Aug 2026· Diseases of the esophagus· Vol 39· 0 citations
TL;DR
FGF19 emerges as a key cytokine driving EGJ glandular remodeling through HLA-DR+ CD4+/CD8+ T-cell associated immune activation, providing candidate molecular targets for early prevention and intervention.
Abstract
Benign Disease: Barrett’s Esophagus: Pathology and Pathophysiology; Non-invasive Neoplasia
Gastroesophageal reflux disease (GERD), Barrett’s esophagus (BE), and esophageal adenocarcinoma (EAC) form a recognized pathological continuum, but the causal immune and inflammatory processes driving progression remain incompletely defined.
Summary-level GWAS data were analyzed for 91 circulating inflammatory proteins (n = 14,824), 731 immune cell phenotypes (n = 3,757), and three esophageal diseases (GERD, BE, and EAC). Bidirectional and two-step Mendelian randomization (MR) were used to infer causal effects and mediation, with Cochran’s Q, MR-Egger, and MR-PRESSO applied to assess heterogeneity and pleiotropy. Causal interaction networks were reconstructed to map immune- and inflammation-dominant regulatory patterns across disease stages, and MR-prioritized signals were experimentally validated in EGJ organoids and mouse models.
MR supported a causal GERD-BE-EAC sequence, with BE mediating 31.95% of the total GERD-to-EAC effect. In total, 139 immune cell traits and 29 inflammatory proteins showed causal links to disease risk. Mediation analyses highlighted M-CSF1 and HLA-DR+CD4+ T cells as central hubs. Guided by the MR-prioritized FGF19-HLA-DR+ T-cell axis, experimental studies demonstrated that FGF19 promotes esophagogastric junction (EGJ) glandular conversion and increases infiltration of HLA-DR+ CD4+/CD8+ T cells, validated in EGJ organoids and mouse models.
This integrated genetic and experimental framework delineates a bidirectional immune-inflammation regulatory network underlying progression from GERD to BE and EAC. FGF19 emerges as a key cytokine driving EGJ glandular remodeling through HLA-DR+ CD4+/CD8+ T-cell associated immune activation, providing candidate molecular targets for early prevention and intervention.
BACKGROUND
Gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), and esophageal adenocarcinoma (EAC) form a recognized pathological continuum, but the causal immune and inflammatory processes driving progression remain incompletely defined.
METHODS
Summary-level genome-wide association study (GWAS) data were analyzed for 91 circulating inflammatory proteins (n = 14,824), 731 immune cell phenotypes (n = 3,757), and three esophageal diseases (GERD, BE, and EAC). Bidirectional and two-step Mendelian randomization (MR) were used to infer causal effects and mediation, with Cochran's Q, MR-Egger, and MR-PRESSO applied to assess heterogeneity and pleiotropy. Causal interaction networks were reconstructed to map immune- and inflammation-dominant regulatory patterns across disease stages, and MR-prioritized signals were experimentally validated in esophagogastric junction (EGJ) organoids and mouse models.
RESULTS
MR supported a causal GERD-BE-EAC sequence, with BE mediating 31.95% of the total GERD-to-EAC effect. In total, 139 immune cell traits and 29 inflammatory proteins showed causal links to disease risk. Mediation analyses highlighted M-CSF1 and HLA-DR+CD4 + T cells as central hubs. Guided by the MR-prioritized FGF19-HLA-DR + T-cell axis, experimental studies demonstrated that FGF19 promotes EGJ glandular conversion and increases infiltration of HLA-DR+ CD4+/CD8 + T cells, validated in EGJ organoids and mouse models.
CONCLUSIONS
This integrated genetic and experimental framework delineates a bidirectional immune-inflammation regulatory network underlying progression from GERD to BE and EAC. FGF19 emerges as a candidate cytokine driving EGJ glandular remodeling through HLA-DR+ CD4+/CD8 + T-cell associated immune activation, providing candidate molecular targets for early prevention and intervention.
Yixin Liu, Zhipeng Gong, Yuwen Tan et al.· Journal of Translational Med...· 0 citations
This study provided novel insights into the protective effect of GD against PCa and identified shared genes and immune mechanisms, offering a deeper understanding of the common mechanisms between GD and PCa.
Mingshun Zuo, Yuanjian Liao, Qiang Xu et al.· The Aging Male· 0 citations
Background Inflammatory bowel disease (IBD) and IgA nephropathy (IgAN) share features of mucosal immune dysregulation, but the genetic basis of their relationship and the contribution of specific IBD subtypes remain unclear. Methods Using public genome-wide association study (GWAS) summary datasets, we performed bidirectional Mendelian randomization (MR) analyses in European and East Asian populations, together with generalized summary-data-based Mendelian randomization (GSMR), Causal Analysis Using Summary Effect Estimates (CAUSE), genetic correlation, enrichment, cross-trait locus analysis, colocalization, and single-cell RNA sequencing. Phenotypic support was assessed in a clinical cohort of 9,371 patients with IBD. Results Crohn’s disease (CD), but not ulcerative colitis (UC), showed a consistent directional genetic association with IgAN across populations, and GSMR provided complementary support for this association (P = 4.02 × 10-5). CAUSE did not clearly favor the causal model over the sharing model. Standard linkage disequilibrium score regression (LDSC) identified a positive genetic correlation between CD and IgAN (rg = 0.392, SE = 0.093, P = 2.53 × 10-5), with constrained-intercept LDSC and genetic covariance analyzer (GNOVA) providing supportive evidence. Functional analyses showed enrichment in whole blood and spleen, but not kidney tissue. Integrative analyses prioritized ERAP2 and CARD9 as leading candidate genes, with the strongest colocalization support observed for ERAP2 in sigmoid-colon expression quantitative trait locus (eQTL) data (posterior probability of colocalization [PPH4] = 90.4%) and for CARD9 at the GWAS level (PPH4 = 98.4%). In the clinical cohort, biopsy-confirmed IgAN was more common in CD than in UC (Firth-adjusted OR = 3.40, 95% CI 1.28–11.28; P = 0.0125). Conclusions These findings support shared genetic architecture between CD and IgAN and suggest a possible directional genetic association between CD liability and IgAN risk. ERAP2 and CARD9 were prioritized as candidate genes within a proposed gut–immune–kidney framework.
Tao Su, Mengjun Liang, Xiaohang Gao et al.· Frontiers in Immunology· 0 citations
Numerous observational studies have suggested a potential shared genetic background between inflammatory bowel disease (IBD) and IgA vasculitis (IgAV). However, the causal relationship between these 2 conditions remains poorly understood. We performed large-scale two-sample and multivariable Mendelian randomization (MR) analyses (MVMR) to examine whether there is a causal relationship between IBD and IgAV. We employed 4 distinct approaches, including MR-Egger, weighted median, random-effects inverse-variance weighted (IVW), and weighted mode, to conduct the MR analysis. The univariable MR analysis demonstrated that IBD and Crohn disease (CD) were associated with an increased risk of IgAV in the International Inflammatory Bowel Disease Genetics Consortium, with an odds ratio (OR) of 1.17 (95% confidence interval [CI]: 1.06–1.28, PIVW = .001) for IBD and an OR of 1.12 (95% CI: 1.01–1.24, PIVW = .016) for CD. Ulcerative colitis was associated with an increased risk of IgAV, which was considered suggestive after Bonferroni correction, with an OR of 1.12 (95% CI: 1.01–1.24, PIVW = .028). Consistent results were observed after adjusting for potential confounders (drug allergy and upper respiratory tract infection) in MVMR. IBD, ulcerative colitis, and CD were associated with an increased risk of IgAV, with an OR of 1.20 (95% CI: 1.08–1.34, PIVW = .001), 1.20 (95% CI: 1.07–1.35, PIVW = .002), and 1.13 (95% CI: 1.03–1.25, PIVW = .0012). Our study identifies a causal relationship between IBD and IgAV, particularly between CD and IgAV, suggesting that IBD is a potential precursor to IgAV rather than the converse. Further studies on the common mechanisms of these 2 diseases are needed.
Bingqing Yi, Yaoyue Luo, Hong Li et al.· Medicine· 0 citations
Esophageal Cancer: Barrett‘s Esophagus: High-Grade Dysplasia and Early Invasive Cancer
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) delay gastric emptying and are linked to increased gastroesophageal reflux, a recognized risk factor for Barrett’s esophagus (BE) progression to esophageal cancer (EC). Extended use of GLP-1 RAs facilitates weight loss, mitigating reflux, possibly offering a protective effect against EC. This large retrospective study aimed to assess the association between GLP-1 use with the development of dysplastic Barrett’s esophagus (BE) and EC in patients with non-dysplastic BE (NDBE).
We used ICD and CPT codes within the TriNetX (a large multicenter claims based) database to identify NDBE patients. The cohort was then categorized as GLP-1 users vs. non-users based on ATC code A10BJ. A 1:1 propensity matched analysis was performed with balancing of confounders (Table 1). Primary outcomes included incidence of dysplastic BE and EC. Time to event analyses were performed.
A total of 4,534 patients were identified in the GLP-1 cohort and 55,621 in the non-GLP-1 cohort. After 1:1 matching, 4,530 patients were included in each cohort. Mean follow-up was 3.57 years in GLP-1 cohort and 3.30 years in non-GLP-1 cohort. Incidence of dysplastic BE/EC in the GLP 1 cohort was 1.24% (N=56) compared to 0.54% (N=24) in non-GLP 1 cohort. GLP-1 users demonstrated significantly higher risk of developing dysplastic BE/EC compared to non-users (RR: 2.30; 95% CI: 1.47–3.70, P = 0.0004. The cumulative incidence of dysplastic BE/EC was higher among GLP-1 cohort at 3 and 5 years—0.90 %, and 1.11%, respectively—compared to 0.47%, and 0.49 % in the non-GLP-1 group.
Our findings indicate that GLP-1 therapy was associated with an increased risk of progression to dysplastic BE/EC in patients with non-dysplastic BE. Further prospective studies are warranted to validate these results.
Russaal S Mann, K. Sachdeva, L. Dhaliwal et al.· Diseases of the esophagus· 0 citations
Inflammatory Bowel Disease (IBD) is an autoinflammatory condition, with increasing incidence in children. TNF inhibitor (TNFi) therapy is the only FDA-approved biologic in pediatric IBD, yet only a third of patients achieve mucosal healing with TNFi. We recently identified polygenic risk scores for IBD as a top predictor of TNFi response in an ensemble model integrating the PRS with clinical measurements. The majority of IBD risk variants are noncoding. If causal, they likely alter transcription factor (TF) binding and downstream gene expression in particular cell types and contexts.
Using single-nuclei multiome sequencing (snRNA-seq and snATAC-seq) of pediatric IBD intestine from TNFi responders and nonresponders, we generated accessible chromatin maps for 27 cell types, resolved by TNFi response status. CD4 T cells and macrophages were top-ranked mediators of IBD genetic risk, especially in the TNFi non-response context (PMID:38405748). We curated ligand-response gene signatures to identify cell-cell signaling responses (1) targeted by IBD genetic risk variants and (2) altered in TNFi nonresponders. In CD4 T cells, we constructed genome-scale gene regulatory networks (GRNs) (PMID:36945549) to predict TF mediators of IBD genetic risk and TNFi response.
Genetic risk colocalization identified Th17 cells and inflammatory monocytes/macrophages as key mediators of IBD risk. In Th17 cells, GRN modeling revealed TF activities associated with TNFi nonresponse, including IBD risk enhancer targets (e.g., CREM, GFI1) and TFs downstream of signaling pathways targeted by next-gen IBD therapeutics (e.g., STAT4 downstream of IL23/IL12). While, in macrophage, IBD risk variant targets and TNFi-nonresponse gene signatures were linked to TNF and IL1 signaling.
Our integrated modeling nominates cell-type-specific regulatory mechanisms linking IBD genetic risk to TNFi non-response and prioritizes next-gen IBD biologic targets.
Cincinnati Children’s Research Foundation by Academic Research Committee (ARC) grant #53671 (ERM, LAD, AGM, LCK, MTW); National Institute of Health (NIH) funding: R01AI153442 (ERM), the CCRF Digestive Health Center grant, P30DK078392 (LAD)
Computational and Systems Immunology (COMP)
Zi F. Yang, J. Wayman, Elizabeth Angerman et al.· Journal of Immunology· 0 citations
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