End-stage renal disease (ESRD) remains a major clinical challenge with high morbidity and mortality, and its molecular mechanisms, particularly those shared among diverse primary kidney diseases during progression to ESRD, have not been studied. Here we conduct a large-scale two-stage epigenome-wide association study of ESRD in two independent cohorts consisting of 704 controls and 1031 ESRD cases. We identify 52 ESRD-associated differentially methylated CpG positions (ESRD DMPs) showing consistent association between the two cohorts and across diverse kidney diseases, implicating 144 candidate genes enriched in inflammatory and immune pathways. Five of the 52 DMPs are associated with ESRD complications, and seven with renal function decline in early-stage chronic kidney disease, demonstrating their potential as prognostic biomarkers for ESRD and its complications. Our findings highlight inflammation, immune dysregulation, and renal fibrosis as shared epigenetic drivers of ESRD progression, and identify biomarkers with potential utility for risk stratification and therapeutic intervention. A two-stage epigenome-wide study identified 52 DNA methylation markers associated with end-stage renal disease across diverse primary kidney diseases, highlighting the shared roles of inflammation, immune dysregulation, and renal fibrosis.
CONTEXT
Youth-onset type 2 diabetes (T2D) is characterized by accelerated β-cell decline and early treatment failure, and there is an urgent need to improve the understanding of molecular drivers of loss of glycemic control (LOGC).
OBJECTIVE
To identify multiprotein signatures associated with loss of glycemic control (LOGC) in youth-onset T2D.
DESIGN
Longitudinal observational study with a mean follow-up of 10.8 ± 3.8 years using data from the TODAY study, with external validation in three youth cohorts and one adult-onset T2D cohort.
SETTING
Multicenter clinical research study.
PARTICIPANTS
Participants from the TODAY study (N = 374; age 14 ± 2 years; 37% male), of whom 72% experienced LOGC over 10.8 ± 3.8 years.
INTERVENTIONS
None.
MAIN OUTCOME MEASURE
LOGC, defined as HbA1c ≥ 8% for ≥6 months or inability to discontinue insulin after acute metabolic decompensation.
RESULTS
Plasma proteomics quantified 7604 aptamers representing 6596 proteins using the SomaScan 7 K platform. Sixty-seven proteins were associated with LOGC after false discovery rate correction and multivariable adjustment. Key proteins included plexin-B2 (HR: 1.46 [95% CI: 1.29-1.66]) and semaphorin-6A (HR: 1.31 [1.18-1.47]), which were also associated with glycemic outcomes in independent youth and adult cohorts. Enrichment analyses implicated pathways related to axon guidance, immune response, inflammation, and metabolism.
CONCLUSIONS
Novel proteins involved in axon guidance, immune response, inflammation, and metabolism associated with LOGC in youth-onset T2D with proteins demonstrating consistent associations across the lifespan and proteomic platforms.
K. Tommerdahl, Kristen R Miller, Jian-Jun Liu et al.· Journal of Clinical Endocrin...· 0 citations
BACKGROUND
Individuals with type 2 diabetes (T2D) have increased risk of acute myocardial infarction (AMI). Cardiovascular risk within T2D is heterogeneous and not fully explained by conventional risk factors, highlighting the need for improved biological risk stratification.
OBJECTIVES
The authors aimed to identify circulating proteins associated with incident AMI in T2D, evaluate their incremental predictive value, and explore potential causal relationships.
METHODS
In 1,830 adults with T2D from the prospective SMART2D cohort, 1,457 plasma proteins were quantified at baseline using Olink proximity extension assays. Participants were followed for incident AMI through linkage with the Singapore Myocardial Infarction Registry over a median of 10.2 years (IQR: 9.1-10.7). Multivariable Cox regression assessed protein-AMI association. Incremental predictive performance was evaluated using Harrell's C-statistic, likelihood ratio tests (LRTs), net reclassification index (NRI), and integrated discrimination index (IDI). Two-sample Mendelian randomization, using cis-protein qualitative-trait loci from SMART2D and outcome data from Biobank Japan (14,992 cases; 146,214 controls), examined causal associations.
RESULTS
During follow-up, 223 participants (12.2%) developed AMI. Seventeen proteins were independently associated with AMI after Bonferroni correction (P < 3.43 × 10-5), with the strongest associations observed for NEFL (HR: 1.70, 95% CI: 1.43-2.01), EDA2R (HR: 2.25, 95% CI: 1.69-2.97), and CHRDL1 (HR: 2.69, 95% CI: 1.83-3.94). An 8-protein panel improved risk classification beyond clinical variables (LRT P = 0.002; IDI: 0.049, 95% CI: 0.022-0.128, P = 0.002; and NRI: 0.318, 95% CI: 0.112-0.411, P = 0.008). Genetically predicted plasma FGF5 levels were associated with myocardial infarction risk.
CONCLUSIONS
Plasma proteomics improves AMI risk stratification in T2D, and FGF5 may play a role in cardiovascular risk in Asian populations.
R. L. Gurung, Huili Zheng, J. Tan et al.· JACC: Asia· 0 citations
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