DNA甲基化在2型糖尿病并发脑卒中中的调控机制及临床转化研究进展

Research Progress on the Regulatory Mechanism and Clinical Translation of DNA Methylation in Type 2 Diabetes Mellitus Complicated with Stroke

摘要: 2型糖尿病(Type 2 Diabetes Mellitus, T2DM)并发脑卒中是导致糖尿病患者致残致死的主要原因，其发病机制涉及遗传易感性与表观遗传调控的交互作用。DNA甲基化作为关键的表观遗传修饰机制，可在不改变DNA序列的情况下可逆地调控基因表达，成为连接环境因素与脑血管病变的重要分子桥梁。本文系统检索PubMed、Embase、Web of Science、Cochrane Library、中国知网、万方及维普数据库(建库至2025年3月)，最终纳入36篇高质量研究进行综述。现有证据表明，T2DM并发脑卒中患者呈现区别于单纯T2DM或单纯脑卒中的特异性DNA甲基化谱：全基因组关联研究(Epigenome-Wide Association Study, EWAS)鉴定出PDE4B (cg18197392)、SLC1A3 (cg04542353)等位点的低甲基化与糖尿病相关脑卒中风险显著相关(False Discovery Rate, FDR < 0.05)；MNX1、ABCG1等代谢调控基因的异常甲基化通过影响胰岛素敏感性、脂质代谢及炎症反应参与疾病发生发展。这些表观遗传改变具有潜在生物标志物价值，联合检测特定CpG位点对T2DM患者5年脑卒中风险的预测效能可达受试者工作特征曲线下面积(Area Under the Curve, AUC) = 0.78。当前研究仍面临细胞异质性干扰、因果推断不足及组织特异性干预手段缺乏等挑战。未来需结合单细胞甲基化测序、纵向队列设计及CRISPR-dCas9表观遗传编辑技术，深入解析T2DM向脑卒中转化过程中的表观遗传动态演变，为精准预防及靶向治疗提供理论依据。

Abstract: Type 2 diabetes mellitus (T2DM) complicated with stroke represents a leading cause of morbidity and mortality among diabetic patients, with pathogenesis involving complex interactions between genetic susceptibility and epigenetic regulation. DNA methylation, as a critical epigenetic modification, can reversibly regulate gene expression without altering DNA sequences, serving as a crucial molecular bridge linking environmental factors to cerebrovascular pathology. We systematically searched PubMed, Embase, Web of Science, Cochrane Library, CNKI, Wanfang, and VIP databases (from inception to March 2025), with 36 high-quality studies finally included for review. Current evidence demonstrates that T2DM patients with stroke exhibit distinct DNA methylation patterns compared to those with T2DM or stroke alone: epigenome-wide association study (EWAS) have identified hypomethylation at PDE4B (cg18197392) and SLC1A3 (cg04542353) loci significantly associated with diabetes-related stroke risk (false discovery rate, FDR < 0.05); aberrant methylation of metabolic regulatory genes including MNX1 and ABCG1 contributes to disease pathogenesis through modulating insulin sensitivity, lipid metabolism, and inflammatory responses. These epigenetic alterations hold potential biomarker value, with combined detection of specific CpG sites achieving an AUC of 0.78 for predicting 5-year stroke risk in T2DM patients. However, current research faces challenges including cellular heterogeneity interference, insufficient causal inference, and lack of tissue-specific intervention strategies. Future studies should integrate single-cell methylome sequencing, longitudinal cohort designs, and CRISPR-dCas9 epigenetic editing technologies to elucidate the dynamic epigenetic trajectories during T2DM-to-stroke transition, providing theoretical foundations for precision prevention and targeted therapy.