SO013
AGING IS ASSOCIATED WITH EPIGENETIC CHANGES IN GENES INVOLVED IN FIBROSIS IN THE KIDNEY: AN EPIGENOME-WIDE STUDY

INTRODUCTION AND AIMS: Advanced donor age is one of the key factors associated with allograft fibrosis and impaired outcome after kidney transplantation. Recently, it has become clear that DNA methylation changes hallmark aging. In this study, we investigated aging-associated changes in DNA methylation in kidney transplants.

METHODS: Whole-genome array-based methylation analysis was performed on two cohorts of kidney allograft biopsies: 95 obtained at implantation (82 brain-dead donors and 13 living donors), using EPIC BeadChips and 67 obtained after reperfusion (58 brain-dead donors and 9 living donors), using Infinium 450K Beadchips. Donor age ranged from 16 to 73 years, and from 16 to 79 years in the two cohorts. Comb-p was used to identify differentially methylated regions (DMRs). The genes mapped to DMRs with a FDR q-value <0.0001 were selected for Inguinity Pathway Analysis.

RESULTS: Donor age associated significantly with methylation levels at 89,293 CpGs (10% of all probes) in the implantation cohort and at 87,393 CpGs (20% of all probes) in the postreperfusion cohort (q-value < 0.05), adjusted for donor gender and cold ischemia time. The CpGs with q-value <0.0001 corresponded to 17,077, respectively 15,225 differentially methylated regions. In both cohorts, the top enriched pathway was the Wnt signaling pathway, which is involved in kidney injury, repair and fibrosis, as well as renal senescence.

CONCLUSIONS: There is a strikingly pervasive association between age and DNA methylation changes in the kidney. These DNA methylation changes occur preferentially at genes involved in fibrosis, suggesting a link between advanced donor age and chronic allograft dysfunction.