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Project description:Eosinophilic esophagitis (EoE) is a rare atopic disorder associated with esophageal dysfunction, including difficulty swallowing, food impaction, and inflammation. EoE develops in a small subset of people with food allergies under the influence of environmental and genetic risk factors. Genome wide association studies (GWAS) have identified 31 independent risk loci for the disease, and linkage disequilibrium (LD) expansion of these loci nominates a set of 531 variants that are potentially causal. These risk variants are non-coding, suggesting a likely role in altered gene regulatory mechanisms. To systematically interrogate the gene regulatory activity of these variants, we designed a massively parallel reporter assay (MPRA) containing the alleles of each variant within their 170 bp genomic sequence context cloned into a GFP reporter library. Transfection of the MPRA library into TE-7 esophageal epithelial cells, HaCaT skin keratinocytes, and Jurkat T cells revealed cell-type-specific gene regulation. We identify 32 allelic enhancer variants (allelic enVars) that regulate reporter gene expression in a genotype-dependent manner in at least one cellular context. By annotating these variants with expression quantitative trait loci (eQTL) and chromatin looping data in related tissues and cell types, we identify putative target genes affected by genetic variation in EoE patients, including TSLP and multiple genes at the HLA locus. Transcription factor enrichment analyses reveal possible roles for cell-type specific regulators, including GATA-3, a key regulator of type 2 inflammation. Collectively, our approach reduces the large set of EoE-associated variants to a set of 32 with allelic regulatory activity, providing new functional insights into the effects of genetic variation in this disease.
2023-11-26 | GSE232337 | GEO
Project description:Eosinophilic esophagitis (EoE) is a rare atopic disorder associated with esophageal dysfunction, including difficulty swallowing, food impaction, and inflammation. EoE develops in a small subset of people with food allergies under the influence of environmental and genetic risk factors. Genome wide association studies (GWAS) have identified 31 independent risk loci for the disease, and linkage disequilibrium (LD) expansion of these loci nominates a set of 531 variants that are potentially causal. These risk variants are non-coding, suggesting a likely role in altered gene regulatory mechanisms. To systematically interrogate the gene regulatory activity of these variants, we designed a massively parallel reporter assay (MPRA) containing the alleles of each variant within their 170 bp genomic sequence context cloned into a GFP reporter library. Transfection of the MPRA library into TE-7 esophageal epithelial cells, HaCaT skin keratinocytes, and Jurkat T cells revealed cell-type-specific gene regulation. We identify 32 allelic enhancer variants (allelic enVars) that regulate reporter gene expression in a genotype-dependent manner in at least one cellular context. By annotating these variants with expression quantitative trait loci (eQTL) and chromatin looping data in related tissues and cell types, we identify putative target genes affected by genetic variation in EoE patients, including TSLP and multiple genes at the HLA locus. Transcription factor enrichment analyses reveal possible roles for cell-type specific regulators, including GATA-3, a key regulator of type 2 inflammation. Collectively, our approach reduces the large set of EoE-associated variants to a set of 32 with allelic regulatory activity, providing new functional insights into the effects of genetic variation in this disease.
2023-11-26 | GSE232336 | GEO
Project description:Background: Eosinophilic esophagitis (EoE) is commonly associated with concomitant atopic diseases including atopic dermatitis (AD) and allergic airway (AA) diseases including asthma. Despite this link and the shared pathologic features across these three disorders, detailed analyses of the unifying molecular pathways are lacking. Objectives: We sought to investigate the mRNA expression profile overlap between EoE, AA, and AD and to identify the involvement of interleukin 13 (IL-13) in modulating gene expression. Methods: Whole-genome mRNA expression analyses were performed on tissue specimens (biopsies or nasal brushes) from patients with EoE, AD, and AA, and IL-13-stimulated primary human epithelial cells from the esophagus, the skin, and the airways. Results: By human disease expression profiles, EoE evidenced a significantly higher overlap (p = 0.0006) with AD (181 transcripts; 10%) than with AA (124 transcripts, 7%). Only 18 genes were found to be commonly dysregulated among the three diseases; these included filaggrin, histamine receptor H1, claudin 1, cathepsin C, plasminogen activator urokinase receptor, and suppressor of cytokine signaling 3. Ontogenetic analysis revealed a common immune/inflammatory response among the three diseases and a different epithelial response (epidermal cell differentiation) between EoE and AA. The overlap between the IL-13-stimulated epithelial cell transcriptome and the respective disease transcriptome was 22, 9, and 5% in EoE, AD, and AA, respectively, indicating a greater involvement of the IL-13 pathway in EoE than AA (p = 0.0007) or AD (p = 0.02). Conclusion: EoE, AD, and AA share a common set of disease-specific transcripts, highlighting common molecular etiology. Their comparative analysis indicates relatively closer relationships between EoE and AD, particularly centered around IL-13-driven pathways. Therefore, these findings provide an increased rationale for shared therapeutic strategies.
| S-EPMC6879454 | biostudies-literature
Project description:Eosinophilic esophagitis (EoE) is a clinicopathological diagnosis seen in children as well as adults. Growing evidence suggests that EoE is strongly associated with atopic disorders. Presenting symptoms differ in children and adults and it is not known whether atopic features vary by age. This study was designed to compare atopic features and allergic sensitization between children and adults with EoE. We conducted a retrospective analysis of demographic and clinical data from 50 children (aged 2-18 years) and 50 adults (aged 21-75 years) with a biopsy-proven diagnosis of EoE referred to our allergy clinic. Data regarding patient characteristics, history of atopic diseases, and allergy test results were collected for analysis. The majority of children and adults were white and male patients. When compared with adults, a higher percentage of children had a history of asthma (52% versus 24%; p < 0.05). There was no statistically significant difference between adults and children regarding history of allergic rhinitis, atopic dermatitis, immunoglobulin E-mediated food allergy, and family history of atopy. There was no statistically significant difference between children and adults regarding immediate-type sensitization to foods and aeroallergens. Compared with adults, a higher percentage of children showed a positive reaction to one or more foods on patch testing (62% versus 31%; p = 0.01). A high prevalence of comorbid atopic diseases and sensitizations to food and environmental allergens was seen in both children and adults. Children had a significantly higher rate of asthma and positive patch test to foods compared with adults.
| S-EPMC5554374 | biostudies-other
Project description:To review the understanding of the pathogenesis of eosinophilic esophagitis (EoE) and the role of the immune system in the disease process.Peer-reviewed articles on EoE from PubMed searching for "Eosinophilic Esophagitis and fibrosis" in the period of 1995 to 2013.Studies on the clinical and immunologic features, pathogenesis, and management of EoE.Recent work has revealed that thymic stromal lymphopoietin and basophil have an increased role in the pathogenesis of disease. Additional understanding on the role of fibrosis in EoE is emerging.The incidence of EoE is increasing like most atopic disease. Similar to other allergic diseases, EoE is treated with topical steroids and/or allergen avoidance.
| S-EPMC4332835 | biostudies-literature
Project description:Eosinophilic esophagitis (EoE) is an allergic disorder characterized by the accumulation of eosinophils in the esophagus. We report association of EoE with variants at chromosome 5q22 encompassing TSLP and WDR36 (rs3806932, combined P = 3.19 x 10(-9)). TSLP is overexpressed in esophageal biopsies from individuals with EoE compared with unaffected individuals, whereas WDR36 expression is unaltered between the two groups. These data implicate the 5q22 locus in the pathogenesis of EoE and identify TSLP as the most likely candidate gene in the region.
| S-EPMC3740732 | biostudies-literature
Project description:Elemental diets, dietary elimination, and steroid therapies are the most common therapies in the clinical trials for eosinophilic esophagitis (EoE). Histological findings (usually reported as eosinophils per microscopic high-powered field [hpf]) remain the most common end-point used to define response. Yet, the threshold for defining "response" and "remission" are ill-defined among consensus guidelines and may vary from study to study. We conducted a systematic literature review of articles on eosinophilic esophagitis, published between January 2007 and November 2017, considering histological remission as the primary outcome. We abstracted treatment information and definitions of histological remission or response. A comparison of definitions of histological remission across and within institutions was performed. A total of 61 articles were included in this review, with approximately 60% of the studies published from centers in the United States. Histological definitions of remission of EoE ranged from 0 to ?20 eosinophils/hpf. The most stringent criteria, ranging from 0 to ?5 eosinophils/hpf, were commonly used in interventional trial studies that examined the effects of new treatments. We found remarkable variability in definitions between studies, treatment types, and regions. Age or epidemiological distribution of study subjects did not influence the criteria for histological remission. Clinical and histological improvements are important measures of the effects of treatment. Histological findings, the most objective measure of treatment, should provide an optimal method for comparing the effectiveness of various treatments. Yet, our findings suggest a lack of consistent remission criteria in published studies. Considering these inconsistencies, it is difficult to compare the effectiveness of various treatments.
| S-EPMC6207047 | biostudies-literature
Project description:Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus triggered by immune hypersensitivity to food. Herein, we tested whether genetic risk factors for known, non-allergic, immune-mediated diseases, particularly those involving autoimmunity, were associated with EoE risk. We used the high-density Immunochip platform, encoding 200,000 genetic variants for major auto-immune disease. Accordingly, 1214 subjects with EoE of European ancestry and 3734 population controls were genotyped and assessed using data directly generated or imputed from the previously published GWAS. We found lack of association of EoE with the genetic variants in the major histocompatibility complex (MHC) class I, II, and III genes and nearly all other loci using a highly powered study design with dense genotyping throughout the locus. Importantly, we identified an EoE risk locus at 16p13 with genome-wide significance (Pcombined=2.05 × 10-9, odds ratio = 0.76-0.81). This region is known to encode for the genes CLEC16A, DEXI, and CIITI, which are expressed in immune cells and esophageal epithelial cells. Suggestive EoE risk were also seen 5q23 (intergenic) and 7p15 (JAZF1). Overall, we have identified an additional EoE risk locus at 16p13 and highlight a shared and unique genetic etiology of EoE with a spectrum of immune-associated diseases.
| S-EPMC6286696 | biostudies-literature
Project description:Canine atopic dermatitis (AD) is clinically similar to human AD, implicating it as a useful model of human eosinophilic allergic disease. To identify cutaneous gene transcription changes in relatively early inflammation of canine AD, microarrays were used to monitor transcription in normal skin (n=13) and in acute lesional AD (ALAD) and nearby visibly nonlesional AD (NLAD) skin (n=13) from dogs. Scanning the putative abnormally transcribed genes, several potentially relevant genes, some abnormally transcribed in both NLAD and ALAD (e.g. IL6, NFAM1, MSRA, and SYK), were observed. Comparison for abnormally transcribed genes common to two related human diseases, human AD and asthmatic chronic rhinosinusitis with nasal polyps (aCRSwNP), further identified genes or gene sets likely relevant to eosinophilic allergic inflammation. These included: (1) genes associated with alternatively activated monocyte-derived cells, including members of the monocyte chemotactic protein (MCP) gene cluster, (2) members of the IL1 family gene cluster, (3) eosinophil-associated seven transmembrane receptor EMR1 and EMR3 genes, (4) interferon-inducible genes, and (5) keratin genes associated with hair and nail formation. Overall, numerous abnormally transcribed genes were observed only in canine AD; however, many others are common to related human eosinophilic allergic diseases and represent therapeutic targets testable in dogs with AD.
| S-EPMC4459581 | biostudies-literature
Project description:Eosinophilic esophagitis is an emerging disease that is distinguished from gastroesophageal reflux disease by the expression of a unique esophageal transcriptome and the interplay of early life environmental factors with distinct genetic susceptibility elements at 5q22 (TSLP) and 2p23 (CAPN14). Rare genetic syndromes have uncovered the contribution of barrier disruption, mediated in part by defective desmosomes and dysregulated transforming growth factor beta production and signaling, to eosinophilic esophagitis pathophysiology. Experimental modeling has defined a cooperative role of activated eosinophils, mast cells, and the cytokines IL-5 and IL-13, mediated by allergic sensitization to multiple foods. Understanding these processes is opening the way to better treatment based on disrupting allergic inflammatory and type 2 cytokine-mediated responses, including anti-cytokine therapeutics and dietary therapy.
| S-EPMC5787048 | biostudies-literature