Abstract: FR-PO253
Impact of DNA Methylation Variation on Risk of Kidney Failure in Type 1 Diabetes Is Mediated through Increased Levels of Circulating Proteins
Session Information
- Diabetic Kidney Disease: Basic - 1
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Satake, Eiichiro, Joslin Diabetes Center, Boston, Massachusetts, United States
- Chen, Zhuo, City of Hope Beckman Research Institute, Duarte, California, United States
- Tye, Sok Cin, Joslin Diabetes Center, Boston, Massachusetts, United States
- Md Dom, Zaipul, Joslin Diabetes Center, Boston, Massachusetts, United States
- Pezzolesi, Marcus G., University of Utah Health, Salt Lake City, Utah, United States
- Natarajan, Rama, City of Hope Beckman Research Institute, Duarte, California, United States
- Krolewski, Andrzej S., Joslin Diabetes Center, Boston, Massachusetts, United States
Background
In our recent study (Chen Z, et al. ASN Kidney Week 2023), we identified 17 whole blood DNA methylation (DNAmet) sites associated with risk of progression to kidney failure (KF) in type 1 diabetes (T1D) patients. Our prior study (Md Dom Z I, et al. ASN Kidney Week 2022) found multiple circulating proteins associated with progression to KF in diabetes. The current study aims to explore the possibility that the effect of DNAmet variation at KF-associated sites on risk of KF is mediated through elevated levels of KF-associated proteins.
Methods
We evaluated data from 264 T1D patients with diabetic kidney disease from the Joslin Kidney Study. The analysis focused on 17 KF-associated DNAmet sites in whole blood DNA and 21 circulating proteins associated with KF progression. Using the SAS MEDIATE Macro, we conducted mediation analyses within a Cox model framework, with the DNAmet as exposures, circulating proteins as mediators, and progression to KF as the outcome.
Results
Out of the 17 DNAmet sites investigated, variations at 5 were significantly associated with variation of at least one of the 21 KF-associated proteins. Among them, three DNAmet sites demonstrated an effect on risk of KF mediated through a single protein, while the remaining two DNAmet sites mediated effects on risk of KF through multiple proteins, cumulatively accounting for over 30% of the total effect on KF progression when combining the proteins as multiple mediators (Figure).
Conclusion
Our findings provide evidence for the first time that the impact of DNAmet variations at certain KF-associated DNAmet sites on risk of kidney failure is partially mediated by variation of plasma levels of multiple KF-associated circulating proteins. These findings may not only propose a novel predictive model for KF risk in patients with diabetes but may also help elucidate the molecular pathways involved in the KF progression in diabetes.
Funding
- NIDDK Support