Nanomaterials and Nanotechnology Research Center (CINN) Spanish National Research Council (CSIC) El Entrego Asturias Spain.
Health Research Institute of the Principality of Asturias (ISPA) Oviedo Asturias Spain.
J Am Heart Assoc. 2024 Nov 5;13(21):e035777. doi: 10.1161/JAHA.124.035777. Epub 2024 Oct 29.
Hypertrophic cardiomyopathy is an autosomal dominant cardiac disease. The mechanisms that determine its variable expressivity are poorly understood. Epigenetics could play a crucial role in bridging the gap between genotype and phenotype by orchestrating the interplay between the environment and the genome regulation. In this study we aimed to establish a possible correlation between the peripheral blood DNA methylation patterns and left ventricular hypertrophy severity in patients with hypertrophic cardiomyopathy, evaluating the potential impact of lifestyle variables and providing a biological context to the observed changes.
Methylation data were obtained from peripheral blood samples (Infinium MethylationEPIC BeadChip arrays). We employed multiple pair-matched models to extract genomic positions whose methylation correlates with the degree of left ventricular hypertrophy in 3 monozygotic twin pairs carrying the same founder pathogenic variant ( p.Gly263Ter). This model enables the isolation of the environmental influence, beyond age, on DNA methylation changes by removing the genetic background. Our results revealed a more anxious personality among more severely affected individuals. We identified 56 differentially methylated positions that exhibited moderate, proportional changes in methylation associated with left ventricular hypertrophy. These differentially methylated positions were enriched in regions regulated by repressor histone marks and tended to cluster at genes involved in left ventricular hypertrophy development, such as , , , or , suggesting that changes in peripheral blood may reflect myocardial alterations.
We present a unique pair-matched model, based on 3 monozygotic twin pairs carrying the same founder pathogenic variant and different phenotypes. This study provides further evidence of the pivotal role of epigenetics in hypertrophic cardiomyopathy variable expressivity.
肥厚型心肌病是一种常染色体显性遗传性心脏病。决定其可变表达的机制尚不清楚。表观遗传学可以通过协调环境与基因组调控之间的相互作用，在基因型和表型之间架起桥梁，从而在其中发挥关键作用。本研究旨在确定肥厚型心肌病患者外周血 DNA 甲基化模式与左心室肥厚严重程度之间可能存在的相关性，评估生活方式变量的潜在影响，并为观察到的变化提供生物学背景。
从外周血样本（Infinium MethylationEPIC BeadChip 阵列）中获取甲基化数据。我们采用多个配对匹配模型，从携带相同致病突变（p.Gly263Ter）的 3 对同卵双胞胎中提取与左心室肥厚程度相关的基因组位置的甲基化数据。该模型通过消除遗传背景，能够分离出年龄以外的环境对 DNA 甲基化变化的影响。我们的结果表明，受影响更严重的个体表现出更焦虑的个性。我们发现了 56 个差异甲基化位置，这些位置的甲基化与左心室肥厚呈中度比例变化。这些差异甲基化位置富集在受抑制组蛋白标记调节的区域，并且倾向于聚集在涉及左心室肥厚发展的基因上，例如、、、或，这表明外周血的变化可能反映了心肌的改变。
我们提出了一种基于携带相同致病突变但表现出不同表型的 3 对同卵双胞胎的独特配对匹配模型。本研究进一步证明了表观遗传学在肥厚型心肌病可变表达中的关键作用。
