Common variants at 5q22 associate with pediatric eosinophilic esophagitis.
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ABSTRACT:
SUBMITTER: Rothenberg ME
PROVIDER: S-EPMC3740732 | biostudies-literature | 2010 Apr
REPOSITORIES: biostudies-literature
Publications
Common variants at 5q22 associate with pediatric eosinophilic esophagitis.
Rothenberg Marc E ME Spergel Jonathan M JM Sherrill Joseph D JD Annaiah Kiran K Martin Lisa J LJ Cianferoni Antonella A Gober Laura L Kim Cecilia C Glessner Joseph J Frackelton Edward E Thomas Kelly K Blanchard Carine C Liacouras Chris C Verma Ritu R Aceves Seema S Collins Margaret H MH Brown-Whitehorn Terri T Putnam Phil E PE Franciosi James P JP Chiavacci Rosetta M RM Grant Struan F A SF Abonia J Pablo JP Sleiman Patrick M A PM Hakonarson Hakon H
Nature genetics 20100307 4
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 ...[more]
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Project description:BackgroundThe genetic cause of eosinophilic esophagitis (EE) has been largely unexplored until a recent genome-wide association study identified a disease susceptibility locus on 5q22, a region that harbors the thymic stromal lymphopoietin (TSLP) gene. However, it is unclear whether the observed genetic associations with EE are disease-specific or confounded by the high rate of allergy in patients with EE. In addition, the genetic contributions of other allergy-associated genes to EE risk have not been explored.ObjectiveWe aimed to delineate single nucleotide polymorphisms (SNPs) that associated with EE apart from allergy.MethodsWe used a custom array containing 738 SNPs in 53 genes implicated in allergic responses, immune responses, or both to genotype 220 allergic or 246 nonallergic control subjects and a discovery cohort of 170 patients with EE. We replicated a statistically significant SNP association in an independent case-control cohort and examined the induction of the candidate gene in primary esophageal epithelial cells.ResultsA single SNP residing in the TSLP gene reached Bonferroni linkage disequilibrium-adjusted significance but only when patients with EE were compared with allergic control subjects (rs10062929; P = 4.11 x 10(-5); odds ratio, 0.35). A nonsynonymous polymorphism in the thymic stromal lymphopoietin receptor (TSLPR) gene on Xp22.3 and Yp11.3 was significantly associated with disease only in male patients with EE. Primary esophageal epithelial cells expressed TSLP mRNA after Toll-like receptor 3 stimulation.ConclusionThese data collectively identify TSLP as a candidate gene critically involved in EE susceptibility beyond its role in promoting T(H)2 responses.
| S-EPMC2904342 | biostudies-literature
Project description:Clinical experiences and recent studies suggest that eosinophilic esophagitis (EoE) has the potential to induce caregiver (CG) and child stress. The specific sources of CG EoE-related stress remain uncertain. To address this, we performed a survey of CGs and youth attending a patient with EoE education symposium that measured potential stressful elements in their daily life. Our results indicated that CGs experienced most stress associated with purchasing, preparation, and completion of meals. We conclude that providers should consider this in choosing therapeutic approaches for children with EoE.
| S-EPMC5449262 | biostudies-literature
Project description:BackgroundAlthough eosinophilic esophagitis (EoE) is associated with certain gene variants, the rapidly increasing incidence of EoE suggests that environmental factors contribute to disease development.ObjectiveWe tested for gene-environment interaction between EoE-predisposing polymorphisms (within TSLP, LOC283710/KLF13, CAPN14, CCL26, and TGFB) and implicated early-life factors (antibiotic use in infancy, cesarean delivery, breast-feeding, neonatal intensive care unit [NICU] admission, and absence of pets in the home).MethodsWe conducted a case-control study using hospital-based cases (n = 127) and control subjects representative of the hospital catchment area (n = 121). We computed case-only interaction tests and in secondary analyses evaluated the combined and independent effects of genotype and environmental factors on the risk of EoE.ResultsCase-only analyses identified interactions between rs6736278 (CAPN14) and breast-feeding (P = .02) and rs17815905 (LOC283710/KLF13) and NICU admission (P = .02) but not with any of the factors examined. Case-control analyses suggested that disease risk might be modifiable in subjects with certain gene variants. In particular, breast-feeding in those with the susceptibility gene variant at rs6736278 (CAPN14) reduced the risk of EoE (adjusted odds ratio, 0.08; 95% CI, 0.01-0.59). Admission to the NICU in those without the susceptibility gene variant at rs17815905 (LOC283710/KLF13) significantly increased the risk of having disease (adjusted odds ratio, 4.83; 95% CI, 1.49-15.66).ConclusionsThe interplay of gene (CAPN14 and LOC283710/KLF13) and early-life environment factors (breast-feeding and NICU admission) might contribute to EoE susceptibility.
| S-EPMC5803324 | biostudies-literature
Project description:Eosinophilic esophagitis (EoE) is an allergic inflammatory disease of the esophagus that occurs in both children and adults. Previous studies of affected tissue from pediatric cohorts have identified prominent signatures of eosinophilia and type 2 inflammation. However, the details of the immune response in adults with EoE are still being elucidated. To determine whether EoE in adults shares inflammatory profiles with those observed in children, we performed RNA sequencing of paired human esophageal biopsies and blood samples from adults with EoE or gastroesophageal reflux disease. Unbiased analysis of differentially expressed genes in tissue revealed a strong IFN signature that was significantly enriched in EoE patients as compared with patients with gastroesophageal reflux disease. Both type I and type II IFN-responsive genes were upregulated in adult biopsies, but not in blood. A similar increase in expression of IFN gene sets was observed in pediatric EoE biopsies as compared with non-EoE samples, and in public pediatric and adult RNA-sequencing data. Finally, we found that human peripheral CD4+ T cells from children with EoE produce IFN-γ upon activation with EoE-causal allergens. Together, this work identifies a conserved IFN signature in pediatric and adult EoE, highlighting a role for non-type 2 inflammatory networks in the disease process in humans.
| S-EPMC7946729 | biostudies-literature
Project description:OBJECTIVE:Proton pump inhibitors (PPIs) are an effective treatment for eosinophilic esophagitis (EoE); however, only 30% to 60% of patients respond. Common genetic variants in CYP2C19 and STAT6 associate with PPI plasma concentration and magnitude of inflammatory response, respectively. Our objective was to determine if genetic variation in the genes for CYP2C19 and STAT6 influence differentiation between PPI responsive esophageal eosinophilia versus PPI nonresponsive EoE (PPI-REE, PPI-nonresponsive EoE). METHODS:Genomic DNA was isolated from 92 esophageal tissue biopsies collected from participants of a prospective clinical trial of high-dose PPI therapy for esophageal eosinophilia in children. RESULTS:Of the 92 patients examined, 57 (62%) were PPI-REE and 35 (38%) were PPI-nonresponsive EoE. Forty-six of the 92 patients were further characterized by pH probe monitoring; there was no association between reflux index and carriage of CYP2C1917 (P = 0.35). In children who received a PPI dose between ?1.54 and ?2.05?mg/kg/day, binary logistic regression modeling showed that carriage of CYP2C1917 associated with PPI-nonresponsive EoE (odds ratio (OR) [95% confidence interval (CI)] = 7.71 [1.21, 49.11], P = 0.031). Carriage of STAT6 allelic variant rs1059513 predicts PPI-REE (OR [95% CI] = 6.16 [1.44, 26.4], P = 0.028), whereas carriage of STAT6 rs324011 synergizes with CYP2C1917 to predict PPI-nonresponsive EoE (rs324011 OR [95% CI] = 5.56 [1.33, 20.72], P?=?0.022; CYP2C1917 OR [95% CI]?=?8.19[1.42, 50.57], P = 0.023). CONCLUSIONS:Common variants in CYP2C19 and STAT6 associate with a PPI-nonresponsive EoE outcome of PPI therapy for esophageal eosinophilia suggesting that response rates may be improved by adopting a genotype-guided approach to PPI dosing.
| S-EPMC6855320 | biostudies-literature
Project description:Eosinophilic esophagitis (EoE) is an allergic inflammatory disease of the esophagus that occurs in both children and adults. Previous studies of affected tissue in pediatric cohorts have identified prominent signatures of eosinophilia and type 2 inflammation. However, the details of the immune response in adults with EoE are still being elucidated. To determine whether EoE in adults shares inflammatory profiles with those observed in children, we performed RNA-sequencing of paired esophageal biopsies and blood samples from adults with EoE or gastroesophageal reflux disease (GERD). Unbiased analysis of differentially expressed genes in tissue revealed a strong interferon signature that was significantly enriched in EoE patients as compared to patients with GERD. Both type I and type II interferon responsive genes were upregulated in adult biopsies, but not in blood. A similar increase in expression of interferon gene sets was observed in pediatric EoE biopsies as compared to non-EoE samples, and in public pediatric and adult RNA-sequencing data. Finally, we found that peripheral CD4+ T cells from children with EoE produce IFNG upon activation with EoE-causal allergens. Together, this work identifies a conserved interferon signature in pediatric and adult EoE, highlighting a role for non-type 2 inflammatory networks in the disease process.
2020-08-22 | GSE156651 | GEO
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:The relation between patient symptoms and histological severity of eosinophilic esophagitis (EE) is not known. We created a pediatric EE symptom score (PEESS) and compared the results with histological findings in the esophagus.Subjects ages 3 to 18 years with a histological diagnosis of EE or their parent completed a survey rating the frequency and severity of their gastrointestinal symptoms. Scores ranged from 0 to 98. Eosinophil numbers in esophageal biopsy specimens were correlated with the PEESS.A total of 49 subjects completed the PEESS. The symptom score did not correlate with the peak eosinophil count (r = 0.079). Newly diagnosed, untreated EE subjects (N = 15) had a mean score of 24.7 +/- 16.4 with a modest correlation between the PEESS and the number of eosinophils in the distal esophagus (r = 0.37). The mean PEESS score in the 34 treated patients was lower than in untreated patients (15.6 +/- 12.9; P = 0.046). The mean score for treated patients in histological remission was the same as for treated patients with active EE, regardless of treatment type. Abdominal pain was the most frequent and severe symptom reported. Among 20 of the 34 subjects (58.8%) in histological remission, 17 (85%) continued to report symptoms with a mean score of 17.4 +/- 9.9 (range 1-38). Three children with active histological EE (10%) reported no symptoms.Children with untreated EE had a higher PEESS than treated subjects. Symptoms persisted in 85% of EE patients despite histological resolution and 10% with active EE reported no symptoms. Our data indicate a dissociation between symptoms and histology in pediatric EE.
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Project description:Unsedated transnasal endoscopy (TNE) is safer and less costly than sedated EGD. The aim of this study was to evaluate the performance of TNE with biopsies in monitoring the esophageal mucosa of pediatric patients with eosinophilic esophagitis.Patients between 8 and 17 years of age with eosinophilic esophagitis and their parents were enrolled. Unsedated TNE was performed. A 2.8-mm (1.2-mm channel) or a 4-mm flexible bronchoscope (2-mm channel) was used, and esophageal biopsy specimens were obtained. Biopsy specimen analysis, duration, adverse events, and billing charges of TNE were assessed. Immediately after TNE and a minimum of 2 weeks later, a modified Group Health Association of America 9 survey and a preference questionnaire were completed, respectively.Twenty-one of 22 enrolled patients underwent TNE. TNE was performed with no serious adverse events. Histopathological analysis revealed 0 eosinophils per high-power field (n = 12), fewer than 15 eosinophils per high-power field (n = 4), and more than 15 eosinophils per high-power field (n = 5). The total epithelial surface area of mucosal biopsy samples from either TNE Forceps (1.2 mm or 2 mm biopsy channel forceps) compared with those obtained during the subject's previous EGD by using standard endoscopic forceps was not statistically different (P = .308 [1.2 mm]/P = .492 [2 mm]). All parents and 76.2% of subjects would undergo the TNE again. TNE was preferred over EGD by 85.7% of parents and 52.4% of subjects. The modified Group Health Association of America 9 survey revealed a high degree of satisfaction (average, 43.19 ± 2.6; maximum score, 45). Charges associated with TNE were 60.1% lower than for previous EGDs.Unsedated TNE is an effective, lower-cost procedure for monitoring the esophageal mucosa of children with eosinophilic esophagitis.
| S-EPMC4698253 | biostudies-literature
Project description:The incidence of eosinophilic esophagitis (EoE) has increased in the past several years, yet our understanding of its pathogenesis remains limited. To test the hypothesis that microRNAs (miRNAs) are altered in children with EoE, miRNAs were profiled in esophageal mucosa biopsies obtained from patients with active disease (n = 5) and healthy control subjects (n = 6). Fourteen miRNAs were significantly altered between groups; four of these miRNAs were decreased in EoE patients. A panel of five miRNAs (miR-203, miR-375, miR-21, miR-223, and miR-142-3p) were selected for validation in an independent set of samples from control (n = 22), active disease (n = 22), inactive disease (n = 22), and gastroesophageal reflux disease (n = 6) patients. Each panel miRNA was significantly altered among groups. miRNA changes in esophageal biopsies were not reflected in the circulating RNA pool, as no differences in panel miRNA levels were observed in sera collected from the four patient groups. In addition, in contrast to previous studies, no change in esophageal miRNA levels was detected following treatment that resolved esophageal eosinophilia. In an effort to identify the ramifications of reduced esophageal miR-203, miR-203 activity was inhibited in cultured epithelial cells via expression of a tough decoy miRNA inhibitor. Luciferase reporter assays demonstrated that miR-203 does not directly regulate human IL-15 through targeting of the IL-15 3'-untranslated region. From these experiments, it is concluded that miRNAs are perturbed in the esophageal mucosa, but not the serum, of pediatric EoE patients. Further investigation is required to decipher pathologically relevant consequences of miRNA perturbation in this context.
| S-EPMC4200319 | biostudies-literature