (relative) formation of type IV collagen strongly associates with stricturing CD. Type I and IV collagen fragments show predictive potential for the risk of penetrating disease progression. These biomarkers may become valuable tools for detection and prediction of stricturing and penetrating CD. [ABSTRACT FROM AUTHOR]
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- 2022
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6. Serological Biomarkers of Extracellular Matrix Turnover and Neutrophil Activity Are Associated with Long-Term Use of Vedolizumab in Patients with Crohn's Disease.
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Alexdottir, Marta S., Bourgonje, Arno R., Karsdal, Morten A., Pehrsson, Martin, Loveikyte, Roberta, van Dullemen, Hendrik M., Visschedijk, Marijn C., Festen, Eleonora A. M., Weersma, Rinse K., Faber, Klaas Nico, Dijkstra, Gerard, and Mortensen, Joachim H.
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EXTRACELLULAR matrix , *LEUCOCYTE elastase , *CROHN'S disease , *PEPTIDE mass fingerprinting , *VEDOLIZUMAB , *MATRIX metalloproteinases - Abstract
Crohn's disease (CD) is a relapsing-remitting inflammatory disease of the gastrointestinal (GI) tract characterized by increased extracellular matrix (ECM) remodeling. The introduction of the α4β7-integrin inhibitor vedolizumab (VEDO) has improved disease management, although there is a high rate of primary non-response in patients with CD. We studied whether ECM biomarkers of neutrophil activity and mucosal damage could predict long-term response to VEDO in patients with CD. Serum levels of human neutrophil elastase (HNE)-derived fragments of calprotectin (CPa9-HNE), and matrix metalloproteinase (MMP)-derived fragments of type I (C1M), III (C3M), IV (C4M), and VI (C6Ma3) collagen, type III collagen formation (PRO-C3), basement membrane turnover (PRO-C4) and T-cell activity (C4G), were measured using protein fingerprint assays in patients with CD (n = 32) before VEDO therapy. Long-term response was defined as VEDO treatment of at least 12 months. CPa9-HNE was significantly increased at baseline in non-responders compared with responders (p < 0.05). C1M, C3M, C4M, C6Ma3, and PRO-C4 were also significantly increased at baseline in non-responders compared with responders (all p < 0.05). All biomarkers were associated with response to VEDO (all p < 0.05). To conclude, baseline levels of serum biomarkers for neutrophil activity and mucosal damage are linked to the pathology of CD, and are associated with long-term use of VEDO in patients with CD. Therefore, these biomarkers warrant further validation and could aid in therapeutic decision-making concerning vedolizumab therapy. [ABSTRACT FROM AUTHOR]
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- 2022
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7. Gut mucosa dissociation protocols influence cell type proportions and single-cell gene expression levels.
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Uniken Venema, Werna T. C., Ramírez-Sánchez, Aarón D., Bigaeva, Emilia, Withoff, Sebo, Jonkers, Iris, McIntyre, Rebecca E., Ghouraba, Mennatallah, Raine, Tim, Weersma, Rinse K., Franke, Lude, Festen, Eleonora A. M., and van der Wijst, Monique G. P.
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GENE expression , *MUCOUS membranes , *NEUROGLIA , *SYNTHETIC genes , *CELL survival , *MICROARRAY technology - Abstract
Single-cell RNA sequencing (scRNA-seq) has revolutionized the study of the cellular landscape of organs. Most single-cell protocols require fresh material, which limits sample size per experiment, and consequently, introduces batch effects. This is especially true for samples acquired through complex medical procedures, such as intestinal mucosal biopsies. Moreover, the tissue dissociation procedure required for obtaining single cells is a major source of noise; different dissociation procedures applied to different compartments of the tissue induce artificial gene expression differences between cell subsets. To overcome these challenges, we have developed a one-step dissociation protocol and demonstrated its use on cryopreserved gut mucosal biopsies. Using flow cytometry and scRNA-seq analysis, we compared this one-step dissociation protocol with the current gold standard, two-step collagenase digestion, and an adaptation of a recently published alternative, three-step cold-active Bacillus licheniformus protease digestion. Both cell viability and cell type composition were comparable between the one-step and two-step collagenase dissociation, with the former being more time-efficient. The cold protease digestion resulted in equal cell viability, but better preserves the epithelial cell types. Consequently, to analyze the rarer cell types, such as glial cells, larger total biopsy cell numbers are required as input material. The multi-step protocols affected cell types spanning multiple compartments differently. In summary, we show that cryopreserved gut mucosal biopsies can be used to overcome the logistical challenges and batch effects in large scRNA-seq studies. Furthermore, we demonstrate that using cryopreserved biopsies digested using a one-step collagenase protocol enables large-scale scRNA-seq, FACS, organoid generation and intraepithelial lymphocyte expansion. [ABSTRACT FROM AUTHOR]
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- 2022
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8. Gut mucosa dissociation protocols influence cell type proportions and single-cell gene expression levels.
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Uniken Venema, Werna T. C., Ramírez-Sánchez, Aarón D., Bigaeva, Emilia, Withoff, Sebo, Jonkers, Iris, McIntyre, Rebecca E., Ghouraba, Mennatallah, Raine, Tim, Weersma, Rinse K., Franke, Lude, Festen, Eleonora A. M., and van der Wijst, Monique G. P.
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GENE expression , *MUCOUS membranes , *NEUROGLIA , *SYNTHETIC genes , *CELL survival , *MICROARRAY technology - Abstract
Single-cell RNA sequencing (scRNA-seq) has revolutionized the study of the cellular landscape of organs. Most single-cell protocols require fresh material, which limits sample size per experiment, and consequently, introduces batch effects. This is especially true for samples acquired through complex medical procedures, such as intestinal mucosal biopsies. Moreover, the tissue dissociation procedure required for obtaining single cells is a major source of noise; different dissociation procedures applied to different compartments of the tissue induce artificial gene expression differences between cell subsets. To overcome these challenges, we have developed a one-step dissociation protocol and demonstrated its use on cryopreserved gut mucosal biopsies. Using flow cytometry and scRNA-seq analysis, we compared this one-step dissociation protocol with the current gold standard, two-step collagenase digestion, and an adaptation of a recently published alternative, three-step cold-active Bacillus licheniformus protease digestion. Both cell viability and cell type composition were comparable between the one-step and two-step collagenase dissociation, with the former being more time-efficient. The cold protease digestion resulted in equal cell viability, but better preserves the epithelial cell types. Consequently, to analyze the rarer cell types, such as glial cells, larger total biopsy cell numbers are required as input material. The multi-step protocols affected cell types spanning multiple compartments differently. In summary, we show that cryopreserved gut mucosal biopsies can be used to overcome the logistical challenges and batch effects in large scRNA-seq studies. Furthermore, we demonstrate that using cryopreserved biopsies digested using a one-step collagenase protocol enables large-scale scRNA-seq, FACS, organoid generation and intraepithelial lymphocyte expansion. [ABSTRACT FROM AUTHOR]
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- 2022
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9. Polygenetic risk scores do not add predictive power to clinical models for response to anti-TNFα therapy in inflammatory bowel disease.
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Karmi, Naomi, Bangma, Amber, Spekhorst, Lieke M., van Dullemen, Hendrik M., Visschedijk, Marijn C., Dijkstra, Gerard, Weersma, Rinse K., Voskuil, Michiel D., and Festen, Eleonora A. M.
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INFLAMMATORY bowel diseases , *CROHN'S disease , *ULCERATIVE colitis - Abstract
Background: Anti-tumour necrosis factor alpha (TNFα) therapy is widely used in the management of Crohn's disease (CD) and ulcerative colitis (UC). However, up to a third of patients do not respond to induction therapy and another third of patients lose response over time. To aid patient stratification, polygenetic risk scores have been identified as predictors of response to anti-TNFα therapy. We aimed to replicate the association between polygenetic risk scores and response to anti-TNFα therapy in an independent cohort of patients, to establish its clinical validity. Materials and methods: Primary non-response, primary response, durable response and loss of response to anti-TNFα therapy was retrospectively assessed for each patient using stringent definitions. Genome wide genotyping was performed and previously described polygenetic risk scores for primary non-response and durable response were calculated. We compared polygenetic risk scores between patients with primary response and primary non-response, and between patients with durable response and loss of response, using separate analyses for CD and UC. Results: Out of 334 patients with CD, 15 (4%) patients met criteria for primary non-response, 221 (66%) for primary response, 115 (34%) for durable response and 35 (10%) for loss of response. Out of 112 patients with UC, 12 (11%) met criteria for primary non-response, 68 (61%) for primary response, 19 (17%) for durable response and 20 (18%) for loss of response. No significant differences in polygenetic risk scores were found between primary non-responders and primary responders, and between durable responders and loss of responders. Conclusions: We could not replicate the previously reported association between polygenetic risk scores and response to anti-TNFα therapy in an independent cohort of patients with CD or UC. Currently, there is insufficient evidence to use polygenetic risk scores to predict response to anti-TNFα therapy in patients with IBD. [ABSTRACT FROM AUTHOR]
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- 2021
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10. Exome sequencing in patient‐parent trios suggests new candidate genes for early‐onset primary sclerosing cholangitis.
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Haisma, Sjoukje‐Marije, Weersma, Rinse K., Joosse, Maria E., Koning, Barbara A. E., Meij, Tim, Koot, Bart G. P., Wolters, Victorien, Norbruis, Obbe, Daly, Mark J., Stevens, Christine, Xavier, Ramnik J., Koskela, Jukka, Rivas, Manuel A., Visschedijk, Marijn C., Verkade, Henkjan J., Barbieri, Ruggero, Jansen, Dianne B. H., Festen, Eleonora A. M., Rheenen, Patrick F., and Diemen, Cleo C.
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CHOLANGITIS , *GENES , *INFLAMMATORY bowel diseases , *RECESSIVE genes , *BILE ducts , *GENE expression , *GENE frequency - Abstract
BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a rare bile duct disease strongly associated with inflammatory bowel disease (IBD). Whole‐exome sequencing (WES) has contributed to understanding the molecular basis of very early‐onset IBD, but rare protein‐altering genetic variants have not been identified for early‐onset PSC. We performed WES in patients diagnosed with PSC ≤ 12 years to investigate the contribution of rare genetic variants to early‐onset PSC. METHODS: In this multicentre study, WES was performed on 87 DNA samples from 29 patient‐parent trios with early‐onset PSC. We selected rare (minor allele frequency < 2%) coding and splice‐site variants that matched recessive (homozygous and compound heterozygous variants) and dominant (de novo) inheritance in the index patients. Variant pathogenicity was predicted by an in‐house developed algorithm (GAVIN), and PSC‐relevant variants were selected using gene expression data and gene function. RESULTS: In 22 of 29 trios we identified at least 1 possibly pathogenic variant. We prioritized 36 genes, harbouring a total of 54 variants with predicted pathogenic effects. In 18 genes, we identified 36 compound heterozygous variants, whereas in the other 18 genes we identified 18 de novo variants. Twelve of 36 candidate risk genes are known to play a role in transmembrane transport, adaptive and innate immunity, and epithelial barrier function. CONCLUSIONS: The 36 candidate genes for early‐onset PSC need further verification in other patient cohorts and evaluation of gene function before a causal role can be attributed to its variants. [ABSTRACT FROM AUTHOR]
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- 2021
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11. Treatment of severe acute ulcerative colitis in SARS-CoV-2 infected patients: report of three cases and discussion of treatment options.
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Bourgonje, Arno R., van Linschoten, Reinier C. A., West, Rachel L., van Dijk, Maarten A., van Leer-Buter, Coretta C., Kats-Ugurlu, Gursah, Pierik, Marieke J., Festen, Eleonora A. M., Weersma, Rinse K., and Dijkstra, Gerard
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SARS-CoV-2 , *ULCERATIVE colitis , *COVID-19 , *INFLAMMATORY bowel diseases , *COVID-19 treatment - Abstract
In the wake of the coronavirus disease 2019 (COVID-19) pandemic, it is unclear how asymptomatic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected patients who present with acute severe ulcerative colitis (UC) can be treated effectively and safely. Standard treatment regimens consist of steroids, immunomodulatory drugs, and biological therapies, but therapeutic decision-making becomes challenging as there are uncertainties about how to deal with these drugs in patients with COVID-19 and active UC. Importantly, guidelines for this particular group of patients with UC are still lacking. To inform therapeutic decision-making, we describe three consecutive cases of patients with active UC and COVID-19 and discuss their treatments based on theoretical knowledge, currently available evidence and clinical observations. Three patients were identified through our national inflammatory bowel disease network [Initiative on Crohn's and Colitis (ICC)] for whom diagnosis of SARS-CoV-2-infection was established by reverse transcription–polymerase chain reaction (RT-PCR) testing in nasopharynx, stools, and/or biopsies. Acute severe UC was diagnosed by clinical parameters, endoscopy, and histopathology. Clinical guidelines for SARS-CoV-2-negative patients advocate the use of steroids, calcineurin inhibitors, or tumor necrosis factor alpha (TNF-α)-antagonists as induction therapy, and experiences from the current three cases show that steroids and TNF-α-antagonists could also be used in patients with COVID-19. This could potentially be followed by TNF-α-antagonists, vedolizumab, or ustekinumab as maintenance therapy in these patients. Future research is warranted to investigate if, and which, immunomodulatory drugs should be used for COVID-19 patients that present with active UC. To answer this question, it is of utmost importance that future cases of patients with UC and COVID-19 are documented carefully in international registries, such as the SECURE-IBD registry. [ABSTRACT FROM AUTHOR]
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- 2021
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12. Environmental factors associated with biological use and surgery in inflammatory bowel disease.
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Sloot, Kimberley W J, Geertsema, Paul, Rijkmans, Hanneke C, Voskuil, Michiel D, Dullemen, Hendrik M, Visschedijk, Marijn C, Festen, Eleonora A M, Weersma, Rinse K, Alizadeh, Behrooz Z, and Dijkstra, Gerard
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INFLAMMATORY bowel diseases , *CROHN'S disease , *SMOKING cessation , *APPENDECTOMY , *ULCERATIVE colitis , *DISEASE progression - Abstract
Background and Aim: While major efforts were made studying the complex etiology of inflammatory bowel disease (IBD) including environmental factors, less is known about underlying causes leading to the heterogeneous and highly variable course of disease. As cigarette smoking cessation is the best‐known environmental factor with beneficial effect in Crohn's disease (CD), more exposome factors are likely involved. Further insights into the role of the exposome in heterogeneity of disease might not only further knowledge of underlying pathways, but also allow for better risk stratification. Methods: Seven hundred twenty‐eight IBD patients completed the validated Groningen IBD Environmental Questionnaire, collecting exposome data for 93 exposome factors. Associations with disease course, that is, for need for surgery or biological therapy, were evaluated using univariate and multivariate‐adjusted logistic regression modeling. Results: No significant associations were seen after Bonferroni correction. However, 11 novel exposome factors were identified with P < 0.05. Two factors were associated with course of CD and ulcerative colitis (UC): beer (CD OR0.3/UC OR0.3) and cannabis (0.5/2.2). While in CD, carpet flooring (0.5) was associated with biological use, and four factors were associated with surgery: working shifts (1.8), appendectomy (2.4), frequent tooth brushing (2.8), and large household size (0.1). For UC, migrants more often required biologicals (10.2). Childhood underweight (3.4), amphetamine use (6.2), and cocaine use (4.8) were associated with surgery. Five factors were replicated. Conclusions: We identified 16 environmental factors nominally associated with biological use and surgery in established IBD. These new insights form an important stepping stone to guide research on biological pathways involved, risk stratification, tailor‐made interventions, and preventive strategies in IBD. [ABSTRACT FROM AUTHOR]
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- 2021
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13. Treatment of severe acute ulcerative colitis in SARS-CoV-2 infected patients: report of three cases and discussion of treatment options.
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Bourgonje, Arno R., van Linschoten, Reinier C. A., West, Rachel L., van Dijk, Maarten A., van Leer-Buter, Coretta C., Kats-Ugurlu, Gursah, Pierik, Marieke J., Festen, Eleonora A. M., Weersma, Rinse K., and Dijkstra, Gerard
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SARS-CoV-2 , *ULCERATIVE colitis , *COVID-19 , *INFLAMMATORY bowel diseases , *TUMOR necrosis factors - Abstract
In the wake of the coronavirus disease 2019 (COVID-19) pandemic, it is unclear how asymptomatic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected patients who present with acute severe ulcerative colitis (UC) can be treated effectively and safely. Standard treatment regimens consist of steroids, immunomodulatory drugs, and biological therapies, but therapeutic decision-making becomes challenging as there are uncertainties about how to deal with these drugs in patients with COVID-19 and active UC. Importantly, guidelines for this particular group of patients with UC are still lacking. To inform therapeutic decision-making, we describe three consecutive cases of patients with active UC and COVID-19 and discuss their treatments based on theoretical knowledge, currently available evidence and clinical observations. Three patients were identified through our national inflammatory bowel disease network [Initiative on Crohn's and Colitis (ICC)] for whom diagnosis of SARS-CoV-2-infection was established by reverse transcription–polymerase chain reaction (RT-PCR) testing in nasopharynx, stools, and/or biopsies. Acute severe UC was diagnosed by clinical parameters, endoscopy, and histopathology. Clinical guidelines for SARS-CoV-2-negative patients advocate the use of steroids, calcineurin inhibitors, or tumor necrosis factor alpha (TNF-α)-antagonists as induction therapy, and experiences from the current three cases show that steroids and TNF-α-antagonists could also be used in patients with COVID-19. This could potentially be followed by TNF-α-antagonists, vedolizumab, or ustekinumab as maintenance therapy in these patients. Future research is warranted to investigate if, and which, immunomodulatory drugs should be used for COVID-19 patients that present with active UC. To answer this question, it is of utmost importance that future cases of patients with UC and COVID-19 are documented carefully in international registries, such as the SECURE-IBD registry. [ABSTRACT FROM AUTHOR]
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- 2021
- Full Text
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14. Latent cytomegalovirus infection does not influence long-term disease outcomes in inflammatory bowel disease, but is associated with later onset of disease.
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van der Sloot, Kimberley W. J., Voskuil, Michiel D., Visschedijk, Marijn C., Festen, Eleonora A. M., van Dullemen, Hendrik M., Weersma, Rinse K., Alizadeh, Behrooz Z., van Leer-Buter, Coretta, and Dijkstra, Gerard
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INFLAMMATORY bowel diseases , *CYTOMEGALOVIRUS diseases , *INFECTION , *CROHN'S disease , *DISEASE duration , *RHEUMATIC heart disease - Abstract
Cytomegalovirus (CMV) infection is common in the general population. CMV infection negatively affects disease course in transplant recipients and HIV patients. Whereas primary CMV infections may occur sporadically in seronegative patients, all seropositive patients with inflammatory bowel syndrome (IBD) are at risk for CMV reactivation due to the inflammatory mucosal and use of immunosuppressive medication. It is unclear whether latent CMV infection, and risk of reactivations, influences long-term disease outcomes. In this study, we aim to explore whether CMV infection affects disease outcomes in IBD patients. We performed a cross-sectional cohort study with 1404 patients with IBD from a single center. Clinical characteristics and disease outcomes were prospectively collected. We scrutinized CMV serology test results and performed additional CMV serology testing if serum was available. Out of 699 IBD patients with CMV serology, 303 (43.3%) were seropositive, comparable to the general Dutch population. CMV seropositivity was associated with older age, longer IBD disease duration, non-Western origin, birth outside the Netherlands and a lower educational level (p-values ≤.004). CMV seropositivity was not associated with more complicated long-term disease outcomes of IBD (p-values >.05). Seropositive patients presented with symptoms and were diagnosed at an older age compared to seronegative patients (p-values <.01). CMV seropositivity does not influence disease outcomes of IBD patients and seems to be associated with a delay in IBD onset. Guidelines regarding CMV screening in patients with IBD are currently based on a low level of evidence. These data support the recommendation that routine CMV serology measurement is not necessary in the clinical care of IBD. [ABSTRACT FROM AUTHOR]
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- 2020
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15. Predicted efficacy of a pharmacogenetic passport for inflammatory bowel disease.
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Bangma, Amber, Voskuil, Michiel D., Uniken Venema, Werna T. C., Brugge, Harm, Hu, Shixian, Lanting, Pauline, Franke, Lude, Dijkstra, Gerard, Festen, Eleonora A. M., and Weersma, Rinse K.
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PHARMACOGENOMICS , *INFLAMMATORY bowel diseases , *PASSPORTS - Abstract
Summary: Background: High inter‐individual variability in therapeutic response to drugs used in the management of Inflammatory Bowel Disease (IBD) leads to high morbidity and high costs. Genetic variants predictive of thiopurine‐induced myelosuppression, thiopurine‐induced pancreatitis and immunogenicity of Tumour Necrosis Factor alpha (TNFα) antagonists have been identified, but uptake of pre‐treatment pharmacogenetic testing into clinical guidelines has been slow. Aim: To explore the efficacy of a pharmacogenetic passport for IBD that includes multiple pharmacogenetic predictors of response. Methods: Patients with IBD exposed to thiopurines and/or TNFα antagonists were retrospectively evaluated for the presence of thiopurine toxicity and/or immunogenicity of TNFα antagonists. All patients were genotyped using both whole‐exome sequencing and the Illumina Global Screening Array. An in‐house‐developed computational pipeline translated genetic data into an IBD pharmacogenetic passport that predicted risks for thiopurine toxicity and immunogenicity of TNFα antagonists per patient. Using pharmacogenetic‐guided treatment guidelines, we calculated clinical efficacy estimates for pharmacogenetic testing for IBD. Results: Among 710 patients with IBD exposed to thiopurines and/or TNFα antagonists, 150 adverse drug responses occurred and our pharmacogenetic passport would have predicted 54 (36%) of these. Using a pharmacogenetic passport for IBD that includes genetic variants predictive of thiopurine‐induced myelosuppression, thiopurine‐induced pancreatitis, and immunogenicity of TNFα antagonists, 24 patients need to be genotyped to prevent one of these adverse drug responses. Conclusions: This study highlights the clinical efficacy of a pharmacogenetic passport for IBD. Implementation of such a pharmacogenetic passport into clinical management of IBD may contribute to a reduction in adverse drug responses. [ABSTRACT FROM AUTHOR]
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- 2020
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16. Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease.
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Walker, Gareth J., Harrison, James W., Heap, Graham A., Voskuil, Michiel D., Andersen, Vibeke, Anderson, Carl A., Ananthakrishnan, Ashwin N., Barrett, Jeffrey C., Beaugerie, Laurent, Bewshea, Claire M., Cole, Andy T., Cummings, Fraser R., Daly, Mark J., Ellul, Pierre, Fedorak, Richard N., Festen, Eleonora A. M., Florin, Timothy H., Gaya, Daniel R., Halfvarson, Jonas, and Hart, Ailsa L.
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CROHN'S disease , *GENETIC polymorphisms , *GENOMES , *HYDROLASES , *RESEARCH funding , *TRANSFERASES , *ULCERATIVE colitis , *WHITE people , *CASE-control method , *HAPLOTYPES , *LEUKOCYTE count , *SEQUENCE analysis , *THERAPEUTICS - Abstract
Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM).Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD).Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients.Exposures: Genetic variants associated with TIM.Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal.Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose.Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required. [ABSTRACT FROM AUTHOR]- Published
- 2019
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17. SLC39A8 missense variant is associated with Crohn's disease but does not have a major impact on gut microbiome composition in healthy subjects.
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Collij, Valerie, Imhann, Floris, Vich Vila, Arnau, Fu, Jingyuan, Dijkstra, Gerard, Festen, Eleonora A. M., Voskuil, Michiel D., Daly, Mark J., Xavier, Ramnik J., Wijmenga, Cisca, Zhernakova, Alexandra, and Weersma, Rinse K.
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CROHN'S disease , *INFLAMMATORY bowel diseases , *ULCERATIVE colitis , *GUT microbiome , *RIBOSOMAL RNA - Abstract
Background: Gene-microbiome interactions are important in aetiology and pathogenesis of inflammatory bowel disease, a chronic inflammatory disorder of the gastrointestinal tract consisting of Crohn’s disease and ulcerative colitis. Scarce studies on gene-microbiome interactions show very little overlap in their results. Therefore, it is of utmost importance that gene-microbiome studies are repeated. We aimed to replicate the association between the SLC39A8 [Thr]391 risk allele and gut microbiome composition in patients with inflammatory bowel disease and healthy controls. Methods: We collected faecal samples, peripheral blood and extensive phenotype data from 291 patients with inflammatory bowel disease and 476 healthy controls. Carrier status information was obtained from whole exome sequencing data, generated using the Illumina HiSeq. The gut microbiome composition was determined by tag-sequencing the 16S rRNA gene. Associations between carrier status and disease were tested using the Wilcoxon-Mann-Whitney test. Associations between carriers and gut microbiome composition were determined using principal coordinate analyses, variance explained, alpha diversity and additive general linear models in inflammatory bowel disease, healthy controls and all groups combined. Results: Crohn’s disease patients were more often carriers of the missense variant (21/171, 12.3%) than controls (30/476, 6.3%) (OR = 2.1, P = 0.01). We could not identify associations between carrier status and overall gut microbiome composition and microbial richness in all tested groups after correcting for potential confounding factors. We did identify 37 different operational taxonomical units to be associated with carrier status among the tested groups. Two of these 37 were identified before in the discovery study. Conclusions: We could confirm the genetic association of the SLC39A8 [Thr]391 risk allele with Crohn’s disease but we could only limited replicate the association in gut microbiome composition. Independent replication of gene-microbiome studies is warranted to identify true biological mechanisms. [ABSTRACT FROM AUTHOR]
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- 2019
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18. MOLGENIS research: advanced bioinformatics data software for non-bioinformaticians.
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Velde, K Joeri van der, Imhann, Floris, Charbon, Bart, Pang, Chao, Enckevort, David van, Slofstra, Mariska, Barbieri, Ruggero, Alberts, Rudi, Hendriksen, Dennis, Kelpin, Fleur, Haan, Mark de, Boer, Tommy de, Haakma, Sido, Stroomberg, Connor, Scholtens, Salome, van de Geijn, Gert-Jan, Festen, Eleonora A M, Weersma, Rinse K, and Swertz, Morris A
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BIOINFORMATICS , *NUCLEOTIDE sequencing , *CLOUD computing , *GENOMICS , *MEDICAL care - Abstract
Motivation The volume and complexity of biological data increases rapidly. Many clinical professionals and biomedical researchers without a bioinformatics background are generating big '-omics' data, but do not always have the tools to manage, process or publicly share these data. Results Here we present MOLGENIS Research, an open-source web-application to collect, manage, analyze, visualize and share large and complex biomedical datasets, without the need for advanced bioinformatics skills. Availability and implementation MOLGENIS Research is freely available (open source software). It can be installed from source code (see http://github.com/molgenis), downloaded as a precompiled WAR file (for your own server), setup inside a Docker container (see http://molgenis.github.io), or requested as a Software-as-a-Service subscription. For a public demo instance and complete installation instructions see http://molgenis.org/research. [ABSTRACT FROM AUTHOR]
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- 2019
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