Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease: an exploratory study

Laura Smyth, Jill Kilner, Viji Nair, Hongobo Liu, Eoin P Brennan, Katie Kerr, Niina Sandholm, Joanne B Cole, Emma Dahlström, Anna Syreeni, Rany M Salem, Robert Nelson, Helen Looker, Christopher Wooster, Kerry Anderson, Gareth McKay, Frank Kee, Ian Young, Darrell Andrews, Carol ForsblomJoel N Hirschhorn, Catherine Godson, Per-Henrik Groop, Peter Maxwell, Katalin Susztak, Matthias Kretzler, Jose C Florez, Amy Jayne McKnight

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Abstract

Background: A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this exploratory investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing to identify potential blood-based biomarkers. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina’s Infinium MethylationEPIC BeadChip arrays (n=862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p≤x10-8 and fold change ±2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM.
Results: Top-ranked genes within which several dmCpGs were located and supported by functional data with methylation look-ups in other cohorts, include; AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9, and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-β signalling and Th17 cell differentiation.
Conclusions: Epigenetic alterations provide a dynamic link between an individual’s genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.
Original languageEnglish
JournalClinical Epigenetics
DOIs
Publication statusPublished - 01 May 2021

Bibliographical note

Available as pre-print on bioRxiv 31st July 2020: https://www.biorxiv.org/content/10.1101/2020.07.30.228734v1

Keywords

  • Association
  • Diabetes
  • EPIC
  • end-stage
  • Kidney
  • Methylation
  • Nephropathy

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