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

Area of Science:

• Genomics and Ophthalmology
• Multiomics research
• Diabetic complications

Background:

• Diabetic retinopathy (DR) is a leading cause of blindness.
• Current therapies for DR are insufficient, necessitating new therapeutic targets.
• Understanding the genetic and molecular underpinnings of DR is crucial.

Purpose of the Study:

• To identify novel genetic risk factors for diabetic retinopathy (DR).
• To investigate the molecular mechanisms linking genetic factors to DR pathogenesis.
• To explore the role of ZFP36L1 in inflammation and angiogenesis in DR.

Main Methods:

• Integrated multiomics analysis including single-cell RNA sequencing of rat retinal tissues.
• Mendelian randomization (MR) using eQTL and DR GWAS data.
• RT-qPCR validation in human peripheral blood samples.

Main Results:

• Mendelian randomization identified ZFP36L1 as a novel DR risk gene (OR = 1.156, p = 0.002).
• ZFP36L1 expression was significantly upregulated in DR patient blood (p < 0.0001) and correlated with inflammatory markers (TNF-α, IL-6).
• Functional analyses suggested links between ZFP36L1 and NF-κB inflammatory and TGF-β angiogenic pathways, with an unexpected positive correlation with VEGF.

Conclusions:

• ZFP36L1 is a candidate DR susceptibility gene with genetically regulated expression linked to DR risk.
• Retinal and pathway analyses suggest ZFP36L1 involvement in DR-related inflammation and angiogenesis.
• Further studies are needed to elucidate ZFP36L1's direct role in retinal pathophysiology in human DR.