Tan Konstanze, Tay Darwin, Tan Wilson, Ng Hong Kiat, Wong Eleanor, Morley Michael P, Singhera Gurpreet K, Lee Chang Jie Mick, Jain Pritesh R, Tai Fei Li, Hanson Paul J, Cappola Thomas P, Margulies Kenneth B, Foo Roger, Loh Marie
Lee Kong Chian School of Medicine, Nanyang Technological University, Clinical Sciences Building, 11 Mandalay Road, Singapore, 308232, Singapore.
Cardiovascular Research Institute, National University Health System, Singapore, Singapore.
Clin Epigenetics. 2025 Mar 8;17(1):45. doi: 10.1186/s13148-025-01854-8.
Methylation changes linked to dilated cardiomyopathy (DCM) affect cardiac gene expression. We investigate DCM mechanisms regulated by CpG methylation using multi-omics and causal analyses in the largest cohort of left ventricular tissues available.
We mapped DNA methylation at ~ 850,000 CpG sites, performed array-based genotyping and conducted RNA sequencing on left ventricular tissue samples from failing and non-failing hearts across two independent DCM cohorts (discovery n = 329, replication n = 85). Summary-data-based Mendelian Randomisation (SMR) was applied to explore the causal contribution of sentinel CpGs to DCM. Fine-mapping of regions surrounding sentinel CpGs revealed additional signals for cardiovascular disease risk factors. Coordinated changes across multiple CpG sites were examined using weighted gene co-expression network analysis (WGCNA).
We identified 194 epigenome-wide significant CpGs associated with DCM (discovery P < 5.96E-08), enriched in active chromatin states in heart tissue. Amongst these, 32 sentinel CpGs significantly influenced the expression of 30 unique proximal genes (± 1 Mb). SMR suggested the causal contribution of two sentinel CpGs to DCM and two other sentinel CpGs to the expression of two unique proximal genes (P < 0.05). For one sentinel CpG, colocalisation analyses provided suggestive evidence for a single causal variant underlying the methylation-gene expression relationship. Fine-mapping revealed additional signals linked to cardiovascular disease-relevant traits, including creatinine levels and the Framingham Risk Score. Co-methylation modules were enriched in gene sets and transcriptional regulators related to cardiac physiological and pathological processes, as well as in transcriptional regulators whose cardiac relevance has yet to be determined.
Using the largest series of left ventricular tissue to date, this study investigates the causal role of cardiac methylation changes in DCM and suggests targets for experimental studies to probe DCM pathogenesis.
与扩张型心肌病（DCM）相关的甲基化变化会影响心脏基因表达。我们在最大规模的左心室组织队列中，使用多组学和因果分析方法研究由CpG甲基化调控的DCM机制。
我们对约85万个CpG位点进行了DNA甲基化图谱绘制，对来自两个独立DCM队列（发现队列n = 329，复制队列n = 85）的衰竭和非衰竭心脏的左心室组织样本进行了基于芯片的基因分型和RNA测序。应用基于汇总数据的孟德尔随机化（SMR）来探究前哨CpG对DCM的因果贡献。对前哨CpG周围区域进行精细定位，发现了与心血管疾病风险因素相关的其他信号。使用加权基因共表达网络分析（WGCNA）检查多个CpG位点的协同变化。
我们鉴定出194个与DCM相关的全表观基因组显著CpG（发现队列P < 5.96E - 08），这些CpG在心脏组织的活性染色质状态中富集。其中，32个前哨CpG显著影响30个独特近端基因（±1 Mb）的表达。SMR表明两个前哨CpG对DCM有因果贡献，另外两个前哨CpG对两个独特近端基因的表达有因果贡献（P < 0.05）。对于一个前哨CpG，共定位分析为甲基化 - 基因表达关系背后的单个因果变异提供了提示性证据。精细定位揭示了与心血管疾病相关性状（包括肌酐水平和弗雷明汉风险评分）相关的其他信号。共甲基化模块在与心脏生理和病理过程相关的基因集和转录调节因子中富集，以及在其心脏相关性尚未确定的转录调节因子中富集。
本研究使用迄今为止最大系列的左心室组织，调查了心脏甲基化变化在DCM中的因果作用，并为探索DCM发病机制的实验研究提出了靶点。
