| 1. |
|
|
| 2. |
- Kalla, Rahul, et al.
(author)
-
EPIGENETIC ALTERATIONS IN IBD : DEFINING GEOGRAPHICAL, GENETIC, AND IMMUNEIN-FLAMMATORY INFLUENCES ON THE CIRCULATING METHYLOME
- 2021
-
In: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 70:Suppl. 4, s. A5-A5
-
Journal article (other academic/artistic)abstract
- Introduction: DNA methylation may provide critical insights into gene-environment interactions in inflammatory bowel disease (IBD).Methods: Using the multi-centre IBD Character inception cohort (295 controls, 154 CD, 161 UC, 28 IBD-U), epigenome-wide methylation was profiled using Illumina HumanMethylation450 platform. Differentially methylated position analysis was performed using age, sex and cell proportions as covariates. Integration of paired genomic and transcriptomic layers was done with Multi-Omics Factor Analysis v2 (MOFA). Unsupervised principal component analyses were performed to examine correlates of treatment escalation and clinical predictors of disease severity.Results: We report 137 differentially methylated positions (DMP) in whole blood in IBD, including VMP1/MIR21 (p=9.11×10-15) and RPS6KA2 (6.43×10-13); with consistency seen across Scandinavia and UK. Cell of origin analysis preferentially implicated the monocyte lineage. Dysregulated loci demonstrate strong genetic influence, notably VMP1 (p=1.53×10-15). Age acceleration is seen in IBD (coefficient 0.94, p<2.2x10-16). Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r -0.32, p 3.64×10-7 vs. non-IBD r -0.14, p=0.77). Multi-omic integration of methylome, genome and transcriptome also identified specific pathways that associate with immune activation, response and regulation at disease inception. At follow up, a signature of 3 DMPs (TAP1, TESPA1, RPTOR) associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 (CI:2.14-12.56, logrank p=9.70×10-4).Conclusion: This study highlights the stability of the IBD-specific circulating methylome across regions with shared ancestry. Through integrative multi-omic analyses we identify key pro-inflammatory genes that are upregulated in IBD at inception. Furthermore, differential methylation within certain genes such as TAP1 associate with disease course over time.
|
|
| 3. |
|
|
| 4. |
- Nowak, Jan Krzysztof, et al.
(author)
-
Age, Inflammation, and Disease Location Are Critical Determinants of Intestinal Expression of SARS-CoV-2 Receptor ACE2 and TMPRSS2 in Inflammatory Bowel Disease
- 2020
-
In: Gastroenterology. - : American Gastroenterology Association Institute. - 0016-5085 .- 1528-0012. ; 159:3, s. 1151-1154
-
Journal article (other academic/artistic)abstract
- Although the respiratory tract is implicated as the primary portal of entry of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), gastrointestinal involvement is well-reported, associated with nausea, vomiting, diarrhea, and highly persistent viral particle shedding in feces.(1,2)There is critical need to establish factors determining susceptibility to Coronavirus Disease 2019 (COVID-19) in patients with inflammatory bowel disease (IBD). Age, comorbidity, disease activity, and exposure to immunomodulatory and biological therapies provide the basis for new guidelines for risk stratification and shielding.(3)We hypothesize that expression levels of the SARS-CoV-2 spike protein receptor, angiotensin-converting enzyme 2 (ACE2),(4) may also determine susceptibility to SARS-CoV-2-inflicted damage. Transmembrane serine protease 2 (TMPRSS2) primes the viral spike protein,(5) allowing for the potent binding of ACE2. Both are known to be highly expressed in healthy ileal epithelium, with lower levels in epithelial cells in the colon. We report dysregulated mucosal ACE2 and TMPRSS2 expression in the colon and ileum in IBD, and identify the critical determinants of altered expression.
|
|
| 5. |
|
|
