Search

Background Epigenetic alterations may provide valuable insights into gene-environment interactions in the pathogenesis of inflammatory bowel disease [IBD]. Methods Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 Crohns disease [CD], 161 ulcerative colitis [UC], 28 IBD unclassified [IBD-U)] with covariates of age, sex and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using the Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Results A total of 137 differentially methylated positions [DMPs] were identified in IBD, including VMP1/MIR21 [p = 9.11 x 10(-15)] and RPS6KA2 [6.43 x 10(-13)], with consistency seen across Scandinavia and the UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 [p = 1.53 x 10(-15)]. Age acceleration is seen in IBD [coefficient 0.94, p < 2.2 x 10(-16)]. Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r = -0.32, p = 3.64 x 10(-7) vs non-IBD r = -0.14, p = 0.77]. Multi-omic integration of the methylome, genome and transcriptome also implicated specific pathways that associate with immune activation, response and regulation at disease inception. At follow-up, a signature of three DMPs [TAP1, TESPA1, RPTOR] were associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 [CI: 2.14-12.56], logrank p = 9.70 x 10(-4)). Conclusion These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease., Funding Agencies|European Commission [2858546]; Wellcome Trust [WT097943MA]

Background: Success in personalized medicine in complex disease is critically dependent on biomarker discovery. We profiled serum proteins using a novel proximity extension assay [PEA] to identify diagnostic and prognostic biomarkers in inflammatory bowel disease [IBD]. Methods: We conducted a prospective case-control study in an inception cohort of 552 patients [328 IBD, 224 non-IBD], profiling proteins recruited across six centres. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Nested leave-one-out cross-validation was used to examine the performance of diagnostic and prognostic proteins. Results: A total of 66 serum proteins differentiated IBD from symptomatic non-IBD controls, including matrix metallopeptidase-12 [MMP-12; Holm-adjusted p=4.1x10(-23)] and oncostatin-M [OSM; p=3.7x10(-16)]. Nine of these proteins are associated with cis-germline variation [59 independent single nucleotide polymorphisms]. Fifteen proteins, all members of tumour necrosis factor-independent pathways including interleukin-1 (IL-1) and OSM, predicted escalation, over a median follow-up of 518 [interquartile range 224-756] days. Nested cross-validation of the entire data set allowed characterization of five-protein models [96% comprising five core proteins ITGAV, EpCAM, IL18, SLAMF7 and IL8], which define a high-risk subgroup in IBD [hazard ratio 3.90, confidence interval: 2.43-6.26], or allowed distinct two- and three-protein models for ulcerative colitis and Crohns disease respectively. Conclusion: We have characterized a simple oligo-protein panel that has the potential to identify IBD from symptomatic controls and to predict future disease course. Further prospective work is required to validate our findings., Funding Agencies|EU FP7 grant: IBD-CHARACTER [2858546]; Wellcome TrustWellcome TrustEuropean Commission

Background: MicroRNAs [miRNAs] are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in inflammatory bowel disease [IBD] pathogenesis. Here we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD. Methods: In a two-stage prospective multi-centre case control study, next generation sequencing was performed on a discovery cohort of immunomagnetically separated leukocytes from 32 patients (nine Crohns disease [CD], 14 ulcerative colitis [UC], eight healthy controls) and differentially expressed signals were validated in whole blood in 294 patients [97 UC, 98 CD, 98 non-IBD, 1 IBDU] using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards. Results: In stage 1, each leukocyte subset [CD4(+) and CD8(+)T-cells and CD14(+) monocytes] was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4(+) T-cells, including miR-1307-3p [p = 0.01], miR-3615 [p = 0.02] and miR-4792 [p = 0.01]. In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (hazard ratio [HR] 1.98, interquartile range [IQR]: 1.20-3.27; logrank p = 1.80 x 10(-3)), in particular CD [HR 2.81; IQR: 1.11-3.53, p = 6.50 x 10(-4)]. Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if two or more criteria were met and 90% for UC if three or more criteria are met. Interpretation: We have identified and validated unique CD4(+) T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated., Funding Agencies|Crohns and Colitis UK [CCUK] [M2016/2]; LifeArc, EdinburghBiotechnology and Biological Sciences Research Council (BBSRC)

Method: We examined faecal samples, using the GA-map (TM) Dysbiosis Test, to associate gut microbiota composition with Crohn's disease (CD) and ulcerative colitis (UC) and to identify markers for future biomarker identification. We conducted a prospective case-control study (EU-ref. no. 305676) in an inception cohort of 324 individuals (64 CD, 84 UC, 116 symptomatic non-IBD controls and 44 healthy controls) across five European centres and examined 54 predetermined bacterial markers. We categorized patients according to the Montreal Classification and calculated the dysbiosis index (DI). Non-parametric tests were used to compare groups and the Bonferroni correction to adjust for multiple comparisons. Results: The fluorescent signals (FSSs) for Firmicutes and Eubacterium hallii were lower in inflammatory bowel disease (IBD) vs. symptomatic controls (p<.05). FSS for Firmicutes, Lachnospiraceae, Eubacterium hallii and Ruminococcus albus/bromii were lower, whereas the signal fo rBacteroides Fragilis was higher in UC vs. symptomatic controls (p<.05). FSS was higher for Bifidobacterium spp., Eubacterium hallii, Actinobacteria and Firmicutes among patients with ulcerative proctitis, compared to extensive colitis (p<.05). In CD, we observed no association with disease location. The DI correlated with faecal-calprotectin in both CD and in UC (p<.001). In terms of treatment escalation and anti-TNF response, differences were observed for some bacterial markers, but none of these associations were statistically significant. Conclusion: Our data reveal that the GA-map (TM) Dysbiosis Test holds the potential to characterize the faecal microbiota composition and to assess the degree of dysbiosis in new-onset IBD. On the other hand, our results cannot demonstrate any proven diagnostic or predictive value of this method to support clinical decision making., Funding Agency:European Union (EU) 2858546

Introduction: Despite its success, there appears to be practical issues with Faecal Calprotectin (FC) testing in Inflammatory Bowel Diseases (IBD), including sample collection, delivery and processing delays. Patients' perception and barriers to FC testing are yet to be explored in clinical practice. Method(s): A prospective patient survey was undertaken at IBD units in UK, Europe and Australia. A 9-point patient-based questionnaire was completed in clinic and included demographics, previous FC testing and FC sample difficulty rating score. Predictors of testing difficulty were derived using multivariable logistic regression analysis. Result(s): A total of 585 patients with IBD completed the survey; 306 males with a median age of 43 years (IQR: 31-54). There were 446 patients (76%) who had prior FC testing experience. Of these, 37% (n = 165) rated FC testing difficult; 'sample collection' (n = 106; 67%) being the most common reason reported. Multivariable regression analysis identified age <49 years (odds ratio (OR): 2.5, CI:1.6-4.0), disease duration <35 months (OR 1.4, CI:0.9-2.1) and testing location (UK centre: OR 1.9, CI:1.2-3.1) as predictors of a difficult FC rating score. Conclusion(s): A total of 37% of patients find FC testing challenging, in particular those aged <49 years, disease duration <35 months. Further studies understanding and addressing these practical issues may aid higher FC uptake in clinic.Copyright © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.

Introduction Faecal Calprotectin is an established biomarker in the investigation and management of Inflammatory Bowel Disease (IBD). Despite its success, there appears to be practical issues with FC testing in clinical practice, including sample collection, sample delivery and processing delays. There are no studies exploring patients' perception of faecal testing in IBD. We investigate patients' perception of FC testing in clinical practice across centres in UK, Europe and Australia. Methods A prospective patient survey was undertaken in an IBD unit in England from 12/2016 to 2/2017 and extended to 3 centres (Spain, Australia and Norway) from 07/2017 until 11/2017. Patients were asked to complete a 9-point based questionnaire in clinic which included diagnosis, patient demographics, previous FC testing, FC sample collection difficulty rating score (0-4) and preference to alternative methods of disease monitoring including blood tests and endoscopy. Predictors of FC testing difficulty were derived using multivari-able logistic regression analysis. Continuous variables were categorised using integer cut points guided by the ROC curves and their relationship to the FC rating score. Results A total of 585 patients with IBD completed the survey. There were 306 males (52%) with a median age of 43 years (IQR: 31-54). A total of 299, 279, and 7 patients had a diagnosis of CD, UC, IBDU respectively Median disease duration of the entire cohort was 36 months (IQR 22-66 months). There were 446 patients (76%) who had prior FC testing experience. Of these, 37% (n = 165) rated FC testing either moderately difficult (score 2), difficult (score 3) or very difficult (score 4). The reasons included 'dropping FC sample' (n = 14; 9%), 'sample collection' (n = 106; 67%) or 'both' (n=39; 25%). In these patients, 80%(n = 130) patients would rather have a blood test over faecal testing. Categorical multi-variable regression analysis was performed to identify factors that predict a high FC