TOPLINE:
A DNA methylation signature outperformed a clinical model at identifying individuals with type 1 diabetes (T1D) who risked progressing to end-stage kidney disease.
METHODOLOGY:
Researchers measured DNA methylation (DNAmet) in blood cells from 277 individuals with T1D and diabetic kidney disease (DKD) and followed them from 7 to 20 years to identify variations in DNAmet linked to the risk for kidney failure (KF).They conducted an epigenetic analysis of the identified 5′-cytosine-phosphate-guanine-3′ loci (CpGs) that were associated with KF, independent of clinical risk factors.They then developed a prediction model for KF risk to compare with a clinical model.
TAKEAWAY:
51% of the cohort developed KF during follow-up. The team’s epigenome-wide analysis identified DNAmet at 17 CpGs that were associated with risk for KF, independent of major clinical risk factors; the DNAmet at these KF-associated CpGs remained stable over a median period of 4.7 years and were previously validated in an independent cohort. DNAmet variations at seven of the KF-associated CpGs were strongly associated with multiple genetic variants at seven genomic regions, suggesting that there is a strong genetic influence on DNAmet. The effects of DNAmet variations at the KF-associated CpGs on risk for KF were partially mediated by multiple KF-associated circulating proteins and KF-associated circulating miRNAs.The new model significantly improved prediction performance (c-statistic=0.93) compared with the clinical model (c-statistic=0.85).
IN PRACTICE:
“We…identified DNAmet variation at certain KF-associated CpGs that can improve the risk prediction of KF, thereby providing potential much needed noninvasive biomarkers,” the researchers wrote. “Our findings can have important translational implications for early detection and prevention of KF in patients with T1D DKD.”
SOURCE:
The study was led by Zhuo Chen, City of Hope, Duarte, California and published online on May 22, 2024, in Science Translational Medicine.
LIMITATIONS:
The study findings are limited by the relatively small sample size and a need for more mechanistic work.
DISCLOSURES:
The study was supported in part by multiple grants from the US National Institutes of Health (NIH); Wanek family project for the Cure of T1D at City of Hope; Novo Nordisk Foundation (NNF); Helmsley Charitable Trust grant; and a Juvenile Diabetes Research Foundation grant. The FinnDiane study (validation cohort) was supported by grants from Folkhälsan Research Foundation, Wilhelm and Else Stockmann Foundation, “Liv och Hälsa” Society, Sigrid Juselius Foundation, Helsinki University Central Hospital Research Funds, NNF, Academy of Finland, and the NIH.
Only the principal investigator disclosed competing interests, mostly as an advisory board member for various pharmaceutical companies and for Medscape Medical News.
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