The Effect of DNA Methylation in the Development and Progression of Chronic Kidney Disease in the General Population: An Epigenome-Wide Association Study Using the Korean Genome and Epidemiology Study Database

Genes (Basel). 2023 Jul 21;14(7):1489. doi: 10.3390/genes14071489.

Abstract

Background: Although knowledge of the genetic factors influencing kidney disease is increasing, epigenetic profiles, which are associated with chronic kidney disease (CKD), have not been fully elucidated. We sought to identify the DNA methylation status of CpG sites associated with reduced kidney function and examine whether the identified CpG sites are associated with CKD development.

Method: We analyzed DNA methylation patterns of 440 participants in the Korean Genome and Epidemiology Study (KoGES) with estimated glomerular filtration rates (eGFRs) ≥ 60 mL/min/1.73 m2 at baseline. CKD development was defined as a decrease in the eGFR of <60 at any time during an 8-year follow-up period ("CKD prediction" analysis). In addition, among the 440 participants, 49 participants who underwent a second methylation profiling were assessed for an association between a decline in kidney function and changes in the degree of methylation of CpG sites during the 8 years ("kidney function slope" analysis).

Results: In the CKD prediction analysis, methylation profiles of a total of 403,129 CpG sites were evaluated at baseline in 440 participants, and increased and decreased methylation of 268 and 189 CpG sites, respectively, were significantly correlated with the development of CKD in multivariable logistic regression. During kidney function slope analysis using follow-up methylation profiles of 49 participants, the percent methylation changes in 913 CpG sites showed a linear relationship with the percent change in eGFR during 8 years. During functional enrichment analyses for significant CpG sites found in the CKD prediction and kidney function slope analyses, we found that those CpG sites represented MAPK, PI3K/Akt, and Rap1 pathways. In addition, three CpG sites from three genes, NPHS2, CHCHD4, and AHR, were found to be significant in the CKD prediction analysis and related to a decline in kidney function.

Conclusion: It is suggested that DNA methylation on specific genes is associated with the development of CKD and the deterioration of kidney function.

Keywords: CHCHD4; DNA methylation; NPHS2; chronic kidney disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Methylation* / genetics
  • Epigenome
  • Humans
  • Phosphatidylinositol 3-Kinases / metabolism
  • Renal Insufficiency, Chronic* / epidemiology
  • Renal Insufficiency, Chronic* / genetics
  • Republic of Korea / epidemiology

Substances

  • Phosphatidylinositol 3-Kinases

Grants and funding

This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF-2020M3E5D7085175) funded by the Ministry of Health and Welfare, Ministry of Science and ICT, Ministry of Trade Industry and Energy, Korea Disease Control and Prevention Agency (The National Project of Bio Big Data) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2021R1A6A3A01087658).