393-P: Epigenome-Wide Association Applied in Early Prediction of Kidney Disease in Diabetes (DKD)—A Pilot Study

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Introduction and Objective: Epigenetic modifications, such as DNA methylation(DNAm), can provide a composite measurement of environmental/genetic influence on gene expression. A significant gap remains in defining DNAm profiles in diabetes, prior to DKD diagnosis. We determined blood-derived DNAm profiles, in type-2 diabetes(T2D) people with normal kidney function, that were predictive of DKD incidence in the DARE cohort.Methods: Blood-derived DNAm was measured at 850,000 genomic loci (CpGs) using the Infinium EPIC V2-BeadChip (Illumina), in 42 people with T2D, with >10 years detailed clinical follow up data, including renal function. All had normal ACR at baseline. The ‘ChAMP package’ in R was used to identify differentially methylated CpGs in T2D individuals who developed urine ACR>3mg/mmol)) vs no increase in ACR (n=21), after 10 years. Age range was 42-79 years (20 female/22 male), with equal split between case/control groups. Bulk RNA sequencing data from the human kidney was extracted from the ‘Nephroseq’ database.Results: Our Epigenome-wide Association study (EWAS) identified 127 differentially methylated CpG sites (p<9×10-5) associated with UACR>3mg/mmol incidence in the DARE cohort, after adjustment for age/sex. Cross-tissue comparisons identified associations between methylation at cg08494812 (sitting within 200bp of AF1B transcription start site) and UACR>3mg/mmol consistent between both blood-derived and kidney-derived DNA. RNA sequencing data (‘Nephroseq’) indicated that TAF1B expression in the kidney tubule was reduced in DKD, and suggested that kidney TAF1B expression correlated with renal function preservation.Conclusion: Our pilot study identified pre-diagnosis DNAm changes predictive of albuminuria incidence and highlights that increased methylation at the TAF1B gene (cg08494812) is associated with decreased TAF1B expression in kidney and rise in ACR. Future work aims to confirm the significance of these findings and to extend our EWAS to the larger DARE cohort.

Disclosure

A.C. Lay: None. A.H. Heald: None. J.M. Gibson: None. P. Kalra: Speaker’s Bureau; Pharmacosmos. Advisory Panel; Medice, CSL Vifor.



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