Lipidome's Role in Diabetic Retinopathy Subtypes via Inflammation: Mendelian Randomization and Mediation Analysis
Xiaotong Xu1,2,3,4, Nianen Liu5,6, Kaixuan Dong1,7
1Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Ophthalmology Science
|November 24, 2025
Summary
Specific plasma lipids, particularly phosphatidylcholines and phosphatidylethanolamines, protect against diabetic retinopathy (DR). Inflammatory cytokines mediate these lipid effects, offering potential therapeutic targets for DR management.
Area of Science:
- Genetics and Molecular Biology
- Metabolic Disorders
- Ophthalmology
Background:
- Diabetic retinopathy (DR) is a leading cause of vision loss, with complex pathogenesis involving lipid metabolism and inflammation.
- Understanding the causal links between plasma lipids, inflammatory cytokines, and DR subtypes is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the causal relationships between plasma lipidome, inflammatory cytokines, and diabetic retinopathy (DR) subtypes.
- To elucidate the mediating role of inflammatory cytokines in the association between lipid species and DR.
Main Methods:
- Utilized a two-sample Mendelian randomization (MR) approach with genome-wide association study (GWAS) data for 179 plasma lipid species and 91 inflammatory cytokines.
- Employed mediation analysis to quantify the extent to which inflammatory cytokines mediate the effects of lipids on DR subtypes.
- Conducted sensitivity analyses using multiple methods (e.g., inverse-variance weighted, weighted median, MR-Egger) to ensure robustness of causal estimates.
Main Results:
- Most identified plasma lipids, primarily phosphatidylcholines and phosphatidylethanolamines, showed a protective effect against DR and its subtypes.
- Triacylglycerols exhibited varied roles depending on DR severity, and inflammatory cytokines displayed distinct causal effects on DR and its subtypes.
- Mediation analyses revealed 10 pathways where inflammatory cytokines mediate lipid effects on DR, with some pathways showing significant mediating effects.
Conclusions:
- The study underscores the intricate interplay between lipid metabolism and inflammation in DR pathogenesis.
- Specific lipid species demonstrate a protective role against DR, with inflammatory cytokines acting as key mediators.
- These findings suggest potential novel therapeutic targets for managing diabetic retinopathy.
