Meta-analyses identify DNA methylation associated with kidney function and damage

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.

Are Alterations in DNA Methylation Related to CKD Development?

“…Sometimes, the CpG site correlated with multiple genes in cis. Schlosser et al [27] also observed the impact of DNA methylation at cg04864179 on IRF5 transcript levels, which might subsequently affect eGFR. Colocalization of IRF5 gene expression with eGFR has been reported in blood as well as tubular and glomerular compartments of kidney tissue [86].…”

“…Therefore, it is plausible that alterations in EBF1 gene methylation may be related to kidney damage. In turn, Schlosser et al [27] identified changes in methylation patterns in 69 CpGC related to eGFR, and 65 of them were also observed in CKD patients. Moreover, the methylation of CpGs cg18194850 in SUCLG2 gene and cg07242931 in MAN1C1 gene correlated not only with eGFR but also with time to kidney failure or acute kidney injury [27].…”

“…In turn, Schlosser et al [27] identified changes in methylation patterns in 69 CpGC related to eGFR, and 65 of them were also observed in CKD patients. Moreover, the methylation of CpGs cg18194850 in SUCLG2 gene and cg07242931 in MAN1C1 gene correlated not only with eGFR but also with time to kidney failure or acute kidney injury [27]. The SUCLG2 (Succinate-CoA Ligase GDP-Forming Subunit Beta) gene, mostly expressed in kidneys, liver, heart, spleen, and skeletal muscle, encodes β-subunit of succinyl-CoA synthetase; this synthetase catalyzes reversible reaction leads to the formation of succinyl-CoA and succinate.…”

“…Currently, the treatment of chronic kidney disease involves the management of common abnormalities, including proteinuria, hyperglycemia, hypertension, etc., however, in some patients these measures are not sufficient and thus they progress to end-stage renal disease (ESRD) [23]. Genome-wide association studies (GWAS) and epigenome-wide association studies (EWAS) have identified frequent variants within more than >400 genetic loci that are associated with renal function and the development of CKD [27][28][29][30]. Moreover, large EWAS including participants of European and African American origin revealed 19 CpGs in whole blood that affected eGFR or CKD [7].…”

“…SLC1A5 encodes a sodium-dependent neutral amino acid transporter. DNA methylation within SLC1A5 was suggested to be the possible link between urinary albumin-to-creatinine ratio (UACR) and blood pressure [27]. One epigenome-wide association study (EWAS) aiming to identify additional CpGs related to gene regulatory mechanisms involved in CKD found that expression alterations induced by DNA methylation did not always apply to the closest gene [27].…”