Accelerated Epigenetic Ageing in Diabetic Kidney Disease: A Comparison of 10 Epigenetic Clock Measures in Individuals With Type 1 Diabetes

To characterize accelerated epigenetic ageing in individuals with diabetic kidney disease (DKD) and type 1 diabetes, 10 epigenetic clocks were generated for those with type 1 diabetes, with (case patients) or without (control participants) DKD, within the All Ireland–Warren 3–Genetics of Kidneys in Diabetes UK and Belfast Renal Transplant (UK-RoI; n = 464) and Finnish Diabetic Nephropathy (FinnDiane; n = 795) cohorts. Experimentally derived and epigenetically predicted telomere(definition) lengths (TLs) were also compared. This study revealed that higher PhenoAge and shorter epigenetically predicted TL were associated with increased DKD risk (principal component [PC] with z score version (zPC) of PhenoAge: odds ratio [OR] 1.4 [95% CI 1.2–1.8]; P = 2.47 × 10−4 in UK-ROI and OR 1.8 [95% CI 1.5–2.1]; P = 2.30 × 10−12 in FinnDiane; zPC–DNA methylation TL: OR 0.6 [95% CI 0.5–0.8]; P = 7.28 × 10−6 in UK-ROI and OR 0.7 [95% CI 0.6–0.8]; P = 1.40 × 10−6 in FinnDiane); age, white cell proportion, and sex adjusted). Case patients were epigenetically older than control participants by ∼2 years (PC-PhenoAge). Results suggested a male-specific association between DunedinPACE–epigenetic age acceleration (EAA) and DKD (OR 1.3 [95% CI 1.0–1.7]; P = 0.026 in UK-ROI and OR 1.5 [95% CI 1.3–1.8]; P = 1.46 × 10−6 in FinnDiane). Longitudinal analyses included 1) methylation at two time points a median of 7.5 years apart (n = 2 × 52) and 2) Cox regression for DKD progression in 384 case participants (median follow-up 7.7 years). Progression from normolbuminuria to severely increased albuminuria was associated with increased EAA. Chronologic age, epigenetic age, and EAA (PhenoAge-EAA P = 0.0011; hazard ratio 1.07 [95% CI 1.03–1.11] per year; C-index = 0.67) were significant predictors of progression to end-stage kidney disease (ESKD). Epigenetic biomarkers demonstrate accelerated biological ageing associated with DKD and progression to ESKD. Article Highlights We investigated whether an association existed between epigenetic age acceleration (EAA) and diabetic kidney disease (DKD) in type 1 diabetes, using 10 clocks and two cohorts, and whether this amplified disease progression. Older EAA phenotypic age and shorter epigenetically predicted telomere lengths were significantly associated with DKD. Progression from normolbuminuria to severely increased albuminuria was associated with increased EAA, and age, epigenetic age, and EAA were significant predictors of progression to end-stage kidney disease. Results support the development of epigenetic biomarkers predicting DKD onset and progression.