Transcriptomic heterogeneity of Coeliac Disease biopsies from the duodenum
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE164883 | GEO | 2021/03/24
REPOSITORIES: GEO
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Project description:Crohn's disease (CD) is a complex and highly heterogeneous chronic inflammatory disorder, primarily affecting the gastrointestinal tract. Genetic and functional studies have highlighted a key role for innate immunity in its pathogenesis. Profound systemic defects in innate immunity and acute inflammation are understood to result in markedly delayed clearance of bacteria from the tissues, leading to local chronic granulomatous inflammation and compensatory adaptive immunological changes. Macrophages, key orchestrators of acute inflammation, are likely to play an important role in the initial impaired innate immune response. Monocyte-derived macrophages from CD patients stimulated with E. coli were shown to release attenuated levels of TNF and IFNM-NM-3 with normal secretion of IL8, IL10 and IL6. In controls, the secretion of these cytokines was strongly positively correlated, which was not seen with CD macrophages. The transcriptomes of CD and control macrophages were examined in an attempt to understand the molecular basis of this defect. There were no differentially expressed genes identified between the two groups, consistent with genetic heterogeneity; however, a number of molecules were found to be under-expressed in subgroups of CD patients. The most common of these was optineurin (OPTN) which was under-expressed in approximately 10% of the CD patients. Reduced OPTN expression coincided with lower intracellular protein levels and diminished cytokine secretion after bacterial stimulation both in the patients and with siRNA knockdown in THP-1 cells. Identifying and studying subgroups of patients with shared defective gene expression could aid our understanding of the mechanisms underlying highly heterogeneous diseases such as CD. Total RNA obtained from monocyte derived macrophages from Crohn's disease patients (n=58) or healthy volenteers (n=42) were cultured for six days before being stimulated with heat killed E. coli for four hours or left unstimulated.
2014-08-06 | E-GEOD-60083 | biostudies-arrayexpress
Project description:Crohn's disease (CD) is a complex and highly heterogeneous chronic inflammatory disorder, primarily affecting the gastrointestinal tract. Genetic and functional studies have highlighted a key role for innate immunity in its pathogenesis. Profound systemic defects in innate immunity and acute inflammation are understood to result in markedly delayed clearance of bacteria from the tissues, leading to local chronic granulomatous inflammation and compensatory adaptive immunological changes. Macrophages, key orchestrators of acute inflammation, are likely to play an important role in the initial impaired innate immune response. Monocyte-derived macrophages from CD patients stimulated with E. coli were shown to release attenuated levels of TNF and IFNγ with normal secretion of IL8, IL10 and IL6. In controls, the secretion of these cytokines was strongly positively correlated, which was not seen with CD macrophages. The transcriptomes of CD and control macrophages were examined in an attempt to understand the molecular basis of this defect. There were no differentially expressed genes identified between the two groups, consistent with genetic heterogeneity; however, a number of molecules were found to be under-expressed in subgroups of CD patients. The most common of these was optineurin (OPTN) which was under-expressed in approximately 10% of the CD patients. Reduced OPTN expression coincided with lower intracellular protein levels and diminished cytokine secretion after bacterial stimulation both in the patients and with siRNA knockdown in THP-1 cells. Identifying and studying subgroups of patients with shared defective gene expression could aid our understanding of the mechanisms underlying highly heterogeneous diseases such as CD.
2014-08-06 | GSE60083 | GEO
Project description:Background: The molecular pathogenesis of small intestinal adenocarcinomas (SBA) is not well understood. Defining its molecular pathogenesis may lead us to better clinical interventions. Aim: to identify the molecular changes characteristic of SBA. Methods: Forty-eight SBA (thirty-three non coeliac disease (CD)-related and 15 CD-related) were characterized for chromosomal aberrations, by high resolution array comparative hybridization (aCGH), microsatellite status (MSI) and APC promoter methylation and mutation status. Furthermore, molecular alterations found in CD-related SBA were compared to non-CD related SBA. Results: Chromosomal changes were observed in 77% of the SBA. The most frequently (>10%) DNA copy number changes found were gains on 5p15.33-5p12, 7p22.3-7q11.21, 7q21.2-7q21.3, 7q22.1-7q34, 7q36.1, 7q36.3, 8q11.21-8q24.3, 9q34.11-9q34.3, 13q11-13q34, 16p13.3, 16p11.2, 19q13.2 and 20p13-20q13.33 and losses of 4p13-4q35.2, 5q15-5q21.1 and 21p11.2-21q22.11. Seven highly amplified regions on 6p21.1, 7q21.1, 8p23.1, 11p13, 16p11.2, 17q12-q21.1 and 19q13.2 were also identified. CD-related and non CD-related SBA displayed similar chromosomal aberrations. Promoter hypermethylation of the APC gene was found in 48% non CD-related and 73% CD-related SBA. No nonsense mutations were found. Last, 10% of the non CD-related SBA were MSI, whereas 43% of the CD-related SBA were MSI. Conclusions: Our study characterized specific chromosomal aberrations and amplifications involved in SBA pathogenesis. At the chromosomal level, CD-related and non CD-related SBA do not differ. The involvement of the MMR system in the pathogenesis of the CD-related SBA was larger than what has been observed in no CD-related SBA. No nonsense mutations were found in SBA, but frequent promoter methylation in CD-related SBA. Forty-eight SBA (thirty-three non coeliac disease (CD)-related and 15 CD-related) were characterized for chromosomal aberrations against a Human pool, by high resolution array comparative hybridization (aCGH),
2009-10-07 | E-GEOD-15470 | biostudies-arrayexpress
Project description:Background: The molecular pathogenesis of small intestinal adenocarcinomas (SBA) is not well understood. Defining its molecular pathogenesis may lead us to better clinical interventions. Aim: to identify the molecular changes characteristic of SBA. Methods: Forty-eight SBA (thirty-three non coeliac disease (CD)-related and 15 CD-related) were characterized for chromosomal aberrations, by high resolution array comparative hybridization (aCGH), microsatellite status (MSI) and APC promoter methylation and mutation status. Furthermore, molecular alterations found in CD-related SBA were compared to non-CD related SBA. Results: Chromosomal changes were observed in 77% of the SBA. The most frequently (>10%) DNA copy number changes found were gains on 5p15.33-5p12, 7p22.3-7q11.21, 7q21.2-7q21.3, 7q22.1-7q34, 7q36.1, 7q36.3, 8q11.21-8q24.3, 9q34.11-9q34.3, 13q11-13q34, 16p13.3, 16p11.2, 19q13.2 and 20p13-20q13.33 and losses of 4p13-4q35.2, 5q15-5q21.1 and 21p11.2-21q22.11. Seven highly amplified regions on 6p21.1, 7q21.1, 8p23.1, 11p13, 16p11.2, 17q12-q21.1 and 19q13.2 were also identified. CD-related and non CD-related SBA displayed similar chromosomal aberrations. Promoter hypermethylation of the APC gene was found in 48% non CD-related and 73% CD-related SBA. No nonsense mutations were found. Last, 10% of the non CD-related SBA were MSI, whereas 43% of the CD-related SBA were MSI. Conclusions: Our study characterized specific chromosomal aberrations and amplifications involved in SBA pathogenesis. At the chromosomal level, CD-related and non CD-related SBA do not differ. The involvement of the MMR system in the pathogenesis of the CD-related SBA was larger than what has been observed in no CD-related SBA. No nonsense mutations were found in SBA, but frequent promoter methylation in CD-related SBA.
2009-10-07 | GSE15470 | GEO
Project description:Background. Assessment of non-HLA variants alongside standard HLA testing was previously shown to improve the identification of potential coeliac disease (CD) patients. We intended to identify new genetic variants associated with CD in the Polish population that would improve CD risk prediction when used alongside HLA haplotype analysis. Results. Association analysis using four HLA-tagging SNPs showed that, as was found in other populations, positive predicting genotypes (HLA-DQ2.5/DQ2.5, HLA-DQ2.5/DQ2.2, and HLA-DQ2.5/DQ8) were found at higher frequencies in CD patients than in healthy control individuals in the Polish population. Both CD-associated SNPs discovered by GWAS were found in the CD susceptibility region, confirming the previously-determined association of the major histocompatibility (MHC) region with CD pathogenesis. The two most significant SNPs from the GWAS were rs9272346 (HLA-dependent; localized within 1 Kb of DQA1) and rs3130484 (HLA-independent; mapped to MSH5). Specificity of CD prediction using the four HLA-tagging SNPs achieved 92.9%, but sensitivity was only 45.5%. However, when a testing combination of the HLA-tagging SNPs and the MSH5 SNP was used, specificity decreased to 80%, and sensitivity increased to 74%.
2015-10-15 | GSE65424 | GEO
Project description:Genome wide DNA methylation profiling in saliva samples from individuals with and without coeliac disease. The Illumina Infinium 450k Human DNA methylation BeadChip was used to obtain DNA methylation profiles across approximately 485,500 CpGs. The study investigated DNA methylation profiles associated with CD.
2019-12-31 | GSE119078 | GEO
Project description:<p><strong>OBJECTIVES</strong>: Celiac disease (CD) is a chronic enteropathy characterized by an autoimmune reaction in the small intestine of genetically susceptible individuals. The underlying causes of autoimmune reaction and its effect on host metabolism remain largely unknown. Herein, we apply lipidomics to elucidate the early events preceding clinical CD in a cohort of Finnish children, followed up in the Type 1 Diabetes Prediction and Prevention study.</p><p><strong>METHODS:</strong> Mass spectrometry-based lipidomics profiling was applied to a longitudinal/prospective series of 233 plasma samples obtained from CD progressors (n = 23) and healthy controls (n = 23), matched for human leukocyte antigen (HLA) risk, sex, and age. The children were followed from birth until diagnosis of clinical CD and subsequent introduction of a gluten-free diet.</p><p><strong>RESULTS:</strong> Twenty-three children progressed to CD at a mean age of 4.8 years. They showed increased amounts of triacylglycerols (TGs) of low carbon number and double bond count and a decreased level of phosphatidylcholines by age 3 months as compared to controls. These differences were exacerbated with age but were not observed at birth (cord blood). No significant differences were observed in the essential TGs.</p><p><strong>DISCUSSION:</strong> Our preliminary findings suggest that abnormal lipid metabolism associates with the development of clinical CD and occurs already before the first introduction of gluten to the diet. Moreover, our data suggest that the specific TGs found elevated in CD progressors may be due to a host response to compromised intake of essential lipids in the small intestine, requiring de novo lipogenesis.</p>
2020-01-22 | MTBLS729 | MetaboLights
Project description:We used RNA sequencing to profile over 70 transcriptomes of CD4+ T cells, a cell type crucial for Coeliac Disease CD pathogenesis, in both stimulated and resting samples from individuals with CD and unaffected controls The data gave us the opportunity to (i) compare gene expression between cases and controls; (ii) specifically assess whether genes that have been genetically associated with the disease were being DE; (iii) and also look for known and novel aspects of pathogenesis in the transcriptome of this specific cellular compartment.
2015-08-17 | GSE69549 | GEO
Project description:Transcriptomic heterogeneity of Coeliac Disease biopsies from the duodenum
| PRJNA692367 | ENA
Project description:Celiac disease is a chronic immune-mediated disorder with an important genetic component. To date, there are 57 independent association signals from 39 non-HLA loci, and a total of 66 candidate genes have been proposed. We aimed to scrutinize the functional implication of 45 of those genes by analyzing their expression in the disease tissue of celiac patients (at diagnosis/treatment) compared to non-celiac controls. The sample set consisted of 15 CD children at diagnosis (on a gluten-containing diet, with CD associated antibodies, atrophy of intestinal villi and crypt hyperplasia), and the same patients in remission after being treated with GFD for >2 years (asymptomatic, antibody negative, and normalized intestinal epithelium at that time), plus 15 tissue samples from non-celiac individuals not suffering from inflammation at the time of endoscopy used as controls
2014-09-30 | E-GEOD-61849 | biostudies-arrayexpress