bluuebunny/crossref_metadata_2025_split huggingface dataset:
OP11 Expanded genome-wide association study of Inflammatory Bowel Disease identifies 174 novel loci and directly implicates new genes in disease susceptibility
Authors: Fachal L ,   O.B.O. the International IBD Genetics Consortium
Published: January 2022

Abstract

Background
Genome-wide association studies (GWASs) have identified 243 loci associated with inflammatory bowel disease (IBD). However, the mapping of additional disease loci and causal variants is still limited by sample size. Larger GWAS can provide further insights into causal biology.

Methods
We performed a GWAS meta-analysis of 33 cohorts, totalling 54,439 IBD patients (N=30,574 with Crohn’s disease (CD), 21,193 with Ulcerative Colitis (UC)) and 37,054 European controls. Genotype imputation was undertaken using the TOPMed diverse population panel and association tests were performed using REGENIE. These results were meta-analysed with summary statistics from 4 additional studies, a Danish cohort, the UK Biobank, deCODE, and FinnGen, totalling 73,030 IBD patients and 1 million controls, Fig1.

Results
We identified 174 novel genome-wide significant signals (32 associated with CD, 36 with UC, 106 with IBD, Fig2).

Of these, 79 are located &gt;1Mb from any known GWAS loci. We also identified two new population specific genetic associations, Fig3.

Six new loci contain genes implicated in monogenic syndromes that include colitis: CARMIL2, DOCK8, G6PC3, HPS4, NCF1, PIK3CD. Several new loci alter the expression of nearby genes, suggesting that aberrant expression of these genes underpins the association. For instance, a new variant associated with decreased risk of IBD increases the expression of VSIR in colon Fig4.

VSIR knockout mice have increased expression of IL23 and develop chronic inflammation in multiple tissues. Fine-mapping analyses identified likely causal missense variants at three new loci. DOK2 (ORCD=1.3, 27p=2x10-12) encodes a protein expressed in macrophages and T cells. Loss of Dok2 in mice causes severe DSS-induced colitis with reduced IL17A and IL22 expression. The same variant has been recently associated with CD in a sequencing study. SHARPIN (ORCD=1.2, p=1x10-16) is part of the linear ubiquitin chain assembly complex that modulates activation of the NF-κB pathway. Loss-of-function (LOF) mutations in other proteins in the complex are associated with immunodeficiency and systemic autoinflammation. CARMIL2 (ORUC=1.2, p=1x10-10) is required for NF-κB signalling in both B and T cells. LOF mutations are associated with primary immunodeficiencies and paediatric forms of IBD.

Conclusion
The greatly expanded sample size in our latest GWAS meta-analysis has enabled the identification of low frequency variants with larger effects on IBD susceptibility than the more common variants typically identified by previous GWAS. The biological overlap between Mendelian and complex forms of IBD is demonstrated by the discovery of common non-coding variants associated with complex forms of IBD that dysregulate the function of a Mendelian IBD gene.
OP12 Segmental vs Total Colectomy for Crohn’s Disease of the colon in the biologic era. Results from the SCOTCH international, multicentric study
Authors: Pellino MD- PhD- FRCS- FEBS Coloproctology- FA G , Rottoli M , Mineccia M , Frontali A , Celentano V , Colombo F , Ardizzone S , Martí M , Espín-Basany E , Ferrero A , Panis Y , Poggioli G , Sampietro G M 
Published: January 2022

Abstract

Background
Previous studies suggested a role for segmental colectomy (SC) and total colectomy (TC) for colonic Crohn’s disease (cCD). TC might reduce recurrence rates, at the cost of impaired quality of life and higher stoma rates. We compared the long-term outcomes of SC and TC.

Methods
This is an international, multicentric study on data from the prospective databases of six centres. All consecutive patients operated on between 2000 and 2019 for cCD with SC or TC were included. Exclusion criteria were colorectal cancer, previous bowel resections, and lack of follow-up data. Disease extension was based on involvement of 1 to 5 colonic segments. Resection of 1–3 segments was classified as SC, resection of 4–5 segments as TC. Primary aim was surgical recurrence after SC vs TC. Secondary aims were perioperative complications, stoma formation rate, and predictors of recurrence.

Results
Data of 687 (56.2% women) patients were analysed. Mean age at diagnosis and at surgery were 30±15.8 and 40.4±15.4 years. Disease duration was 10.4 ± 8.6 years. 16.6% of patients were A1, whereas most (62.2%) were diagnosed between 17 and 40 years. Isolated cCD (L2) was present in 61.1%, ileocolic CD (L3) in 38.9%, and concomitant jejuno-ileal CD (L4) in 3.2%. Most had stricturing (B2) cCD (41.9%). Active perianal disease was found in 28.9% patients. SC was performed in 285 patients, TC in 402. The latter more frequently had isolated cCD, inflammatory (B1) disease, current (37.8 vs 16.5%, p&lt;0.001) or previous (56 vs 32.6%, p&lt;0.001) perianal CD, and longer disease duration (11.3 ± 8.9 vs 9.2 ± 7.9, p&lt;0.001). Postoperative complications and mortality were similar, but TC patients more frequently required 90-day readmission (6% vs 2.1%, p=0.02). Temporary (31.6 vs 21.4%, p&lt;0.001) and definitive (39.3vs8%, p&lt;0.001) stomas were more likely after TC. The 15-year cumulative surgical recurrence was 36%, more likely in the TC group (44 vs 27%, Log-Rank p=0.006), and it was not affected by the number of colonic segments involved (23 vs 28%, 1–3 vs 4–5 segments p=0.2) (Fig 1). In patients with 1–3 segments involved, postoperative treatment with biologics, compared to any other regimen, reduced the risk of recurrence (25 vs 51%, p&lt;0.001), while early age at diagnosis (p=0.02) and perianal CD (p=0.01) increased the risk. Omission of biological therapy (HR 5.4, 95%CI 5.1–5.8 p&lt;0.001), and paediatric diagnosis (HR 2.1, 95%CI 2.3–3.1 p&lt;0.001) were the strongest predictors of recurrence in this subgroup.

Conclusion
In this study, SC was safe, required less frequently stoma and repeated surgery, compared with TC. These findings question previous data on the topic and might be supported by the efficacy of postoperative biologic therapy on cCD.
DOP22 Clinical, biochemical and endoscopic disease activity of Inflammatory Bowel Diseases are not associated with the severity or long-term outcomes of COVID-19 – A Danish prospective population-based cohort study
Authors: Attauabi M , Dahlerup J F , Poulsen A , Hansen M R , Vester-Andersen M K , Eraslan S , Prahm A P , Pedersen N , Larsen L , Jess T , Neumann A , Haderslev K V , Molazahi A , Lødrup A B , Glerup H , Oppfeldt A M , Jensen M D , Theede K , Kiszka-Kanowitz M , Seidelin J B , Burisch J 
Published: January 2022

Abstract

Background
Whether the disease activity of ulcerative colitis (UC) and Crohn’s disease (CD) is correlated with the severity of coronavirus disease 2019 (COVID-19) remains poorly investigated with only few selected cohort studies having addressed this in the past.

Methods
We conducted a population-based study investigating the outcomes of COVID-19 among patients with UC and CD in Denmark. The Danish COVID-19 IBD Database is an extensive population-based database which prospectively monitors the disease course of laboratory-confirmed COVID-19 among patients with UC and CD. Severe COVID-19 was defined as COVID-19 necessitating intensive care unit admission, ventilator use, or death, while adverse COVID-19 was defined as requirement of COVID-19 related hospitalization. Clinical disease activity was measured by simple clinical colitis index and Harvey-Bradshaw Index in UC and CD, respectively. The biochemical activity was defined as C-reactive protein higher than 5 mg/L or fecal calprotectin higher than 250 μg/g. The endoscopic activity was defined as Mayo Endoscopic Subscore of at least 2 in UC, or Simple Endoscopic Score Crohn’s Disease of at least 3 for CD. Sequelae following COVID-19 were defined as symptoms that (i) developed during or after an infection consistent with COVID-19, (ii) and were present for more than 12 weeks, (iii) and were not attributable to alternative diagnoses.

Results
During the inclusion period between January 28th, 2020, to April 1st, 2021, the study included 319 patients with UC and 197 patients with CD who developed laboratory confirmed COVID-19. Of these, data on clinical, biochemical, and endoscopic activity were available among 265/319 (83.1%), 319/319 (100.0%), and 66/319 (20.7%) of patients with UC, respectively, and 140/197 (71.1%), 131/197 (66.5%), and 42/197 (21.3%) of patients with CD. Figures 1–2 outlines the outcomes of COVID-19 according to the degree of clinical, biochemical and endoscopic disease activity. In both UC and CD, clinical, biochemical, and endoscopic activity were not associated with adverse or severe COVID-19, nor long-term outcomes, in unadjusted nor adjusted analysis (Table 1).

Conclusion
In this population-based study, we found no association between disease activity of UC or CD and severity of COVID-19. These findings have implications for the risk stratification of patients with IBD acquiring COVID-19.
DOP65 Development and validation of the TUMMY-UC, a patient-reported outcome in pediatric Ulcerative Colitis: A multicenter prospective study
Authors: Turner D , Marcovitch L , Focht G , Carmon N , Tersigni C , Ledder O , Lev Tzion R , Frost K , Church P C , Baldassano R , Otley A , Kappelman M , Griffiths A 
Published: January 2022

Abstract

Background
In developing a patient-reported outcome (PRO) for pediatric ulcerative colitis (UC) with guidance from FDA and EMA, 8 items were previously selected based on 79 concept elicitation interviews. An observer RO (ObsRO) was determined to be required for children younger than 8 years. Here, we aimed to finalize the included items and to validate the TUMMY-UC for its psychometric properties.

Methods
The structure and exact wording of the PRO and the ObsRO versions were determined by cognitive debriefing interviews with children and their caregivers. Weights were assigned to each item based on ranking of importance. Then, in a prospective multicenter study, children with UC between 2–18 years who either underwent colonoscopy or provided stool for calprotectin completed the TUMMY-UC during 4 consecutive days, as well as 7 and 21 days thereafter for evaluating reliability and responsiveness. Construct and discriminative validity were assessed by different measures of disease severity and quality of life (QOL).

Results
In an iterative process of 129 cognitive interviews, the exact wording of the TUMMY-UC was determined. The PRO and ObsRO were formatted with identical structure to ensure conceptual equivalence for incorporating into one score. 71 children were included in the validation study (39 with colonoscopy and 32 with calprotectin; age 12.3±4.1 years, 26 (36%) in remission, 20 (29%) with moderate-severe disease). There was excellent reliability in the repeated day assessments (ICC 0.93 (0.88–0.96); p&lt;0.001) and after 1 week in those judged as unchanged (0.90 (0.81–0.95); p&lt;0.001). The TUMMY-UC total score had moderate to strong correlations with all constructs of disease severity: r=0.64 with UC Endoscopic Index of Severity (UCEIS, Figure 1), r=0.66 with IMPACT QOL questionnaire, r=0.43 with calprotectin, r=0.82 with the PUCAI, r=0.76 with patient/caregiver global assessment, r=0.5 with CRP, and r=-0.36 with albumin (all p&lt;0.015). There was a slight superiority to combining TUMMY-UC scores of two consecutive days. The index had excellent discrimination of disease activity categories (figure 2) with a score&lt;9 defining remission (Sen=93%, Spec=84%, AUROC=0.95 (95%CI 0.89–0.99). Showing high responsiveness, the DTUMMY-UC differentiated well between children who improved, worsened or remained unchanged after 3 weeks (Figure 3). The best cutoff of the TUMMY-UC to define response was a change of ≥10 points (AUROC 0.93 (95%CI 0.86–0.99)).

Conclusion
The TUMMY-UC, constructed from a PRO and ObsRO versions for children 8–18 and 2–7 years, respectively, is a reliable, valid and responsive index which can be now used in clinical practice and as an outcome measure in clinical trials.
P029 Expression of miR-21 in mucosal biopsies give clues to anti-TNF treatment non-response in IBD children and adults
Authors: Pallikkunnath James J , Schnack Nielsen B , Langholz E , Mikkel M , Estrid H , Buhl Riis L 
Published: January 2022

Abstract

Background
The use of anti-tumor necrosis factor (TNF) treatment has improved the treatment of IBD patients. However, approximately 30% of patients fail to respond to TNF inhibitors, and up to 50% of the patients who initially benefited from treatment with TNF inhibitors lose the response over time. Thus, identifying predictors of non-response and deciding on a treatment strategy according to biomarker profiles could enhance overall IBD disease management. MicroRNA-21 (miR-21) has been found to confer drug resistance to e.g. trastuzumab, 5-fluorouracil, and cisplatin. In this study, we hypothesized that miR-21 may play a role in anti-TNF drug resistance and therefore, miR-21 levels may be a predictive biomarker of anti TNF response in IBD.

Methods
Archived formalin-fixed, paraffin-embedded (FFPE) mucosal biopsies of IBD patients (30 adults and 27 children) were used in this study. All biopsies were collected at the time of initiation of biologics. Patients were stratified into three groups according to treatment response: Responders, Primary non-responders (PNR), and Secondary non-responders (SNR). Responders were treated with anti-TNF for a minimum of 3 years and did not experience loss of response thereafter. PNRs lost response during the first year of treatment. SNRs were treated for a minimum of 3 years with subsequent loss of response. MiR-21 expressions were quantified using Quantitative Real-Time PCR (miRCURY LNA RT Kit, Qiagen). Expression of miR-27a was used as the endogenous reference microRNA based on previous studies.

Results
In adults, responders had less miR-21 expression compared to PNRs and SNRs (relative median of miR-21 expression in folds [IQR]: 3.45[3.36 - 4.2], 5.05 [3.61 - 6.88], and 7.58 [6.21 - 8.2] in responders, PNRs, and SNRs respectively, p=0.04 and p=&lt;0.01). In children, however, responders had an increased miR-21 expression compared to PNRs and SNRs (relative median of miR-21 expression in folds [IQR]: 19.94[15.88–24.59], 9.79[7.69– 14.44], and 10.58[5.66–12.91] in responders, PNRs, and SNRs respectively, p=0.03 and p=0.01). Expression of MiR-21 was found to be higher in children than adults (relative median of miR-21 expression in folds [IQR]: 4.65[3.45–7.21], and 13.6[8.37–19.05], respectively, p=&lt;0.01).

Conclusion
Higher miR-21 expression indicates a higher response rate in children, whereas higher miR-21 expression could predict resistance to anti-TNF treatment in adults. MiR-21 expression could potentially be used as a predictive biomarker for anti-TNF treatment response in IBD patients with varying measures for children and adults.
P034 DISRUPTive liquid biopsies in Inflammatory Bowel Disease (DISRUPT-IBD): Release of exosomal and molecular tissue signals by transabdominal ultrasound?
Authors: Tran F , Scharmacher A , Mishra N , Barann N , Sievers L K , Juzenas S , Bernardes J P , Lessing M , Lassen A , Rosenstiel P , Schreiber S 
Published: January 2022

Abstract

Background
A major drawback in diagnosis and monitoring of IBD are insufficient biomarkers that do not correlate well with tissue disease activity. Inflammation and cellular stress lead to an increased release of exosomes (Lipinski et al, 2019, EMBO J) carrying inflammatory signal proteins as cargo (Wozniak et al, 2020, J Cell Biol). Interestingly, colorectal cancer cells strongly release tumor markers after stimulation by sonography waves, probably through the disruptive energy of standard ultrasound (D’Souza et al, 2009, PNAS). We thus hypothesize that application of ultrasound waves on inflamed intestinal tissue in active IBD induces the release of tissue-specific exosomes that can be detected in the peripheral blood and used as novel biomarkers.

Methods
26 patients with different degrees of disease activity and various ongoing therapies with IBD were included in a pilot trial. Serum was taken before and 30 minutes after diagnostic transabdominal ultrasound. Serum exosomes were precipitated (using ExoQuick) and exosomal (exo-)miRNA were isolated for miRNA sequencing using SeraMir protocol. Exosomal proteins were isolated for quantification of inflammatory markers (as exosomal cargo).

Results
We found a correlation between exo-miRNA concentration and disease severity, determined by clinical assessment scores and sonographic findings. Exo-miRNA sequencing revealed a select few miRNAs to be induced by sonography. However, the overall composition of annotated miRNA transcripts did not separate samples according to sampling timepoints. Among these “inducible” exo-miRNA, we found hsa-miR-942, which is involved in cell cycle and Wnt signaling in intestinal epithelial cells, to be significantly induced in higher grade intestinal inflammation. The exosomal protein concentrations did not correlate with disease severity at baseline, but were increased after sonography in severe intestinal inflammation. We did not find markers of the inflammasome apparatus as inducible exosomal cargos.

Conclusion
Sonography-induced exosomal markers, e.g., exo-miRNAs, could become novel biomarkers for intestinal inflammation in IBD. Further exploration of the functional role of inducible biomarkers and continued investigation of exosomal miRNA and protein profiling will be performed.
P050 A comparison of the Gut Microbiota in Pregnant Women with and without Inflammatory Bowel Disease and Their Offspring in Hong Kong and United States
Authors: Hu J , Agrawal M , Tarassishin L , Rendon A , Picker M , Kalash O , Eisele C , Ching J Y , Wong A , Zhan H , Ng S C , Colombel J F , Peter I 
Published: January 2022

Abstract

Background
Data on the impact of geographic location on the gut microbiota of pregnant women with and without inflammatory bowel disease (IBD) and their infants are lacking.

Methods
420 pregnant women with or without IBD and 331 infants were prospectively enrolled in the MECONIUM (Exploring MEChanisms Of disease traNsmission In Utero through the Microbiome) study in Hong Kong (HK) and United States (US). Of these individuals, the fecal microbiota compositions from 105 mothers (47 from HK and 58 from US) at third trimester and 54 babies (26 from HK and 28 from US) at 1 month were surveyed using 16s rRNA sequencing.

Results
The birthweight of infants in HK was significantly lower compared to that of infants in the US (p-value&lt;0.001), while other baseline characteristics were comparable (Table 1). We observed differential gut microbiome beta-diversity between pregnant women without IBD (PERMANOVA test, p-value&lt;0.05) and their infants (p&lt;0.05) from HK and the US (Figure 1A). At the genus level, compared to pregnant women without IBD in the US, those in HK had a higher abundance of 15 taxa including Bifidobacterium, Faecalibacterium and Bacteroides and lower abundance of 6 taxa including Blautia and Turicibacter (Figure 1B). Compared to infants born to women without IBD in the US, those in HK had higher abundance of 3 taxa including Klebstella and Escherichia/Shigella and lower abundance of Enterococcus (Figure 1B). When comparing the gut microbiome alpha-diversity of women with and without IBD (Figure 1C), and that of their infants, both were lower in HK, (p-values= 0.077, 0.13, respectively) and in the US (p-values=0.0024, 0.019, respectively).

Conclusion
Our results suggest the impact of geographic location on the gut microbiome diversity and composition irrespective of IBD status. Maternal IBD is associated with reduced microbiome diversity in infants in both the US and HK.
P058 IL-36 signaling in Crohn’s disease – characterization of a patient with an IL36RA mutation
Authors: Hecker J , Letizia M , Loescher B S , Franke A , Weidinger C , Siegmund B 
Published: January 2022

Abstract

Background
The interleukin 36 (IL-36) family consists of three agonists (IL-36α, IL-36β, IL-36γ), which activate the NF-κB pathway and lead to the production of pro-inflammatory cytokines and the natural antagonist (IL-36RA), which inhibits IL-36 signaling.
While it is known that IL-36 signaling is important in the skin, it has been only recently reported that IL-36 might play an important role in maintaining gut homeostasis and in the development of fibrosis (Scheibe et al., 2019). However, it is not clear how IL-36 signaling contributes to the development of intestinal inflammation and which cell types are involved in this process.
To shed more light on the role of IL-36 in intestinal inflammation, we took the opportunity to perform an in-depth characterization of a Crohn’s disease patient with a mutation in IL36RA and identify cell subsets responding to IL-36 stimulation.

Methods
By whole exome-sequencing of EDTA blood we identified in a Crohn’s disease patient a heterozygous mutation in IL36RA (p.Ser113Leu), which we confirmed by Sanger sequencing. By ELISA, we quantified IL-36RA serum levels in comparison to other Crohn’s disease (CD) patients and healthy donors (HD). Finally, we stimulated peripheral blood mononuclear cells (PBMCs) of the IL-36RA patient, CD patients, and HDs with ionomycin/PMA, LPS or IL-36α and performed deep immune profiling by mass cytometry with 35 markers.

Results
Our IL36RA mutation carrying patient presented with a severe course of Crohn’s disease and consecutive of fibrosis, which was resistant to all commonly used treatment options. As an individual treatment, autologous stem cell transplantation was performed, but did not lead to long-term improvement in symptoms.
By ELISA, we found strongly elevated IL-36RA levels in the serum of our patient compared to CDs and HDs. Mass cytometry analysis revealed that the IL36RA mutation does not lead to major shifts in the immune cell composition of the blood, as the frequencies of B, T, NK, and myeloid cells in PBMCs of our patient were comparable to those in HDs and CDs. Furthermore, our data revealed that IL-36α stimulation mainly induced TNFα and IL-6 expression in myeloid cells as well as IFNγ expression in NK cells but did not affect T and B cells.

Conclusion
Our data is the first description of a Crohn’s disease patient with an IL36RA mutation and indicate that defects in IL-36 signaling should be considered as a possible cause for therapy-refractory and fibrotic Crohn’s disease. Furthermore, we identified NK cells and myeloid cells as main responders to IL-36α stimulation. As next step, we plan to use recombinant produced, mutant IL-36RA in in-vitro assays with immune cells and fibroblasts to study the effect of the mutation on the IL-36RA function in more depth.