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.

Details

Title
Epigenome-wide association studies identify DNA methylation associated with kidney function
Author
Chu, Audrey Y 1 ; Tin, Adrienne 2 ; Schlosser, Pascal 3   VIAFID ORCID Logo  ; Yi-An, Ko 4 ; Qiu, Chengxiang 4 ; Chen, Yao 1 ; Joehanes, Roby 5   VIAFID ORCID Logo  ; Grams, Morgan E 2 ; Liang, Liming 6 ; Gluck, Caroline A 4   VIAFID ORCID Logo  ; Liu, Chunyu 1 ; Coresh, Josef 2   VIAFID ORCID Logo  ; Shih-Jen Hwang 1 ; Levy, Daniel 1 ; Boerwinkle, Eric 7 ; Pankow, James S 8 ; Yang, Qiong 9   VIAFID ORCID Logo  ; Fornage, Myriam 7 ; Fox, Caroline S 1 ; Susztak, Katalin 4 ; Köttgen, Anna 10 

1  The Population Sciences Branch, Division of Intramural Research, NHLBI, NIH, Bethesda, MD, USA; NHLBI’s Framingham Heart Study, Framingham, MA, USA 
2  Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA 
3  Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center—University of Freiburg, Freiburg, Germany 
4  Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA 
5  Institute of Aging Research, Hebrew Senior Life, Boston, MA, USA; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA; The Population Sciences Branch, Division of Intramural Research, NHLBI, NIH, Bethesda, MD, USA; NHLBI’s Framingham Heart Study, Framingham, MA, USA 
6  Department of Biostatistics, Harvard University School of Public Health, Boston, MA, USA 
7  Human Genetics Center, University of Texas Health Science Center, Houston, TX, USA 
8  Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA 
9  Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; NHLBI’s Framingham Heart Study, Framingham, MA, USA 
10  Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center—University of Freiburg, Freiburg, Germany 
Pages
1-12
Publication year
2017
Publication date
Nov 2017
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-017-01297-7
ProQuest document ID
2128534674
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.