Genetic Evidence Supporting a Causal Association Between mTORC1-Dependent Circulating Protein Levels and Diabetic Retinopathy.

PURPOSE

The mechanistic target of rapamycin (mTOR) signaling pathway is essential for the onset and progression of diabetic retinopathy (DR). Nevertheless, the impact of mTORC1 downstream proteins in DR remains uncertain. Therefore, we performed a Mendelian randomization (MR) research to assess the causal effect of downstream mTORC1 proteins on DR risk.

METHODS

Summary statistics on mTORC1 downstream proteins and DR were obtained from the INTERVAL and FinnGen studies (14,584 patients and 176,010 controls), respectively. We used various MR techniques, including inverse-variance-weighted, weighted median, and MR-Egger. Possible pleiotropy and heterogeneity were identified through sensitivity analysis.

RESULTS

Genetically predicted eIF4E was positively correlated to DR risk (odds ratio = 1.057; 95% confidence interval, 1.008-1.109; P = 0.022]. No relationship has been shown for circulating RP-S6K, eIF4G, eIF4A, eIF4E-BP and eIF4B levels with DR formation. There was no heterogeneity or unbalanced level pleiotropy identified.

CONCLUSIONS

Higher levels of serum eIF4E promote the progression of DR, proposing that pharmacological inhibition of eIF4E activity may be a prospective DR therapeutic strategy.

TRANSLATIONAL RELEVANCE

The present study has highlighted the role of eIF4E in the development of DR, establishing the foundation for basic research into DR targets.