Differential Methylation of Telomere-Related Genes Is Associated with Kidney Disease in Individuals with Type 1 Diabetes

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  • Claire Hill
  • Seamus Duffy
  • Laura M. Kettyle
  • Liane McGlynn
  • Niina Sandholm
  • Rany M. Salem
  • Alex Thompson
  • Elizabeth J. Swan
  • Jill Kilner
  • Rossing, Peter
  • Paul G. Shiels
  • Maria Lajer
  • Per Henrik Groop
  • Alexander Peter Maxwell
  • Amy Jayne McKnight
  • on behalf of the GENIE Consortium

Diabetic kidney disease (DKD) represents a major global health problem. Accelerated ageing is a key feature of DKD and, therefore, characteristics of accelerated ageing may provide useful biomarkers or therapeutic targets. Harnessing multi-omics, features affecting telomere biology and any associated methylome dysregulation in DKD were explored. Genotype data for nuclear genome polymorphisms in telomere-related genes were extracted from genome-wide case–control association data (n = 823 DKD/903 controls; n = 247 end-stage kidney disease (ESKD)/1479 controls). Telomere length was established using quantitative polymerase chain reaction. Quantitative methylation values for 1091 CpG sites in telomere-related genes were extracted from epigenome-wide case–control association data (n = 150 DKD/100 controls). Telomere length was significantly shorter in older age groups (p = 7.6 × 10−6). Telomere length was also significantly reduced (p = 6.6 × 10−5) in DKD versus control individuals, with significance remaining after covariate adjustment (p = 0.028). DKD and ESKD were nominally associated with telomere-related genetic variation, with Mendelian randomisation highlighting no significant association between genetically predicted telomere length and kidney disease. A total of 496 CpG sites in 212 genes reached epigenome-wide significance (p ≤ 10−8) for DKD association, and 412 CpG sites in 193 genes for ESKD. Functional prediction revealed differentially methylated genes were enriched for Wnt signalling involvement. Harnessing previously published RNA-sequencing datasets, potential targets where epigenetic dysregulation may result in altered gene expression were revealed, useful as potential diagnostic and therapeutic targets for intervention.

Udgave nummer5
Antal sider24
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
S.D. was supported by a QUB International PhD fellowship. This work was supported by the Northern Ireland Health and Social Care Research and Development Office (STL/5569/19), and the Medical Research Council (MC_PC_20026). C.H. is supported by a Science Foundation Ireland and the Department for the Economy Northern Ireland partnership award 15/IA/3152. FinnDiane was funded by the Folkhälsan Research Foundation, the Wilhelm and Else Stockmann Foundation, the Academy of Finland (316664), the Novo Nordisk Foundation (NNF OC0013659), the Sigrid Juselius Foundation, the “Liv och Hälsa” Society, EVO governmental grants (TYH2020305), and the Finnish Diabetes Research Foundation. A.T. and L.M.K. were supported by Blood Cancer UK (formerly Bloodwise).

Funding Information:
The Genetics of Nephropathy, an International Effort (GENIE) study was conducted by the GENIE Investigators and supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The data from the GENIE study reported here were supplied by the GENIE investigators from the Broad Institute of MIT and Harvard, Queens University Belfast and the University of Dublin.

Publisher Copyright:
© 2023 by the authors.

ID: 366048448