Abstract
Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.
Highlights
A recent GWAS meta-analysis of estimated glomerular filtration rate (eGFR) integrated open chromatin regions with small sets of single nucleotide polymorphisms (SNPs)[10]
We investigated the association of kidney traits with DNA methylation in blood at up to 441,870 CpG sites (CpGs), the overlap of CpGs covered by the Illumina MethylationEPIC BeadChip and the Illumina HumanMethylation[450] BeadChip array, which were used for measurement by all but one study (Supplementary Data 3)
We evaluated whether eGFR-associated CpGs preferentially mapped to binding sites of 169 transcription factors (TFs) based on chromatin immunoprecipitation DNA-sequencing (ChIP-seq) data from the ENCODE project that was aggregated by a consensus calls across 91 human cell types (161 TF tracks) and supplemented with eight kidney tissue-based tracks
Summary
A recent GWAS meta-analysis of eGFR integrated open chromatin regions with small sets of single nucleotide polymorphisms (SNPs)[10]. We previously conducted an EWAS including 4859 adults from two population-based studies and identified 18 validated, differentially methylated sites in whole blood associated with eGFR14. We conducted an EWAS of kidney function traits to identify additional CpGs related to gene regulatory mechanisms of potential importance to CKD. We extended the former EWAS for eGFR and CKD by substantially increasing the sample size to 33,605 individuals. We replicated our EWAS results in separate samples, related the CpG sites to gene expression levels in different tissues, applied the findings to clinical outcomes, and assessed causality between DNA methylation and kidney function (Supplementary Fig. 1)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
