Genetic Susceptibility and Genetic Variant-Diet Interactions in Diabetic Retinopathy: A Cross-Sectional Case-Control...

Area of Science:

• Genetics
• Ophthalmology
• Metabolic Diseases

Background:

• Diabetic retinopathy (DR) is a major cause of blindness in diabetes patients.
• Genetic and environmental factors contribute to DR susceptibility.
• Identifying novel genetic variants and their interactions is crucial for understanding DR pathogenesis.

Purpose of the Study:

• Identify novel genetic variants associated with DR in a Korean population.
• Evaluate interactions between polygenic risk scores (PRS) and lifestyle factors in DR development.
• Explore potential shared mechanisms between DR and neurodegenerative diseases.

Main Methods:

• Genome-wide association studies (GWAS) comparing diabetic retinopathy (DM-DR) and non-retinopathy (DM-NR) groups.
• Generalized multifactor dimensionality reduction (GMDR) for epistatic interaction analysis.
• Development of polygenic risk scores (PRS) and analysis of PRS-lifestyle interactions.

Main Results:

• Five novel genetic variants (ABCA4, MMP2-AS1, FOXP1, MRPS33, DRD2) associated with DR were identified.
• A significant three-way epistatic interaction was found among ABCA4, MMP2-AS1, and FOXP1 variants.
• High PRS individuals exhibited a 49-fold increased odds of DR; PRS-lifestyle interactions modified genetic risk.
• Enrichment in protein degradation, vascular, and neuronal signaling pathways, particularly in brain tissues.

Conclusions:

• Novel genetic variants and epistatic interactions contribute to DR pathogenesis.
• PRS-based risk stratification enables personalized monitoring and lifestyle interventions.
• Shared mechanisms with neurodegenerative diseases suggest novel therapeutic targets for DR.