DNA methylation profile associated with rapid decline in kidney function: Findings from the CRIC Study

Maria R. Wing, Joseph M. Devaney, Marshall M. Joffe, Dawei Xie, Harold I. Feldman, Elizabeth A. Dominic, Nicolas J. Guzman, Ali Ramezani, Katalin Susztak, James G. Herman, Leslie Cope, Brennan Harmon, Bernard Kwabi-Addo, Heather Gordish-Dressman, Alan S. Go, Jiang He, James P. Lash, John W. Kusek, Dominic S. Raj

Research output: Contribution to journalArticle

Abstract

BackgroundEpigenetic mechanisms may be important in the progression of chronic kidney disease (CKD).MethodsWe studied the genome-wide DNA methylation pattern associated with rapid loss of kidney function using the Infinium HumanMethylation 450 K BeadChip in 40 Chronic Renal Insufficiency (CRIC) study participants (n = 3939) with the highest and lowest rates of decline in estimated glomerular filtration rate.ResultsThe mean eGFR slope was 2.2 (1.4) and -5.1 (1.2) mL/min/1.73 m2 in the stable kidney function group and the rapid progression group, respectively. CpG islands in NPHP4, IQSEC1 and TCF3 were hypermethylated to a larger extent in subjects with stable kidney function (P-values of 7.8E-05 to 9.5E-05). These genes are involved in pathways known to promote the epithelial to mesenchymal transition and renal fibrosis. Other CKD-related genes that were differentially methylated are NOS3, NFKBIL2, CLU, NFKBIB, TGFB3 and TGFBI, which are involved in oxidative stress and inflammatory pathways (P-values of 4.5E-03 to 0.046). Pathway analysis using Ingenuity Pathway Analysis showed that gene networks related to cell signaling, carbohydrate metabolism and human behavior are epigenetically regulated in CKD. Conclusions Epigenetic modifications may be important in determining the rate of loss of kidney function in patients with established CKD.

Original languageEnglish (US)
Pages (from-to)864-872
Number of pages9
JournalNephrology Dialysis Transplantation
Volume29
Issue number4
DOIs
StatePublished - Apr 2014

Keywords

  • DNA methylation
  • chronic renal disease
  • chronic renal disease progression
  • epigenetics

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

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    Wing, M. R., Devaney, J. M., Joffe, M. M., Xie, D., Feldman, H. I., Dominic, E. A., Guzman, N. J., Ramezani, A., Susztak, K., Herman, J. G., Cope, L., Harmon, B., Kwabi-Addo, B., Gordish-Dressman, H., Go, A. S., He, J., Lash, J. P., Kusek, J. W., & Raj, D. S. (2014). DNA methylation profile associated with rapid decline in kidney function: Findings from the CRIC Study. Nephrology Dialysis Transplantation, 29(4), 864-872. https://doi.org/10.1093/ndt/gft537