MiR-146a rs2910164 G > C polymorphism modulates Notch-1/IL-6 signaling during infection: a possible risk factor for Crohn’s disease

Abstract Background MiR-146a, an effector mediator, targets Notch-1 and regulates the innate and adaptive immune systems response. Recently, we reported that Notch-1 signaling plays a key role in macrophage polarization and response during infection. We employed Mycobacterium avium paratuberculosis (MAP) infection in Crohn’s disease (CD) as a model to demonstrate the role of Notch-1/IL-6 signaling on MCL-1 based apoptosis and intracellular MAP infection and persistence. This study was designed to investigate the impact of polymorphisms in miR146a on the immune response and infection in our MAP-CD model. Methods We determined the incidence of miR-146a rs2910164 G > C in 42 blood samples from clinical CD patients and controls. We also measured the effect of rs2910164 on expression of Notch-1 and IL-6, and plasma IL-6 protein levels in our study group. Finally, we analyzed the blood samples for MAP DNA and studied any correlation with miR-146a polymorphism. Samples were analyzed for statistical significance using unpaired tow-tailed t-test, unpaired two-tailed z-score and odds ratio. P < 0.05 considered significant. Results MiR-146a rs2910164 GC was detected at a higher incidence in CD (52.6%) compared to healthy controls (21.7%) rs2910164 GC Heterozygous polymorphism upregulated Notch-1 and IL-6, by 0.9 and 1.7-fold, respectively. As expected, MAP infection was detected more in CD samples (63%) compared to healthy controls (9%). Surprisingly, MAP infection was detected at a higher rate in samples with rs2910164 GC (67%) compared to samples with normal genotype (33%). Conclusions The data clearly associates miR-146a rs2910164 GC with an overactive immune response and increases the risk to acquire infection. The study is even more relevant now in our efforts to understand susceptibility to SARS-CoV-2 infection and the development of COVID-19. This study suggests that genetic variations among COVID-19 patients may predict who is at a higher risk of acquiring infection, developing exacerbating symptoms, and possibly death. A high scale study with more clinical samples from different disease groups is planned.

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PWE-082 The Impact Of Nod2 Variants On Gut Microbiota In Crohn’s Disease And Healthy Controls

Gut ◽

10.1136/gutjnl-2014-307263.342 ◽

2014 ◽

Vol 63 (Suppl 1) ◽

pp. A159.2-A160 ◽

Cited By ~ 2

Author(s):

NA Kennedy ◽

AW Walker ◽

SH Berry ◽

CA Lamb ◽

S Lewis ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Gut Microbiota ◽

Healthy Controls ◽

The Impact

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Mo1816 The Impact of NOD2 Variants on Gut Microbiota in Crohn's Disease and Healthy Controls

Gastroenterology ◽

10.1016/s0016-5085(15)32446-x ◽

2015 ◽

Vol 148 (4) ◽

pp. S-718

Author(s):

Nicholas A. Kennedy ◽

Alan W. Walker ◽

Susan H. Berry ◽

Christopher A. Lamb ◽

Sophie Lewis ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Gut Microbiota ◽

Healthy Controls ◽

The Impact

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Differential Expression of SMAD Genes and S1PR1 on Circulating CD4+ T Cells in Multiple Sclerosis and Crohn’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21020676 ◽

2020 ◽

Vol 21 (2) ◽

pp. 676 ◽

Cited By ~ 3

Author(s):

Judith Abarca-Zabalía ◽

Ma Isabel García ◽

Alberto Lozano Ros ◽

Ignacio Marín-Jiménez ◽

Maria L. Martínez-Ginés ◽

...

Keyword(s):

Multiple Sclerosis ◽

Inflammatory Bowel Disease ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Autoimmune Diseases ◽

Differential Expression ◽

Validation Cohort ◽

Healthy Controls ◽

Blood Samples ◽

Inflammatory Bowel

The Th17 immune response plays a key role in autoimmune diseases such as multiple sclerosis (MS) and inflammatory bowel disease (IBD). Expression of Th17-related genes in inflamed tissues has been reported in autoimmune diseases. However, values are frequently obtained using invasive methods. We aimed to identify biomarkers of MS in an accessible sample, such as blood, by quantifying the relative expression of 91 Th17-related genes in CD4+ T lymphocytes from patients with MS during a relapse or during a remitting phase. We also compared our findings with those of healthy controls. After confirmation in a validation cohort, expression of SMAD7 and S1PR1 mRNAs was decreased in remitting disease (–2.3-fold and –1.3-fold, respectively) and relapsing disease (–2.2-fold and –1.3-fold, respectively). No differential expression was observed for other SMAD7-related genes, namely, SMAD2, SMAD3, and SMAD4. Under-regulation of SMAD7 and S1PR1 was also observed in another autoimmune disease, Crohn’s disease (CD) (−4.6-fold, -1.6-fold, respectively), suggesting the presence of common markers for autoimmune diseases. In addition, expression of TNF, SMAD2, SMAD3, and SMAD4 were also decreased in CD (–2.2-fold, –1.4-fold, –1.6-fold, and –1.6-fold, respectively). Our study suggests that expression of SMAD7 and S1PR1 mRNA in blood samples are markers for MS and CD, and TNF, SMAD2, SMAD3, and SMAD4 for CD. These genes could prove useful as markers of autoimmune diseases, thus obviating the need for invasive methods.

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Genome-wide transcriptional patterns of candidate genes linked to distinctive pathogenesis in Crohn’s disease

10.21203/rs.2.15540/v1 ◽

2019 ◽

Author(s):

Shengbo Chen ◽

Zhijun Li ◽

Chen Li ◽

Yi Liu ◽

Fachao Zhi ◽

...

Keyword(s):

Gene Expression ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Expression Profiles ◽

Clinical Samples ◽

Peroxisome Proliferator ◽

Healthy Controls ◽

Genome Wide ◽

Gene And Protein Expression ◽

Inflammatory Bowel

Abstract Background: Crohn’s disease (CD) is an inflammatory bowel (IBD) disease with variable and complex pathophysiology. The objective of the present study was to identify genome-wide gene expression profiles underlying the progression of CD. Methods: Surgery biopsies (n=48) were analyzed by Illumina cDNA-mediated annealing, selection, extension, and a ligation microarray process specifically designed for formalin-fixed, paraffin-embedded clinical samples. Tissue samples were collected from consecutive actively-involved and uninvolved sites from the same CD patient. The CD-involved and CD-uninvolved samples were compared with non-inflammatory bowel disease healthy controls. Results: CD patients’ uninvolved sites demonstrated an average gene expression between CD-involved patients and healthy controls suggesting the CD uninvolved site was unable to restore the full healthy control phenotype. In addition, peroxisome proliferator-activated receptors (PPAR) signaling-associated genes were involved in both CD involved and uninvolved sites, showing a stepwise decrease in the gene and protein expression of PPAR and downregulation of 3-hydroxy-3-methylglutaryl-CoA synthase 2, as confirmed by gene expression analysis and immunohistochemistry. Conclusions: The results of the present study provide evidence for clear differentiation of the two states, and in some cases repeated flares appeared chronically at the previous uninvolved locus.

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Outcomes of Passable and Non-passable Strictures in Clinical Trials of Crohn’s Disease: A Post-hoc Analysis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab045 ◽

2021 ◽

Author(s):

Neeraj Narula ◽

Emily C L Wong ◽

Parambir S Dulai ◽

John K Marshall ◽

Jean-Frederic Colombel ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Activity Index ◽

Disease Activity Index ◽

Symptom Improvement ◽

Logistic Regression Models ◽

Post Hoc Analysis ◽

Endoscopic Remission ◽

Post Hoc ◽

The Impact

Abstract Background and Aims There is paucity of evidence on the reversibility of Crohn’s disease [CD]-related strictures treated with therapies. We aimed to describe the clinical and endoscopic outcomes of CD patients with non-passable strictures. Methods This was a post-hoc analysis of three large CD clinical trial programmes examining outcomes with infliximab, ustekinumab, and azathioprine, which included data on 576 patients including 105 with non-passable strictures and 45 with passable strictures, as measured using the Simple Endoscopic Score for Crohn’s Disease [SES-CD]. The impact of non-passable strictures on achieving clinical remission [CR] and endoscopic remission [ER] was assessed using multivariate logistic regression models. CR was defined as a Crohn’s Disease Activity Index [CDAI] <150, clinical response as a CDAI reduction of ≥100 points, and ER as SES-CD score <3. Results After 1 year of treatment, patients with non-passable strictures demonstrated the ability to achieve passable or no strictures in 62.5% of cases, with 52.4% and 37.5% attaining CR and ER, respectively. However, patients with non-passable strictures at baseline were less likely to demonstrate symptom improvement compared with those with passable or no strictures, with reduced odds of 1-year CR (adjusted odds ratio [aOR] 0.17, 95% CI 0.03–0.99, p = 0.048). No significant differences were observed between patients with non-passable strictures at baseline and those with passable or no strictures in rates of ER [aOR 0.82, 95% CI 0.23–2.85, p = 0.751] at 1 year. Conclusions Patients with non-passable strictures can achieve symptomatic and endoscopic remission when receiving therapies used to treat CD, although they are less likely to obtain CR compared with patients without non-passable strictures. These findings support the importance of balancing the presence of non-passable strictures in trial arms.

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Anastomotic Ulcers After Ileocolic Resection for Crohn’s Disease Are Common and Predict Recurrence

Inflammatory Bowel Diseases ◽

10.1093/ibd/izz224 ◽

2019 ◽

Vol 26 (7) ◽

pp. 1050-1058 ◽

Cited By ~ 3

Author(s):

Robert P Hirten ◽

Ryan C Ungaro ◽

Daniel Castaneda ◽

Sarah Lopatin ◽

Bruce E Sands ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Multivariable Analysis ◽

Disease Recurrence ◽

Ileocolic Resection ◽

Anastomotic Ulcer ◽

Endoscopic Recurrence ◽

Academic Center ◽

Endoscopic Remission ◽

The Impact

Abstract Background Crohn’s disease recurrence after ileocolic resection is common and graded with the Rutgeerts score. There is controversy whether anastomotic ulcers represent disease recurrence and should be included in the grading system. The aim of this study was to determine the impact of anastomotic ulcers on Crohn’s disease recurrence in patients with prior ileocolic resections. Secondary aims included defining the prevalence of anastomotic ulcers, risk factors for development, and their natural history. Methods We conducted a retrospective cohort study of patients undergoing an ileocolic resection between 2008 and 2017 at a large academic center, with a postoperative colonoscopy assessing the neoterminal ileum and ileocolic anastomosis. The primary outcome was disease recurrence defined as endoscopic recurrence (>5 ulcers in the neoterminal ileum) or need for another ileocolic resection among patients with or without an anastomotic ulcer in endoscopic remission. Results One hundred eighty-two subjects with Crohn’s disease and an ileocolic resection were included. Anastomotic ulcers were present in 95 (52.2%) subjects. No factors were associated with anastomotic ulcer development. One hundred eleven patients were in endoscopic remission on the first postoperative colonoscopy. On multivariable analysis, anastomotic ulcers were associated with disease recurrence (adjusted hazard ratio [aHR] 3.64; 95% CI, 1.21–10.95; P = 0.02). Sixty-six subjects with anastomotic ulcers underwent a second colonoscopy, with 31 patients (79.5%) having persistent ulcers independent of medication escalation. Conclusion Anastomotic ulcers occur in over half of Crohn’s disease patients after ileocolic resection. No factors are associated with their development. They are associated with Crohn’s disease recurrence and are persistent.

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P237 Annual incidence and prevalence of ulcerative colitis and Crohn’s disease from 2010 to 2017 in four Nordic countries: Results from the TRINordic study

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.366 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S261-S262

Author(s):

M Lördal ◽

J Burisch ◽

E Langholz ◽

T Knudsen ◽

M Voutilainen ◽

...

Keyword(s):

Ulcerative Colitis ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Observational Study ◽

Nordic Countries ◽

Annual Incidence ◽

University Hospital ◽

Retrospective Observational Study ◽

Western World ◽

The Impact

Abstract Background Incidence and prevalence of inflammatory bowel diseases (IBD) have been increasing for the past decades in the western world, however with an emerging trend of incidence stabilisation in recent years. There is an indication of higher IBD incidence and prevalence in northern Europe, especially in the Nordic region, compared with southern Europe. Methods This retrospective observational study collected data from the National Patient Registries and National Prescription Registries (Sweden [SWE], Norway [NOR], Denmark [DEN]) and one university hospital database (Turku, Finland [FIN]) during 2010–2017 to investigate the annual incidence and prevalence of ulcerative colitis (UC) and Crohn’s disease (CD). Patients with ≥2 ICD-10 diagnosis codes for UC (K51) or CD (K50) from 2010 or later and no K51 or K50 codes prior to 2010 were included; patients were classified according to their last code. The look-back period for SWE was until 2000, for NOR until 2008, for DEN until 1995, and for FIN until 2004. Incidence proportions highlight results through 2016, as 2017 patients had less than 1-year follow-up. Results In total, 69,876 patients were included (SWE n = 27,902, NOR n = 20,761, FIN n = 2,118, DEN n = 19,095), of which 44 367 patients were diagnosed with UC and 25,509 with CD. In 2016, the annual incidence of UC was 28 patients per 100,000 persons in NOR, 32 patients per 100,000 persons in DEN, 25 patients per 100,000 persons in SWE, and 44 patients per 100,000 in FIN. The corresponding results for the annual incidence of CD per 100,000 persons were 22 in NOR, 16 in DEN, 16 in SWE, and 21 in FIN. The prevalence per 100,000 persons of both UC and CD was the highest in DEN, followed by SWE and NOR, and lowest in FIN. Prevalence estimates increased in all four Nordic countries during 2010–2017: for UC, from 409 to 488 patients in SWE, from 256 to 428 in NOR, from 129 to 375 in FIN, and from 577 to 798 in DEN. For CD, it increased from 261 to 313 patients in SWE, from 164 to 258 in NOR, from 54 to 164 in FIN, and from 280 to 400 in DEN. Conclusion This retrospective observational study showed that during 2016, the annual incidence of UC ranged from 25–44 patients per 100,000 persons across the evaluated Nordic countries, whereas the annual incidence of CD was 16–22 patients per 100,000 persons. Prevalence of both UC and CD increased during 2010–2017 in all four countries. Estimates of UC and CD incidence and prevalence in this analysis are greater than reported in the published literature. Additional analyses are underway to further explore the impact of methodological decisions on the estimates of UC and CD annual incidence and prevalence.

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P007 CROHN’S DISEASE: PREDICTORS OF HOSPITAL DISPOSITION AND COSTS USING DEMOGRAPHIC, CLINICAL, AND TREATMENT DATA

Inflammatory Bowel Diseases ◽

10.1093/ibd/zaa010.122 ◽

2020 ◽

Vol 26 (Supplement_1) ◽

pp. S48-S48

Author(s):

Hartman Brunt ◽

Mason Adams ◽

Michael Barker ◽

Diana Hamer ◽

J C Chapman

Keyword(s):

Logistic Regression ◽

Crohn’S Disease ◽

Abdominal Pain ◽

Crohn's Disease ◽

Hospital Admission ◽

Categorical Variables ◽

History Of ◽

The Difference ◽

The Impact ◽

Total Charges

Abstract Purpose Crohn’s disease (CD) is an inflammatory bowel disease (IBD) caused by an abnormal immune response to intestinal microbes in a genetically susceptible host. The objective of this cohort analysis is to compare demographic characteristics, cost difference, and treatment modalities between patients who were discharged from the Emergency Department (ED) and those who were admitted to the hospital. Methods This study is a retrospective chart review of adult patients diagnosed with CD who were discharged from the ED and those who were admitted to the hospital between January 1, 2014 and January 1, 2017. We compared demographic and clinical characteristics as well as total charges incurred by these patients. A chi square test of independence and a Mann Whitney U-Test were used to compare categorical variables. Linear and logistic regression analyses were utilized to identify predictors of hospitalization and total charges. Results Of a total 195 patients, 97 were discharged from the ED and 98 were admitted to the hospital (Table 1). Patients who presented with fever, nausea/vomiting, or abdominal pain or who had a history of a fistula or stenosis were more likely to be hospitalized, as were patients who presented on steroids, 5-ASA compounds, or narcotics (Table 2). A logistic regression adjusted for these factors showed patients presenting with abdominal pain (OR=0.239, 95% CI 0.07 – 0.77) are less likely, while patients presenting with fever (OR=7.0, 95% CI 1.9 – 24.5) and history of stenosis (OR=17.8, 95% CI 5.7 – 55.9) are more likely to have a hospital admission. An increase in age and white blood cell count was associated with an increase in likelihood of admission (OR=1.04, 95% CI 1.01 – 1.07 and OR=1.2, 95% CI 1.1 – 1.4), while an increase in HGB was associated with a decrease in likelihood of admission (OR=0.682, 95% CI 0.55 – 0.83). Patients on 5-ASA compounds had the strongest association with hospital admission (OR=4.5, 95% CI 1.03 – 20.4). A linear regression analysis predicting total charges of hospitalization identified an increase of $37,500 (95% CI 6,600 – 68,489) for obese patients and of $29,000 (95% CI 20 – 57,000) for patients on narcotics prior to hospitalization. Notably, blacks were on average 6 years younger than whites (μ=36.2, st.d.=13.2 v μ=42.7, st.d.=18.2, p=0.031, respectively). No other differences in presentation or outcomes of CD were identified between these races. Conclusion This study describes the difference between CD patients who were admitted to the hospital compared to those who were discharged from the ED. The impact that 5-ASA compound, steroid, and narcotic use prior to presentation has on hospital admission and charges highlights the need for consistent outpatient care to manage the symptoms and disease progression in patients with CD in Baton Rouge. The difference in age at presentation between blacks and whites should also be considered in future research.

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