Objective:

To examine the causal association between non-alcoholic fatty liver disease (NAFLD) and diabetic retinopathy (DR) and identify circulating proteins that may mediate this association.

Approach:

• Mendelian Randomization Framework: Utilized a multistage network MR framework incorporating NAFLD/DR genome-wide association study data and blood proteome-wide datasets.
• Statistical Analysis: Applied inverse-variance weighted regression and multimodal models to evaluate causal effects, alongside proteome-wide MR to identify proteins associated with DR.
• Single-Cell Sequencing: Verified transcriptional expression of identified mediator proteins in liver tissue.
• Clinical Sample Analysis: Measured mediator-protein levels in serum, aqueous humor, and vitreous humor samples from clinical patients.

Key Findings:

• NAFLD is associated with an increased risk of DR (OR = 1.04, 95% CI: 1.01-1.08) and specifically with progression of non-proliferative DR (NPDR) (OR = 1.26, 95% CI: 1.05-1.52).
• Four proteins were identified as candidate mediators of the NAFLD-DR association, with LTB showing the strongest effect.
• Increased LTB protein levels were found in the aqueous humor, vitreous humor, and serum of NAFLD patients with DR compared to those without.

Interpretation:

The study suggests a causal link between NAFLD and an increased risk of developing DR, particularly in early NPDR stages, with LTB potentially mediating this relationship.

Limitations:

• The study relies on genetic instruments, which may not capture all confounding factors.
• The findings are based on observational data, which may limit causal inferences.

Conclusion:

NAFLD is associated with a heightened risk of developing DR, with LTB as a potential mediator in this relationship.