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

Clinical Epigenetics

H. C. Looker¹  R. G. Nelson¹  H. Liu²  K. Susztak²  R. M. Salem³  E. Brennan⁴  C. Godson⁴  D. Andrews⁴  E. Dahlström⁵  N. Sandholm⁵  A. Syreeni⁵  C. Forsblom⁵  P. H. Groop⁶  M. Kretzler⁷  V. Nair⁷  J. Kilner⁸  L. J. Smyth⁸  K. Anderson⁸  I. Young⁸  C. Wooster⁸  K. Kerr⁸  F. Kee⁸  A. J. McKnight⁸  G. J. McKay⁸  A. P. Maxwell⁹  J. N. Hirschhorn^1,10  J. C. Florez^1,11  J. Cole^1,12 

[1] Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA;Department of Department of Medicine/ Nephrology, Department of Genetics, Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA;Department of Family Medicine and Public Health, UC San Diego, San Diego, CA, USA;Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine, University College Dublin, Dublin 4, Ireland;Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland;Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland;Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland;Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland;Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland;Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland;Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia;Internal Medicine, Department of Nephrology, University of Michigan, Ann Arbor, MI, USA;Molecular Epidemiology Research Group, Centre for Public Health, Queen’s University Belfast, Belfast, UK;Molecular Epidemiology Research Group, Centre for Public Health, Queen’s University Belfast, Belfast, UK;Regional Nephrology Unit, Belfast City Hospital, Belfast, Northern Ireland, UK;Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA;Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA, USA;Department of Genetics, Harvard Medical School, Boston, MA, USA;Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA;Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA, USA;Department of Medicine, Harvard Medical School, Boston, MA, USA;Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA;Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA, USA;Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA;

关键词: Association;    Diabetes;    EPIC;    End-stage;    Kidney;    Methylation;    Nephropathy;   

DOI  :  10.1186/s13148-021-01081-x

来源: Springer

【 摘 要 】

BackgroundA 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 ≤ × 10–8 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.ResultsTop-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.ConclusionsEpigenetic 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.

【 授权许可】

CC BY