Blood DNA methylation markers are associated with diabetic kidney disease progression in type 1 diabetes
Year: 2026
Type: article
Study design: Observational Study
Abstract: Aims/hypothesis DNA methylation has been shown to be associated with kidney function and diabetic kidney disease (DKD), but prospective studies are scarce. Therefore, we conducted epigenome-wide association studies (EWASs) on early- and late-stage DKD progression using DNA methylation data obtained by analysing baseline blood samples from participants in the Finnish Diabetic Nephropathy Study type 1 diabetes cohort. Methods We included 403 individuals with normal AER (early-stage progression group) and 372 individuals with severe albuminuria (late-stage progression group), and followed up DKD progression, defined as a decrease in eGFR to <60 ml/min per 1.73 m 2 in the early-stage progression group, and end-stage kidney disease (ESKD) in the late-stage group. Replication was conducted in two type 1 diabetes cohorts in addition to publicly available EWAS summary statistics from diabetes and general population cohorts. Significant loci were further characterised by integration with genetic and proteomic data. Results We identified 11 methylation sites associated with DKD progression ( p <9.4 × 10 −8 ). Methylation at cg01730944 near the podocyte-specific gene CDKN1C and three other CpGs associated with early-stage DKD progression were independent of baseline eGFR, whereas late-stage progression CpGs were strongly associated with eGFR. The identified lead ESKD risk locus cg17944885 (chr19p13.2, p =2.6 × 10 −17 ) and several novel methylation sites associated with late-stage DKD progression were supported by the results of previous studies. Proteomic analysis of cis proteins identified potential target genes for two CpGs: cg14999724 methylation was associated with PRG3 and PRG2, and cg12272104 was associated with BSG, FSTL3 and PALM. Furthermore, UK Biobank data show associations between these proteins and severe kidney endpoints. Finally, survival models that included methylation markers in addition to clinical risk factors significantly improved the identification of individuals at risk of early-stage DKD progression. Conclusions/interpretation The current study detected 11 loci associated with DKD progression, identifying methylation changes predictive of early-stage DKD progression in type 1 diabetes for the first time. Future research is needed to establish prognostic DNA methylation markers for DKD progression. Graphical Abstract
Source: Diabetologia
Institutions: University of Helsinki, Helsinki University Hospital, Folkhälsans Forskningscentrum, Queen's University Belfast, City Of Hope National Medical Center, City of Hope, Beckman Research Institute, Joslin Diabetes Center, Harvard University, Broad Institute, Boston Children's Hospital, Massachusetts General Hospital, Baker Heart and Diabetes Institute, Monash University
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,490
Funders: Foundation for the National Institutes of Health, Helsingin Yliopisto, Wilhelm och Else Stockmanns Stiftelse, Medicinska Understödsföreningen Liv och Hälsa, Finska Läkaresällskapet, Folkhälsanin Tutkimussäätiö, Academy of Finland, China Scholarship Council, Sigrid Juséliuksen Säätiö, Novo Nordisk Fonden, Diabetestutkimussäätiö, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases
OpenAlex ID: W7125435985