What question did this study set out to answer?

May 10, 2026Translational Vision Science & Technology0 citationsOpen Access

Circulating Inflammatory Proteins and Fuchs Endothelial Corneal Dystrophy: A Mendelian Randomization and Bioinformatics-Based Investigation

DWDan WuEye & ENT Hospital of Fudan University GLGang LiChinese Academy of Medical Sciences & Peking Union Medical College XCXinhan CuiChinese Academy of Medical Sciences & Peking Union Medical College

Key Points

This study investigates the causal relationships between circulating inflammatory proteins and Fuchs endothelial corneal dystrophy (FECD).
Bidirectional two-sample Mendelian randomization analysis using inflammatory protein summary statistics (N=14,824) and FECD data (N=448,712) from the GWAS Catalog.
Key findings were validated in two independent datasets and analyzed through meta-analysis.
Differential gene expression profiles were explored using GEO datasets and an in vitro assay.
Initial MR analysis identified three potential causal links, with TNFRSF11B showing a robust risk effect (odds ratio = 1.193; 95% CI, 1.039-1.369; P-meta = 0.01212).
MIP-1β and NRTN had marginal or inconsistent replication significance.
Transcriptomic profiling confirmed elevated TNFRSF11B expression in affected tissues and increased expression in human corneal endothelial cells upon H2O2 exposure.

Abstract

Purpose: Fuchs endothelial corneal dystrophy (FECD) is an age-related ocular disorder characterized by gradual loss of corneal endothelial cells, with growing evidence implicating chronic inflammation in its pathogenesis. This study aims to investigate causal relationships between circulating inflammatory proteins (IPs) and FECD. Methods: We performed bidirectional two-sample Mendelian randomization (MR) analysis using IP summary statistics (N = 14,824) and FECD data from the GWAS Catalog (N = 448,712). Key findings were then validated in two independent FECD datasets and subjected to meta-analysis. Differential gene expression profiles were explored using GEO datasets and an in vitro assay. Results: The initial MR analysis identified potential causal links for three IPs. Only TNFRSF11B demonstrated a robust risk effect confirmed by a subsequent cross-cohorts meta-analysis (odds ratio = 1.193; 95% confidence interval, 1.039-1.369; P-meta = 0.01212). In contrast, the associations for MIP-1β and NRTN were limited by marginal statistical significance and inconsistent replication directions, respectively. Transcriptomic profiling further confirmed elevated TNFRSF11B expression in FECD-affected tissues. TNFRSF11B expression was also increased in human corneal endothelial cells upon H2O2 exposure in vitro. Conclusions: This study highlights the involvement of inflammatory pathways in FECD pathogenesis and identifies genetically predicted TNFRSF11B levels as a robust risk factor. Supported by consistent meta-analysis and expression validation, TNFRSF11B emerges as a high-priority candidate biomarker and a plausible therapeutic target worthy of further investigation. Translational Relevance: Our findings advance the understanding of the genetic architecture of inflammatory mechanisms in FECD and provide a strong rationale for exploring TNFRSF11B inhibition as a novel therapeutic strategy.

问 AI

Bookmark

View Full Paper