Abstract: TH-PO465

Analysis of Genome-Wide Arterial Media-Specific DNA Methylation Demonstrates No Epigenetic Evidence of Aging but Reveals New Targets in CKD Associated Cardiovascular Pathology

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 303 CKD: Epidemiology, Outcomes - Cardiovascular

Authors

  • Dritsoula, Athina, University College London, London, LONDON, United Kingdom
  • Oomatia, Amin, University College London, London, LONDON, United Kingdom
  • Kislikova, Maria, University College London, London, LONDON, United Kingdom
  • Webster, Amy P, University College London, London, United Kingdom
  • Beck, Stephan, University College London, London, United Kingdom
  • Norman, Jill T, University College London, London, LONDON, United Kingdom
  • Wheeler, David C., University College London, London, LONDON, United Kingdom
  • Oates, Thomas, University College London, London, LONDON, United Kingdom
  • Caplin, Ben, University College London, London, LONDON, United Kingdom
Background

Cardiovascular disease (CVD) is the primary cause of morbidity and mortality among patients with chronic kidney disease (CKD). In CKD-related CVD, structural and morphological changes occur in the vascular bed leading to arterial stiffness, matrix deposition and calcification that have been described as accelerated arterial aging. These changes are mediated by the activation of vascular smooth muscle cells. Altered DNA methylation has been proposed to mediate the aging process and is also a manifestation of CKD. We aim to investigate tissue specific changes in DNA methylation that occur in CKD-related CVD.

Methods

DNA methylation analysis was performed (Illumina EPIC array) in bisulfite converted genomic DNA, isolated from the arterial media of 25 recipients (CKD patients; epigastric artery) and 7 donors (controls; renal artery) during kidney transplantation procedures, after the advintitia was removed and the endothelium was brushed away. Bioinformatics analysis was performed using Bioconductor packages in R (SNP and XY chromosome-related CpGs were excluded). BMIQ and Combat analysis were used for normalization and to correct technical variation respectively. DNA methylation age (DMAge) was estimated using the algorithm by Horvath et al. Methylation-specific PCR was used to validate the array data. P-values were adjusted for multiple comparisons.

Results

3x105 differentially methylated CpGs encompassing 703 differentially methylated regions (DMR) were identified (adj p<0.05) spread across all autosomal chromosomes. Significant enrichment was found in promoters, exons, introns and 5’ UTRs. DMRs were found in or in proximity to interfering RNAs (miR-196b) along with genes associated with vascular remodelling and ECM production (COL6/7/9, ADAMTS8/9, MMP2, LOXL1), and signalling mechanisms involved in fibrosis and vascular pathologies (TGFβ1, FGF1/6, SMAD3, GATA3/4/5). DMAge and chronological age were highly correlated but there was no evidence of higher DMAge in CKD cases.

Conclusion

Overall, these data implicate altered arterial media-specific DNA methylation in CKD-related CVD, but this methylation profile does not reflect a process of accelerated aging.