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

Audrey Y Chu,Morgan E Grams,Anna Köttgen,Caroline S Fox,Pascal Schlosser,Eric Boerwinkle,Josef Coresh,Chengxiang Qiu,Liming Liang,Myriam Fornage,Yi An Ko ,Katalin Suszták ,Caroline Gluck ,Daniel Levy,Shih Jen Hwang ,Adrienne Tin,Chen Yao,James S Pankow,Roby Joehanes,Chunyu Liu,Qiong Yang

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.

Highlights

Chronic kidney disease (CKD) is defined by reduced estimated glomerular filtration rate
To expand on previous work in the field and address limitations of early studies, here we present our study that had the following aims: first, to use Epigenome-wide association studies (EWAS) to discover and validate CpG sites (CpGs) at which methylation quantified from whole blood is associated with estimated glomerular filtration rate (eGFR) and the presence and development of CKD among up to 4859 aging adults from population-based studies; second, to characterize validated CpGs for association with fibrosis and gene expression in kidney tissue; and third, to identify common pathways and mechanisms that may link differential DNA methylation to reduced kidney function
We identify and replicate 19 eGFR- and CKD-associated CpGs from whole blood, five of which show concordant and significant changes between DNA methylation quantified from kidney cortex of CKD patients and renal fibrosis

Summary

Introduction

Chronic kidney disease (CKD) is defined by reduced estimated glomerular filtration rate (eGFR). To expand on previous work in the field and address limitations of early studies, here we present our study that had the following aims: first, to use EWAS to discover and validate CpGs at which methylation quantified from whole blood is associated with eGFR and the presence and development of CKD among up to 4859 aging adults from population-based studies; second, to characterize validated CpGs for association with fibrosis and gene expression in kidney tissue; and third, to identify common pathways and mechanisms that may link differential DNA methylation to reduced kidney function. We identify and replicate 19 eGFR- and CKD-associated CpGs from whole blood, five of which show concordant and significant changes between DNA methylation quantified from kidney cortex of CKD patients and renal fibrosis.

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Results

Conclusion