#2056 Epigenetic profiles differ by level of kidney function in idiopathic nephrotic syndrome

Abstract

Abstract Background and Aims DNA methylation (DNAm) is an epigenetic mechanism which can therefore induce changes in gene expression without any change to the underlying DNA sequence. Although generally quite stable, DNAm patterns in whole blood do vary across individuals, with DNAm levels associating with age and responding to environmental factors. We aimed to investigate whether peripheral blood cell DNAm associates with level of kidney function in patients with Idiopathic Nephrotic Syndrome (INS). Method Peripheral blood cell DNAm values were generated using the Illumina MethylationEPIC Beadchip (>850,000 CpG sites) for 293 INS patients recruited to the National Unified Renal Translational Research Enterprise–National Study of INS (NURTuRE- INS and NephroS). All patients were younger than 30 years old at INS diagnosis. An Epigenome Wide Association Study (EWAS) was performed using generalised linear models to evaluate associations between DNAm sites and estimated glomerular filtration rate (eGFR). Regions of differentially methylated sites were identified using the ‘dmrff’ R package. Sex chromosomes were excluded from the analyses and all analyses were adjusted for estimated cell type proportions, age, sex and technical variation. A Bonferroni adjusted p value of 5.88 × 10−8 was used as a significance threshold to adjust for multiple tests. Results Of the selected 293 INS patients, 173 (59%) were male, 213 (73%) were white and the median age at INS diagnosis was 4 years old (IQR 2-10). One hundred and forty-three (48%) patients were steroid responsive at diagnosis and the remainder were steroid resistant. Sixty-eight of the steroid resistant patients had pathogenic NS variants. We identified 6 CpG sites associated with eGFR (p < 5.88 × 10−8) in this cohort of INS patients, one replicating a previously reported association. We identified 3 differentially methylated regions, one coinciding with the transcriptional start site of an RNA binding protein which regulates alternative splicing, and another located in the body of a transcription factor regulator containing genetic variants associated with chronic kidney disease. Conclusion We have demonstrated variation in peripheral blood DNAm by level of kidney function in children and young adults with INS. Associations between DNAm and eGFR have previously been demonstrated in diabetic kidney disease and heterogenous chronic kidney disease cohorts, including one of the sites which we have identified in our study. Further work is underway to determine if these differences in DNAm are likely to be a cause or consequence of reduced kidney function, which will help to determine their potential clinical utility.