What question did this study set out to answer?

The aim is to identify genetic variants influencing progression to different types of diabetic retinopathy or protection against advanced cases.

June 7, 2026

1007-OR: Genetic Modifiers of Phenotypic Divergence in Diabetic Retinopathy

Puntos clave

The aim is to identify genetic variants influencing progression to different types of diabetic retinopathy or protection against advanced cases.
Applied extreme phenotype genomic approaches in cohorts with isolated PDR, isolated DME, and long-duration diabetes.
Employ genetic analyses, including whole-exome sequencing and stringent quality control measures.
Conducted pathway annotation and burden testing to assess rare variants' impact.
Distinct rare-variant architectures characterize PDR and DME, with a higher burden of variants in PDR linked to immune and inflammatory pathways.
DME-associated and protective variants are enriched in pathways related to vascular barrier integrity and anti-inflammatory processes.
Shared inflammation-associated genes suggest a convergent state influenced by specific rare variants.

Resumen

Introduction and Objective: Diabetic retinopathy (DR) exhibits pronounced phenotypic heterogeneity, with most affected cases developing either proliferative diabetic retinopathy (PDR) or diabetic macular edema (DME), while others remain protected to advanced DR despite long duration of diabetes. This divergence suggests genetic modifiers influence susceptibility or protection. We aimed to identify genetic variants and pathways driving progression to PDR, DME, or long-term protection against advanced DR. Methods: We applied extreme phenotype genomic approaches in deeply phenotyped cohorts with isolated PDR, isolated DME, or long-duration diabetes (20 years) with minimal or no DR. DR severity was graded on ultrawide-field images using ETDRS criteria by masked readers. Whole-exome or whole-genome sequencing was followed by stringent quality control, rare-variant filtering, burden testing, gene-level aggregation, exome-wide association, SKAT analyses, and pathway and network annotation. Results: Distinct rare-variant architectures characterized PDR and DME. PDR showed a higher burden of predicted high-impact variants enriched in immune, inflammatory, metabolic, and angiogenic pathways. In contrast, DME-associated and DR-protective variants were enriched in pathways related to vascular barrier integrity, sensory signaling, and anti-inflammatory or antiproliferative processes. Protective variants were enriched in the No DR cohort, particularly in genes involved in innate immunity and cellular stress responses (TLR5, RNASEL, STIM1, EDA2R, OSBPL1A), concordant with reduced systemic cytokine levels. Despite phenotypic differences, a shared core of inflammation associated genes emerged, indicating a convergent inflammatory state shaped by phenotype specific rare variants. Conclusion: Our study indicate that functional genetic variation modulates DR outcomes, distinguishing progression to PDR or DME and DR progression. These phenotype-specific biomarkers facilitate precise risk stratification and the development of targeted interventions. Disclosure S. Rangasamy: None. C. Legendre: None. J. Don: None. D. Subramani: None. F. Monickaraj: None. N. Schork: None. D. Duggan: None. J. Sun: Research Support; Current; Adaptive Sensory Technology. Other - Research support and food at meeting; Current; Boehringer Ingelheim International GmbH. Research Support; Current; Roche Pharmaceuticals. Research Support; Ended; Genentech, Inc. Research Support; Current; LKC Technologies, Konan. Other - Research support and food at meeting; Current; Novo Nordisk. Research Support; Current; Optovue, Incorporated. Research Support; Ended; Physical Sciences, Inc. Other - Food at meeting; Ended; Alcon. L.P. Aiello: Advisory Panel; Current; Optos plc. Research Support; Current; Boehringer Ingelheim International GmbH. Consultant; Current; Ceramedix. A. Das: None. Funding NIH 1R01EY028606

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