{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:59:04Z","timestamp":1790877544993,"version":"4.1.0"},"reference-count":0,"publisher":"American Diabetes Association","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"name":"Novo Nordisk Foundation","award":["NNF18OC0052457"],"award-info":[{"award-number":["NNF18OC0052457"]}],"id":[{"id":"https:\/\/ror.org\/04txyc737","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Novo Nordisk Foundation","award":["READ-GEN"],"award-info":[{"award-number":["READ-GEN"]}],"id":[{"id":"https:\/\/ror.org\/04txyc737","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Danish Diabetes and Endocrinology Academy","award":["NNF17SA0031406"],"award-info":[{"award-number":["NNF17SA0031406"]}]},{"name":"Australian NHMRC","award":["AEO 1154650"],"award-info":[{"award-number":["AEO 1154650"]}]},{"name":"Australian National Health and Medical Research Council -Clinical Trials and Cohort Studies","award":["3-SRA-2024-1593-A-N"],"award-info":[{"award-number":["3-SRA-2024-1593-A-N"]}],"id":[{"id":"https:\/\/ror.org\/011kf5r70","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Australian National Health and Medical Research Council -Clinical Trials and Cohort Studies","award":["Breakthrough T1D"],"award-info":[{"award-number":["Breakthrough T1D"]}],"id":[{"id":"https:\/\/ror.org\/011kf5r70","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Australian National Health and Medical Research Council -Clinical Trials and Cohort Studies","award":["NHMRC -CTCS: 2014763"],"award-info":[{"award-number":["NHMRC -CTCS: 2014763"]}],"id":[{"id":"https:\/\/ror.org\/011kf5r70","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease in type 1 diabetes (T1D); however, albuminuria and estimated glomerular filtration rate (eGFR) lack the precision necessary for early prognostication. We sought blood-derived DNA methylation biomarkers that predict DKD progression and reflect renal epigenomic remodeling. In the PROFIL cohort, we performed high-depth genome-wide methylation sequencing of leukocyte DNA from 101 adults with T1D and 20 control participants without diabetes, stratified by Kidney Disease: Improving Global Outcomes (KDIGO) risk and observed for a median of 5.6 years. Differentially methylated regions were identified across baseline KDIGO strata and prioritized based on hypomethylation, four or more CpGs per region, and discrimination between KDIGO categories; their associations with eGFR decline and rising albumin excretion were then evaluated. From these candidates, we derived a four-locus methylation risk score (MRS; SLC4A4, FSTL4, ICA1, and PTK2), validated by targeted assays in an independent subset of 330 participants with T1D with low or moderate KDIGO risk at baseline. Those with T1D showed global loss of 5-methylcytosine, with hypomethylated regions enriched at regulatory sites. In the discovery cohort, the combined MRS plus clinical model discriminated baseline KDIGO moderate- and high\/very-high-risk strata (areas under the curve 0.91 and 0.86, respectively). In the independent validation cohort, the four-locus MRS predicted DKD progression within baseline low- and moderate-risk categories and improved risk stratification beyond clinical covariates, including eGFR and albumin excretion. In human podocytes, high glucose induced locus-specific hypomethylation, altered chromatin binding, and increased expression of MRS genes. These findings support a four-locus MRS for earlier, mechanistically grounded DKD risk stratification in T1D.<\/jats:p>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>We undertook this study because albuminuria and estimated glomerular filtration rate often identify diabetic kidney disease risk only after substantial kidney injury in type 1 diabetes. We asked whether blood DNA methylation patterns could predict future DKD progression and improve clinical risk stratification. Genome-wide leukocyte methylation sequencing identified hypomethylated regions and a four-locus methylation risk score (SLC4A4, FSTL4, ICA1, and PTK2) that improved prediction beyond clinical risk models and was validated in 330 participants. Podocyte multiomics showed concordant hyperglycemia-induced hypomethylation and gene activation, supporting the biological plausibility of the blood-derived risk score.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db26-0015","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:17:36Z","timestamp":1790875056000},"update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":0,"title":["Blood-Derived DNA Methylation Biomarkers Predict Diabetic Kidney Disease and Map to Epigenomic Remodeling in Renal Cells"],"prefix":"10.2337","author":[{"given":"Ishant","family":"Khurana","sequence":"first","affiliation":[{"name":"1Epigenetics in Human Health and Disease Program, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia"},{"name":"2Central Clinical School, Department of Diabetes, Monash University, Melbourne, Victoria, Australia"},{"name":"3Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, Victoria, Australia"},{"name":"4Department of Technology, Biomedical Laboratory Science, Faculty of Health, University College Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tine Willum","family":"Hansen","sequence":"additional","affiliation":[{"name":"5Steno Diabetes Center, Copenhagen, Denmark"},{"name":"6Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Persson","sequence":"additional","affiliation":[{"name":"5Steno Diabetes Center, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00f8rine","family":"Birkelund","sequence":"additional","affiliation":[{"name":"1Epigenetics in Human Health and Disease Program, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarunveer","family":"Singh Ahluwalia","sequence":"additional","affiliation":[{"name":"5Steno Diabetes Center, Copenhagen, Denmark"},{"name":"7Bioinformatics Center, Department of Biology, University of Copenhagen, Copenhagen, Denmark"},{"name":"8Department of Science and Environment, Roskilde University, Roskilde, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Maxwell","sequence":"additional","affiliation":[{"name":"1Epigenetics in Human Health and Disease Program, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia"},{"name":"2Central Clinical School, Department of Diabetes, Monash University, Melbourne, Victoria, Australia"},{"name":"4Department of Technology, Biomedical Laboratory Science, Faculty of Health, University College Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram Abou","family":"Zaki","sequence":"additional","affiliation":[{"name":"1Epigenetics in Human Health and Disease Program, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia"},{"name":"2Central Clinical School, Department of Diabetes, Monash University, Melbourne, Victoria, Australia"},{"name":"3Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, Victoria, Australia"},{"name":"9Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harikrishnan","family":"Kaipananickal","sequence":"additional","affiliation":[{"name":"1Epigenetics in Human Health and Disease Program, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sargunpreet Singh","family":"Gill","sequence":"additional","affiliation":[{"name":"1Epigenetics in Human Health and Disease Program, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Nazli","sequence":"additional","affiliation":[{"name":"1Epigenetics in Human Health and Disease Program, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Theilade","sequence":"additional","affiliation":[{"name":"5Steno Diabetes Center, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vina Margaretha","family":"Miguna","sequence":"additional","affiliation":[{"name":"1Epigenetics in Human Health and Disease Program, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nete","family":"Tofte","sequence":"additional","affiliation":[{"name":"5Steno Diabetes Center, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evy Connie","family":"Ottesen","sequence":"additional","affiliation":[{"name":"5Steno Diabetes Center, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1531-4294","authenticated-orcid":false,"given":"Peter","family":"Rossing","sequence":"additional","affiliation":[{"name":"5Steno Diabetes Center, Copenhagen, Denmark"},{"name":"6Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7968-7375","authenticated-orcid":false,"given":"Assam","family":"El-Osta","sequence":"additional","affiliation":[{"name":"1Epigenetics in Human Health and Disease Program, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia"},{"name":"2Central Clinical School, Department of Diabetes, Monash University, Melbourne, Victoria, Australia"},{"name":"3Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, Victoria, Australia"},{"name":"4Department of Technology, Biomedical Laboratory Science, Faculty of Health, University College Copenhagen, Copenhagen, Denmark"},{"name":"5Steno Diabetes Center, Copenhagen, Denmark"},{"name":"9Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon"},{"name":"10Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong SAR, China"},{"name":"11Hong Kong Institute of Diabetes and Obesity, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2026,10,1]]},"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/doi\/10.2337\/db26-0015\/897734\/db260015.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/doi\/10.2337\/db26-0015\/897734\/db260015.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:17:38Z","timestamp":1790875058000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/doi\/10.2337\/db26-0015\/172713\/Blood-Derived-DNA-Methylation-Biomarkers-Predict"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":0,"URL":"https:\/\/doi.org\/10.2337\/db26-0015","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]},"article-number":"db260015"}}