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Background <p>Patients with type 2 diabetes (T2D) are at an increased risk of developing acute myocardial infarction (AMI), yet the role of 5-hydroxymethylcytosines (5hmC) changes in T2D-associated cardiovascular events remains poorly understood. Despite therapeutic advances, patients with T2D who suffer an AMI continue to exhibit markedly elevated cardiovascular risk and poor prognosis, underscoring the need for improved detection and risk assessment.</p> Methods <p>We evaluated genome-wide 5hmC modifications in circulating cell-free DNA (cfDNA) for their value as noninvasive biomarkers for AMI in T2D. Genome-wide mapping of 5hmC in plasma cfDNA were obtained using the 5hmC-Seal technique from 225 participants, including 57 T2D patients with AMI (T2D + AMI), and 168 T2D patients without AMI (T2D + non-AMI). A weighted 5hmC-based model was developed to compute an epigenetic score for each individual, which was first derived from baseline cross-sectional data to discriminate between the patients from the two groups. Subsequently, the utility of the epigenetic score for predicting composite cardiovascular outcomes (CCO) was assessed prospectively within the same cohort using 5-year longitudinal follow-up data.</p> Results <p>255 differential 5hmC-gene bodies (<i>P</i> &lt; 0.05) associated with T2D + AMI, involving pathways related to cardiac functions, such as heart process and heart contraction. A seven-feature weighted model based on 5hmC signatures was developed for distinguishing T2D + AMI from T2D + non-AMI, which achieved an area under the curve (AUC) of 99.2% (95% CI 98.1–100.0%) in training set and 95.6% (95% CI 89.8–100.0%) in testing set. Furthermore, we established and tested a 5hmC-derived weighted epigenetic score for predicting cardiovascular events in <i>d</i>iabetic population (eSCORE-CARD) over a median follow-up of 5.3 years. Multivariate Cox regression analysis showed that the eSCORE-CARD values were significantly associated with an increased risk of CCO (HR = 4.25; 95% CI 1.41–12.80; <i>P &lt;</i> 0.05). When combined with other established risk tools (SCORE2-Diabetes and SCORE2-OP), eSCORE-CARD demonstrated improved performance achieving an AUC of 76.4% (95% CI 65.9–86.8%), which holds promise for detection and prognosis of cardiovascular events in T2D.</p> Conclusions <p>Our work indicated specific 5hmC signatures implicated in AMI with T2D background, and provided the foundation for a comprehensive cardiovascular risk management tool for diabetic population.</p>

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A 5-hydroxymethylcytosine-based noninvasive model for acute myocardial infarction in type 2 diabetes: implications in cardiovascular outcomes from a 5-year median follow-up study

  • 期刊论文

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  • 发表日期：

    2026年1月30日

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  • Kun Yang,
  • Shanshan Qin,
  • Shaohua Xu,
  • Xiaolong Cui,
  • Zhou Zhang,
  • Jianlei Cao,
  • Mengyao Xiao,
  • Ying Yang,
  • Chuan He,
  • Xiang Zhou,
  • Xiaocheng Weng,
  • Wei Zhang,
  • Song-Mei Liu

摘要

Background

Patients with type 2 diabetes (T2D) are at an increased risk of developing acute myocardial infarction (AMI), yet the role of 5-hydroxymethylcytosines (5hmC) changes in T2D-associated cardiovascular events remains poorly understood. Despite therapeutic advances, patients with T2D who suffer an AMI continue to exhibit markedly elevated cardiovascular risk and poor prognosis, underscoring the need for improved detection and risk assessment.

Methods

We evaluated genome-wide 5hmC modifications in circulating cell-free DNA (cfDNA) for their value as noninvasive biomarkers for AMI in T2D. Genome-wide mapping of 5hmC in plasma cfDNA were obtained using the 5hmC-Seal technique from 225 participants, including 57 T2D patients with AMI (T2D + AMI), and 168 T2D patients without AMI (T2D + non-AMI). A weighted 5hmC-based model was developed to compute an epigenetic score for each individual, which was first derived from baseline cross-sectional data to discriminate between the patients from the two groups. Subsequently, the utility of the epigenetic score for predicting composite cardiovascular outcomes (CCO) was assessed prospectively within the same cohort using 5-year longitudinal follow-up data.

Results

255 differential 5hmC-gene bodies (P < 0.05) associated with T2D + AMI, involving pathways related to cardiac functions, such as heart process and heart contraction. A seven-feature weighted model based on 5hmC signatures was developed for distinguishing T2D + AMI from T2D + non-AMI, which achieved an area under the curve (AUC) of 99.2% (95% CI 98.1–100.0%) in training set and 95.6% (95% CI 89.8–100.0%) in testing set. Furthermore, we established and tested a 5hmC-derived weighted epigenetic score for predicting cardiovascular events in diabetic population (eSCORE-CARD) over a median follow-up of 5.3 years. Multivariate Cox regression analysis showed that the eSCORE-CARD values were significantly associated with an increased risk of CCO (HR = 4.25; 95% CI 1.41–12.80; P < 0.05). When combined with other established risk tools (SCORE2-Diabetes and SCORE2-OP), eSCORE-CARD demonstrated improved performance achieving an AUC of 76.4% (95% CI 65.9–86.8%), which holds promise for detection and prognosis of cardiovascular events in T2D.

Conclusions

Our work indicated specific 5hmC signatures implicated in AMI with T2D background, and provided the foundation for a comprehensive cardiovascular risk management tool for diabetic population.