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Abstract: TH-PO222

Significant Differential Methylation of Telomere-Related Genes in Diabetic Kidney Disease and Its Potential Role in Regulating Gene Expression and Wnt Signalling

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Hill, Claire, Centre for Public Health, Queen's University Belfast, Belfast, United Kingdom
  • Sandholm, Niina, Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
  • Kilner, Jill, Centre for Public Health, Queen's University Belfast, Belfast, United Kingdom
  • Rossing, Peter, Steno Diabetes Center Copenhagen, Herlev, Denmark
  • Lajer, Maria, Steno Diabetes Center Copenhagen, Herlev, Denmark
  • Groop, Per-Henrik, Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
  • Maxwell, Alexander P., Centre for Public Health, Queen's University Belfast, Belfast, United Kingdom
  • Mcknight, A.J., Centre for Public Health, Queen's University Belfast, Belfast, United Kingdom
Background

Diabetic kidney disease (DKD) significantly impacts patients, families and health service globally. Accelerated cellular senescence has previously been suggested as a key target for therapeutic development within DKD. The telomereprotective chromosome end structures undergo shortening with advancing age and senescence.

Methods

Genotype data in telomere-related genes was extracted from genome-wide case-control association data (n=1,830) while telomere length was calculated relative to a single copy gene and established using quantitative polymerase chain reaction. Cases were defined as individuals with Type 1 Diabetes (T1D) with persistent proteinuria, hypertension, and retinopathy. Controls were individuals with T1D for at least 15 years, normoalbuminuric and not taking antihypertensive medication or ACE inhibitors. Quantitative CpG methylation values for telomere-related genes were extracted from epigenome-wide case-control association data (n=250).

Results

Telomere length was significantly shorter in DKD patients vs. controls (P=0.002); however, not sustained following covariate adjustment or replication. DKD and ESKD were nominally associated with telomere-related genetic variation, with Mendelian Randomisation highlighting no significant association between genetically-predicted telomere length and disease outcomes. Investigating 1,091 CpG sites in 378 telomere-related genes, 496 sites in 212 genes reached epigenome-wide significance (P≤10-8) for DKD association, and 412 sites in 193 unique genes for ESKD. Functional prediction via gene ontology analysis of differentially methylated genes revealed enriched processes such as developmental regulation and Wnt signalling. Harnessing previously published RNA-sequencing datasets, differential methylation was correlated with gene expression changes during DKD, highlighting prospective targets where epigenetic regulation may result in altered gene expression, potentially influencing disease outcomes.

Conclusion

This study utilised multiple telomere focused omic datasets to provide insights into the genomic landscape of DKD, highlighting genes and molecular pathways for downstream analysis to aid the development of diagnostic and therapeutic interventions for CKD.

Funding

  • Other NIH Support