Multiomics Integration Prioritizes ZFP36L1 as a Candidate Susceptibility Gene Associated With Inflammatory and...

Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes and a leading cause of blindness despite available therapies, underscoring the need for novel therapeutic targets.

Integrated multiomics analysis combining (1) exploratory single-cell RNA sequencing of rat retinal tissues (three DRs vs. two controls), (2) Mendelian randomization (MR) using whole-blood eQTL data and DR GWAS data (14,584 cases vs. 202,082 controls), and (3) supportive RT-qPCR validation in peripheral-blood clinical samples (30 DRs vs. 30 controls).

(1) Genetic causality was as follows: MR analysis demonstrated ZFP36L1 as a novel DR risk gene (OR = 1.156, 95% CI = 1.054-1.269, p = 0.002), with significant upregulation in patient blood samples (p < 0.0001). (2) Inflammatory regulation was as follows: ZFP36L1 showed strong correlations with proinflammatory markers (TNF-α and IL-6) and immune cell infiltration (parainflammation and Tregs), while negatively correlating with B cells. (3) Pathway mechanisms were as follows: Functional enrichment analyses suggested potential links between ZFP36L1 and NF-κB-related inflammatory signaling as well as TGF-β-related angiogenic pathways. Despite its known VEGF mRNA destabilizing function, we observed a positive ZFP36L1-VEGF correlation (r = 0.180, p < 0.001), an unexpected finding under diabetic conditions.

ZFP36L1 is a candidate DR susceptibility gene whose genetically regulated expression in blood is associated with DR risk. Retinal single-cell and pathway analyses provide supportive, hypothesis-generating evidence that ZFP36L1 may be linked to inflammatory and angiogenic processes relevant to DR. Further retina-specific and functional studies are required to determine whether ZFP36L1 directly regulates retinal inflammation or angiogenesis in human DR.