{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T14:29:18Z","timestamp":1776263358215,"version":"3.50.1"},"reference-count":56,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T00:00:00Z","timestamp":1758067200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF)","award":["RS-2023-00208567"],"award-info":[{"award-number":["RS-2023-00208567"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Diabetic retinopathy is a leading cause of blindness in diabetic patients, with disease susceptibility influenced by both genetic and environmental factors. This study aimed to identify novel genetic variants associated with DR and evaluate interactions between polygenic risk scores (PRS) and lifestyle factors in a Korean diabetic cohort. Methods: After excluding subjects with non-diabetic retinopathy eye diseases (n = 2519), we analyzed data from 50,361 non-diabetic controls, 4873 diabetic participants without retinopathy (DM-NR), and 165 with diabetic retinopathy (DM-DR). We conducted genome-wide association studies comparing DM-NR and DM-DR groups, performed generalized multifactor dimensionality reduction (GMDR) analysis for epistatic interactions, developed unweighted PRS models, and examined PRS\u2013lifestyle interactions using two-way analysis of covariance. Results: DM-DR prevalence showed strong associations with metabolic syndrome and its components. Five novel genetic variants were identified: ABCA4_rs17110929, MMP2-AS1_rs2576531, FOXP1_rs557869288, MRPS33_rs1533933, and DRD2_rs4936270. A significant three-way epistatic interaction among the first three variants was discovered through GMDR analysis. High-PRS individuals (scores 5\u20136) showed a 49-fold higher odds ratio of DM-DR compared to low-PRS individuals (scores 0\u20132; p &lt; 0.0001). MAGMA analysis revealed enrichment in pathways related to protein degradation, vascular function, and neuronal signaling, with predominant upregulation in brain tissues. Significant PRS \u00d7 lifestyle interactions were identified for fruit intake, coffee consumption, alcohol intake, eating duration, and physical activity, with lifestyle factors modifying genetic risk effects (all p &lt; 0.003). Conclusions: These findings identify novel genetic variants and epistatic interactions in DM-DR pathogenesis, supporting the use of PRS-based risk stratification for intensive monitoring and personalized lifestyle interventions. The discovery of brain tissue-enriched pathways suggests DM-DR shares mechanisms with neurodegenerative diseases, expanding therapeutic targets beyond traditional vascular approaches.<\/jats:p>","DOI":"10.3390\/nu17182983","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T14:10:19Z","timestamp":1758118219000},"page":"2983","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic Susceptibility and Genetic Variant-Diet Interactions in Diabetic Retinopathy: A Cross-Sectional Case\u2013Control Study"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6092-8340","authenticated-orcid":false,"given":"Sunmin","family":"Park","sequence":"first","affiliation":[{"name":"Department of Food and Nutrition, Obesity\/Diabetes Research Center, Hoseo University, Asan 31499, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suna","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Food and Nutrition, Obesity\/Diabetes Research Center, Hoseo University, Asan 31499, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donghyun","family":"Jee","sequence":"additional","affiliation":[{"name":"Division of Vitreous and Retina, Department of Ophthalmology, St. Vincent\u2019s Hospital, College of Medicine, The Catholic University of Korea, Suwon 16247, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1007\/s00125-023-05964-x","article-title":"Genetics of diabetes-associated microvascular complications","volume":"66","author":"Lyssenko","year":"2023","journal-title":"Diabetologia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1186\/s12933-023-01821-8","article-title":"Impact of individual microvascular disease on the risks of macrovascular complications in type 2 diabetes: A nationwide population-based cohort study","volume":"22","author":"Yen","year":"2023","journal-title":"Cardiovasc. 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