Long-Term Impact of Cumulative Hyperglycaemia on DNA Methylation and its Role in Diabetic Kidney Disease
Luo, X.; Syreeni, A.; Hill, C.; Smyth, L. J.; Dahlstrom, E. H.; Mutter, S.; Chen, Z.; Natarajan, R.; Pan, S.; Parton, A.; Jackson, H.; McKay, G.; Susztak, K.; Hirschhorn, J. N.; Florez, J. C.; Maxwell, A. P.; Groop, P.-H.; McKnight, A. J.; Sandholm, N.
Show abstract
Hyperglycaemia is a hallmark of diabetes and a major risk factor for diabetic kidney disease (DKD). However, the molecular consequences of long-term cumulative hyperglycaemia (CH) remain unclear. As a stable epigenetic modification, DNA methylation may capture past glycaemic exposure. Here, we assessed CH-associated DNA methylation in 1,245 participants with type 1 diabetes (T1D) from Finland and the United Kingdom-Republic of Ireland cohorts. We identified 17 CH-associated CpGs, with the strongest association at cg19693031 (TXNIP). Longitudinal analyses demonstrate that these CH-associated DNA methylation levels remain stable despite short-term glycaemic fluctuations, suggesting lasting epigenetic imprints of earlier metabolic control. Integrative analyses combining genomic, epigenetic, and proteomic data characterized these CpGs and potential target proteins. Mendelian randomization suggested a causal association between cg20853880 (KLF11) and DKD, supported by chromatin accessibility and kidney KLF11 expression. Our findings suggest that epigenetic changes contribute to metabolic memory and may mediate the effects of hyperglycaemia on DKD.
Matching journals
The top 3 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Epigenome-wide association study of incident type 2 diabetes in Black and White participants from the Atherosclerosis Risk in Communities Study 94%
- Circulating Metabolites in Progression to Islet Autoimmunity and Type 1 Diabetes 92%
- The power of TOPMed imputation for the discovery of Latino enriched rare variants associated with type 2 diabetes 92%
Similar papers in this journal
Similar papers in this journal
- An atlas of genetic effects on the monocyte methylome across European and African populations 92%
- Type 2 Diabetes risk alleles in Peptidyl-glycine Alpha-amidating Monooxygenase influence GLP-1 levels and response to GLP-1 Receptor Agonists 91%
- Longitudinal analysis of genetic and environmental interplay in human metabolic profiles and the implication for metabolic health 89%
Similar papers in this journal
- Kidney-specific methylation patterns correlate with kidney function and are lost upon kidney disease progression 91%
- Transcriptional, epigenetic and metabolic signatures in cardiometabolic syndrome defined by extreme phenotypes. 90%
- Epigenetic clocks predict prevalence and incidence of leading causes of death and disease burden 89%
Similar papers in this journal
- Specific type 1 diabetes risk genes underpin age-at-diagnosis and indicate joint defects in immunity, beta-cell fragility and responses to viral infections in early-onset disease. 90%
- Exploring diseases/traits and blood proteins causally related to expression of ACE2, the putative receptor of SARS-CoV-2: A Mendelian Randomization analysis highlights tentative relevance of diabetes-related traits 90%
- The impact of ancestry on performance of type 1 diabetes genetic risk scores: high discrimination performance is maintained in African ancestry populations, but population specific thresholds may improve risk prediction 90%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.