Epigenome-wide association studies identify DNA methylation associated with kidney function

Nat Commun. 2017 Nov 3;8(1):1286. doi: 10.1038/s41467-017-01297-7.

Abstract

Chronic kidney disease (CKD) is defined by reduced estimated glomerular filtration rate (eGFR). Previous genetic studies have implicated regulatory mechanisms contributing to CKD. Here we present epigenome-wide association studies of eGFR and CKD using whole-blood DNA methylation of 2264 ARIC Study and 2595 Framingham Heart Study participants to identify epigenetic signatures of kidney function. Of 19 CpG sites significantly associated (P < 1e-07) with eGFR/CKD and replicated, five also associate with renal fibrosis in biopsies from CKD patients and show concordant DNA methylation changes in kidney cortex. Lead CpGs at PTPN6/PHB2, ANKRD11, and TNRC18 map to active enhancers in kidney cortex. At PTPN6/PHB2 cg19942083, methylation in kidney cortex associates with lower renal PTPN6 expression, higher eGFR, and less renal fibrosis. The regions containing the 243 eGFR-associated (P < 1e-05) CpGs are significantly enriched for transcription factor binding sites of EBF1, EP300, and CEBPB (P < 5e-6). Our findings highlight kidney function associated epigenetic variation.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Binding Sites / genetics
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • CpG Islands
  • DNA Methylation / genetics*
  • Disease Progression
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / metabolism
  • Epigenesis, Genetic
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Glomerular Filtration Rate / genetics
  • Humans
  • Kidney / metabolism
  • Male
  • Middle Aged
  • Prospective Studies
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
  • Renal Insufficiency, Chronic / genetics*
  • Renal Insufficiency, Chronic / physiopathology*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • CCAAT-Enhancer-Binding Protein-beta
  • CEBPB protein, human
  • EBF1 protein, human
  • Trans-Activators
  • Transcription Factors
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6