Department of Cardiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Department of Radiology, Amsterdam UMC, Amsterdam, The Netherlands.
Clin Epigenetics. 2021 Dec 11;13(1):217. doi: 10.1186/s13148-021-01204-4.
Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene (FBN1). Here, we undertook the first epigenome-wide association study (EWAS) in patients with MFS aiming at identifying DNA methylation loci associated with MFS phenotypes that may shed light on the disease process.
The Illumina 450 k DNA-methylation array was used on stored peripheral whole-blood samples of 190 patients with MFS originally included in the COMPARE trial. An unbiased genome-wide approach was used, and methylation of CpG-sites across the entire genome was evaluated. Additionally, we investigated CpG-sites across the FBN1-locus (15q21.1) more closely, since this is the gene defective in MFS. Differentially Methylated Positions (DMPs) and Differentially Methylated Regions (DMRs) were identified through regression analysis. Associations between methylation levels and aortic diameters and presence or absence of 21 clinical features of MFS at baseline were analyzed. Moreover, associations between aortic diameter change, and the occurrence of clinical events (death any cause, type-A or -B dissection/rupture, or aortic surgery) and methylation levels were analyzed.
We identified 28 DMPs that are significantly associated with aortic diameters in patients with MFS. Seven of these DMPs (25%) could be allocated to a gene that was previously associated with cardiovascular diseases (HDAC4, IGF2BP3, CASZ1, SDK1, PCDHGA1, DIO3, PTPRN2). Moreover, we identified seven DMPs that were significantly associated with aortic diameter change and five DMP's that associated with clinical events. No significant associations at p < 10 or p < 10 were found with any of the non-cardiovascular phenotypic MFS features. Investigating DMRs, clusters were seen mostly on X- and Y, and chromosome 18-22. The remaining DMRs indicated involvement of a large family of protocadherins on chromosome 5, which were not reported in MFS before.
This EWAS in patients with MFS has identified a number of methylation loci significantly associated with aortic diameters, aortic dilatation rate and aortic events. Our findings add to the slowly growing literature on the regulation of gene expression in MFS patients.
马凡综合征（MFS）是一种由原纤维蛋白 1 基因（FBN1）突变引起的结缔组织疾病。在这里，我们进行了首例马凡综合征患者的全基因组表观遗传关联研究（EWAS），旨在确定与 MFS 表型相关的 DNA 甲基化位点，这些位点可能揭示疾病的发生过程。
我们使用 Illumina 450k DNA 甲基化阵列对最初纳入 COMPARE 试验的 190 名 MFS 患者的储存外周全血样本进行检测。采用无偏基因组方法，评估整个基因组中 CpG 位点的甲基化情况。此外，我们更密切地研究了 FBN1 基因座（15q21.1）上的 CpG 位点，因为这是 MFS 中缺陷的基因。通过回归分析确定差异甲基化位置（DMP）和差异甲基化区域（DMR）。分析基线时 MFS 患者的主动脉直径和 21 种临床特征与甲基化水平之间的相关性。此外，分析主动脉直径变化与临床事件（任何原因死亡、A型或 B 型夹层/破裂或主动脉手术）的发生以及与甲基化水平之间的相关性。
我们鉴定出 28 个与 MFS 患者主动脉直径显著相关的 DMP。其中 7 个 DMP（25%）可分配到一个先前与心血管疾病相关的基因（HDAC4、IGF2BP3、CASZ1、SDK1、PCDHGA1、DIO3、PTPRN2）。此外，我们鉴定出 7 个与主动脉直径变化显著相关的 DMP 和 5 个与临床事件相关的 DMP。没有发现任何与非心血管表型 MFS 特征的 p 值小于 10 或 p 值小于 10 的显著关联。研究 DMR 时，主要在 X 染色体和 Y 染色体以及 18-22 号染色体上看到簇。其余 DMR 表明涉及到 5 号染色体上一大组原钙粘蛋白，以前在 MFS 中没有报道过。
这项 MFS 患者的 EWAS 鉴定出了一些与主动脉直径、主动脉扩张率和主动脉事件显著相关的甲基化位点。我们的研究结果增加了关于 MFS 患者基因表达调控的缓慢增长的文献。
