{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T05:42:45Z","timestamp":1792215765369,"version":"4.4.0"},"reference-count":112,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Diabetic retinopathy (DR), a complication of type 2 diabetes mellitus (T2DM), is typically asymptomatic in its early stages. Diagnosis typically relies on routine fundoscopy for the clinical detection of microvascular abnormalities. However, permanent retinal damage may occur well before clinical signs are appreciable. In the early stages of DR, the retina undergoes distinct epigenetic changes, including DNA methylation and histone modifications. Recent evidence supports unique epigenetic \u2018signatures\u2019 in patients with DR compared to non-diabetic controls. These DNA \u2018signature\u2019 sequences may be specific to the retina and may circulate in peripheral blood in the form of cell-free DNA (cfDNA). In this review, we explore the literature and clinical application of cfDNA sampling as an early, non-invasive, accessible assessment tool for early DR detection. First, we summarize the known epigenetic signatures of DR. Next, we review current sequencing technologies used for cfDNA detection, such as magnetic bead-based enrichment, next-generation sequencing, and bisulfite sequencing. Finally, we outline the current research limitations and emerging areas of study which aim to improve the clinical utility of cfDNA for DR evaluation.<\/jats:p>","DOI":"10.3390\/diagnostics15091161","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T11:35:13Z","timestamp":1746185713000},"page":"1161","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Circulating Cell-Free DNA as an Epigenetic Biomarker for Early Diabetic Retinopathy: A Narrative Review"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6834-9466","authenticated-orcid":false,"given":"Boaz","family":"Li","sequence":"first","affiliation":[{"name":"Faculty of Medicine, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan M.","family":"Yim","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2200-2984","authenticated-orcid":false,"given":"Yu Xuan","family":"Jin","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7069-3162","authenticated-orcid":false,"given":"Brendan K.","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5S 2L9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jim S.","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5S 2L9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5948-0331","authenticated-orcid":false,"given":"Michael","family":"Balas","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5S 2L9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haaris","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, The University of British Columbia, Vancouver, BC V5Z 3N9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wai-Ching","family":"Lam","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, The University of British Columbia, Vancouver, BC V5Z 3N9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5S 2L9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5525-1913","authenticated-orcid":false,"given":"Eduardo V.","family":"Navajas","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, The University of British Columbia, Vancouver, BC V5Z 3N9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"556","DOI":"10.2337\/dc11-1909","article-title":"Global Prevalence and Major Risk Factors of Diabetic Retinopathy","volume":"35","author":"Yau","year":"2012","journal-title":"Diabetes Care"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1001\/archopht.1984.01040030405011","article-title":"The Wisconsin Epidemiologic Study of Diabetic Retinopathy. 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