In:
Diabetes, American Diabetes Association, Vol. 73, No. Supplement_1 ( 2024-06-14)
Abstract:
Introduction & Objective: Our prior research has shown a clear distinction between two types of diabetic retinopathy (DR): predominantly exudative diabetic macular edema (DME) and predominantly proliferative diabetic retinopathy (PDR). These clinical presentations often occur separately, with a large percentage of patients (85% for PDR, 80% for DME) not showing signs of the other type. This suggests that DME and PDR may not be a single disease entity that progresses linearly but rather distinct diseases driven by different molecular mechanisms and genetic factors. Methods: We analyzed two distinct patient groups: i) only PDR and no signs of DME (n=182), and the other with only center-involving DME and no PDR (n =77). The severity of PDR was graded using the ETDRS standard protocol on ultrawide field retinal images. Whole-exome and whole-genome sequencing were performed to identify genetic factors, and a novel algorithm was used to evaluate the impact of coding variants in the cohort. Results: Comparative analysis of patients with exclusive manifestations of PDR compared to DME revealed a unique genetic framework differentiating the two cohorts. Notably, the prevalence of rare functional variants was significantly elevated in the PDR group (p & lt;0.05). We discovered functional variants in genes, including CD36, MMRN2, EPHB2, PLAUR, and RAPGEF3, which are enriched in the angiogenesis pathway. Phenotype-centric gene variant analysis underscored the role of MMRN2, a key player in angiogenesis (p & lt;0.001). MMRN2 (Multimerin-2) is a crucial regulator of endothelial cell movement, functioning as a negative modulator of angiogenesis by inhibiting KDR activation through its interaction with VEGFA. Conclusions: Rare functional variants may act as phenotype modifiers, potentially modulating the trajectory of DR into DME or PDR. Functional validation of these factors could represent new biomarkers and therapeutic targets for DR. Disclosure S. Rangasamy: None. F. Monickaraj: None. J.K. Sun: Research Support; Optovue, Boehringer-Ingelheim, Novo Nordisk, Roche Pharmaceuticals. Other Relationship; Roche Pharmaceuticals. Research Support; Physical Sciences, Inc, Boston Micromachines. L.P. Aiello: Advisory Panel; Novo Nordisk. Stock/Shareholder; Kalvista. Other Relationship; Optos. Consultant; Ceramedix. A. Das: None. Funding 5R01EY028606
Type of Medium:
Online Resource
ISSN:
0012-1797
Language:
English
Publisher:
American Diabetes Association
Publication Date:
2024
detail.hit.zdb_id:
1501252-9
