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.