Journal Article

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

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

2017

Overview

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. Genome-wide association studies of kidney function show enrichment of associated genetic variants in regulatory regions. Here, the authors perform epigenome-wide association studies of kidney function and disease, identifying 19 CpG sites significantly associated with these.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/208/176/1988 / 692/4022/272 / Aged / Binding sites / Binding Sites - genetics / CCAAT-Enhancer-Binding Protein-beta - genetics / CCAAT-Enhancer-Binding Protein-beta - metabolism / CpG Islands / Deoxyribonucleic acid / Disease Progression / DNA / DNA methylation / DNA Methylation - genetics / E1A-Associated p300 Protein - genetics / E1A-Associated p300 Protein - metabolism / Enhancers / Epidermal growth factor receptors / Epigenesis, Genetic / Epigenetics / Female / Fibrosis / Genetic diversity / Genetic Predisposition to Disease / Genetic variance / Genome-wide association studies / Genome-Wide Association Study / Genomes / Genotype & phenotype / Glomerular filtration rate / Glomerular Filtration Rate - genetics / Heart / Humanities and Social Sciences / Humans / Kidney - metabolism / Kidney diseases / Kidney transplantation / Kidneys / Male / Middle Aged / multidisciplinary / Prohibitins / Prospective Studies / Protein Tyrosine Phosphatase, Non-Receptor Type 6 - genetics / Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism / Regulatory mechanisms (biology) / Regulatory sequences / Renal cortex / Renal Insufficiency, Chronic - genetics / Renal Insufficiency, Chronic - physiopathology / Science / Science (multidisciplinary) / Studies / Trans-Activators - genetics / Trans-Activators - metabolism / Transcription Factors - genetics / Transcription Factors - metabolism