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- Bergemalm, Daniel, 1977-, et al.
(författare)
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Systemic Inflammation in Preclinical Ulcerative Colitis
- 2021
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Ingår i: Gastroenterology. - : AGA Institute. - 0016-5085 .- 1528-0012. ; 161:5, s. 1526-1539.e9
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins.Methods: We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored.Results: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1β, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis.Conclusions: A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors.
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| 2. |
- Kalla, Rahul, et al.
(författare)
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EPIGENETIC ALTERATIONS IN IBD : DEFINING GEOGRAPHICAL, GENETIC, AND IMMUNEIN-FLAMMATORY INFLUENCES ON THE CIRCULATING METHYLOME
- 2021
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Ingår i: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 70:Suppl. 4, s. A5-A5
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)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.
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| 4. |
- Schreiber, Stefan, et al.
(författare)
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Defining Comprehensive Disease Control for use as a Treatment Target for Ulcerative Colitis in Clinical Practice : International Delphi Consensus Recommendations
- 2024
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Ingår i: Journal of Crohn's & Colitis. - : Oxford University Press. - 1873-9946 .- 1876-4479. ; 18:1, s. 91-105
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Treatment of ulcerative colitis (UC) requires a patient-centric, definition of comprehensive disease control that considers improvements in aspects not typically captured by classical landmark trial endpoints. In an international initiative we reviewed aspects of UC that affect patients and/or indicate mucosal inflammation, to achieve consensus on which aspects to combine in a definition of comprehensive disease control, using a modified Delphi process.METHODS: The Delphi panel comprised 12 gastroenterologists and one patient advocate. Two gastroenterologists were elected as chairs and did not vote. To inform statements, we asked 18 patients and the panel members about their experiences of remission and reviewed published literature. Panel members voted on statements anonymously in three rounds, with a live discussion before round 3. Consensus was met if ≥ 67% of the panel agreed. Statements without consensus in rounds 1 and 2 were revised or discarded after round 3.RESULTS: The panel agreed to measure individual patient benefit using a definition of comprehensive disease control that combines aspects currently measured in trials (rectal bleeding, stool frequency, disease-related quality of life, endoscopy, histological inflammatory activity, inflammatory biomarkers, and corticosteroid use), with additional patient-reported symptoms (bowel urgency, abdominal pain, extraintestinal manifestations, fatigue, and sleep disturbance). The panel agreed on scoring systems and thresholds for many aspects.CONCLUSIONS: Using a robust methodology, we defined comprehensive disease control in UC. Next, we will combine the measurement and scoring of these aspects into a multi-component tool and adopt comprehensive disease control as a treatment target in clinical practice and trials.
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| 5. |
- Zheng, Tenghao, et al.
(författare)
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Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes
- 2024
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Ingår i: Journal of Crohn's and Colitis. - : OXFORD UNIV PRESS. - 1873-9946 .- 1876-4479. ; 18:3, s. 349-359
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies. Methods: We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied. Results: We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 × 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [rg = 0.77; p = 0.048] and oesophageal diseases [rg = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 × 10-8, OR = 1.31]. No significant association was detected for LC. Conclusion: Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.
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