Identifying causal genetic markers and cellular mechanisms in diabetic retinopathy through single-cell sc-eQTL analysis and Mendelian randomization.

Diabetic retinopathy (DR) requires robust biomarkers. To overcome the limitations of bulk sequencing, we integrated single-cell eQTL mapping with Mendelian randomization to identify causal cell populations and genes. CD8 Teff cells were expanded in peripheral blood, showing elevation in non-DR diabetes and reaching maximal levels in DR. Mendelian randomization analysis implicated IL2RB as a putative causal marker, with the lead eQTL SNP rs3184504 demonstrating strong association (p = 8.5467 × 10-18). Colocalization analysis with DR GWAS and validation in bulk data reinforced this signal. In tissues, CellChat predicted more interactions for IL2RB+ compared to IL2RB- CD8 Teff cells, including IL16-CD4 with macrophages and NAMPT interactions with both ITGA5+ITGB1 and INSR on endothelial cells, implicating immune-vascular regulation. Together, these findings nominate IL2RB as a biomarker and therapeutic target while clarifying mechanisms underlying DR.