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oai:figshare.com:article/33467938 2026-10-01T16:55:46Z category_24454 portal_785 item_type_1 month_year_10_2026

<b>Blood-Derived DNA Methylation Biomarkers Predict Diabetic Kidney Disease and Map to Epigenomic Remodeling in Renal Cells</b> Ishant Khurana (818321) Tine Willum Hansen (24725261) Frederik Persson (4242010) Sørine Birkelund (9651637) Tarunveer Singh Ahluwalia (373447) Scott Maxwell (4835985) Ram Abou Zaki (21482681) Harikrishnan Kaipananickal (14703973) Sargunpreet Singh Gill (24725292) John Nazli (24725302) Simone Theilade (4535881) Vina Margaretha Miguna (24725303) Nete Tofte (7928177) Evy Connie Ottesen (24725311) Peter Rossing (135121) Assam El-Osta (182253) Other biological sciences not elsewhere classified Type 1 Diabetes DNA Methylation Kidney Disease Epigenetics Risk Scores <p dir="ltr"><a href="" target="_blank">Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease in type 1 diabetes (T1D), yet albuminuria and eGFR lack precision 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 non-diabetic controls, stratified by KDIGO risk and followed for a median of 5.6 years. Differentially methylated regions were identified across baseline KDIGO strata and prioritised based on hypomethylation, ≥4 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; <i>SLC4A4</i>, <i>FSTL4</i>, <i>ICA1</i>, <i>PTK2</i>), validated by targeted assays in an independent subset of 330 T1D participants with low or moderate KDIGO risk at baseline. T1D showed global loss of 5-methylcytosine with hypomethylated regions enriched at regulatory sites. In the discovery cohort, the combined MRS+clinical model discriminated baseline KDIGO moderate-risk and high/very-high-risk strata (AUC 0.91 and 0.86, respectively). In the independent validation cohort, the four-locus MRS predicted DKD progression within baseline LR and MR 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.</a></p> 2026-10-01T16:55:46Z Image Figure 10.2337/figshare.33467938.v1 https://figshare.com/articles/figure/_b_Blood-Derived_DNA_Methylation_Biomarkers_Predict_Diabetic_Kidney_Disease_and_Map_to_Epigenomic_Remodeling_in_Renal_Cells_b_/33467938 CC BY-NC-SA 4.0