The Danish Twin Registry and the Research Unit for Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Campusvej 55, 5230, Odense M, Denmark.
Center for Individualized Medicine in Arterial Diseases, Department of Biochemistry, Odense University Hospital, J.B. Winsloews Vej 4, 5000, Odense C, Denmark.
Clin Epigenetics. 2024 Aug 26;16(1):117. doi: 10.1186/s13148-024-01727-6.
Cardiovascular diseases (CVDs) are major causes of mortality and morbidity worldwide; yet the understanding of their molecular basis is incomplete. Multi-omics studies have significant potential to uncover these mechanisms, but such studies are challenged by genetic and environmental confounding-a problem that can be effectively reduced by investigating intrapair differences in twins. Here, we linked data on all diagnoses of the circulatory system from the nationwide Danish Patient Registry (spanning 1977-2022) to a study population of 835 twins holding genome-wide DNA methylation and gene expression data. CVD diagnoses were divided into prevalent or incident cases (i.e., occurring before or after blood sample collection (2007-2011)). The diagnoses were classified into four groups: cerebrovascular diseases, coronary artery disease (CAD), arterial and other cardiovascular diseases (AOCDs), and diseases of the veins and lymphatic system. Statistical analyses were performed by linear (prevalent cases) or cox (incident cases) regression analyses at both the individual-level and twin pair-level. Significant genes (p < 0.05) in both types of biological data and at both levels were inspected by bioinformatic analyses, including gene set enrichment analysis and interaction network analysis.
In general, more genes were found for prevalent than for incident cases, and bioinformatic analyses primarily found pathways of the immune system, signal transduction and diseases for prevalent cases, and pathways of cell-cell communication, metabolisms of proteins and RNA, gene expression, and chromatin organization groups for incident cases. This potentially reflects biology related to response to CVD (prevalent cases) and mechanisms related to regulation and development of disease (incident cases). Of specific genes, Myosin 1E was found to be central for CAD, and DEAD-Box Helicase 5 for AOCD. These genes were observed in both the prevalent and the incident analyses, potentially reflecting that their DNA methylation and gene transcription levels change both because of disease (prevalent cases) and prior disease (incident cases).
We present novel biomarkers for CVD by performing multi-omics analysis in twins, hereby lowering the confounding due to shared genetics and early life environment-a study design that is surprisingly rare in the field of CVD, and where additional studies are highly needed.
心血管疾病（CVD）是全球主要的死亡和发病原因；然而，其分子基础的理解并不完整。多组学研究具有揭示这些机制的巨大潜力，但此类研究受到遗传和环境混杂的挑战——通过研究双胞胎个体内的差异，可以有效地减少这个问题。在这里，我们将全国丹麦患者登记处（1977-2022 年）中所有循环系统诊断的数据与一个包含全基因组 DNA 甲基化和基因表达数据的 835 对双胞胎的研究人群相关联。CVD 诊断分为现患或新发病例（即发生在血液样本采集之前或之后（2007-2011 年））。这些诊断被分为四类：脑血管疾病、冠状动脉疾病（CAD）、动脉和其他心血管疾病（AOCDs）以及静脉和淋巴系统疾病。个体水平和双胞胎对水平的线性（现患病例）或 Cox（新发病例）回归分析进行了统计学分析。在两种类型的生物数据和两个水平上都有显著意义的基因（p < 0.05）通过生物信息学分析进行了检查，包括基因集富集分析和相互作用网络分析。
一般来说，现患病例的基因比新发病例多，生物信息学分析主要发现现患病例的免疫系统、信号转导和疾病途径，以及新发病例的细胞间通讯、蛋白质和 RNA 代谢、基因表达和染色质组织途径。这可能反映了与 CVD 反应相关的生物学（现患病例）和与疾病调节和发展相关的机制（新发病例）。在特定基因中，肌球蛋白 1E 被发现是 CAD 的核心，DEAD-Box 解旋酶 5 是 AOCD 的核心。这些基因在现患和新发分析中都有观察到，这可能反映了它们的 DNA 甲基化和基因转录水平的变化既是由于疾病（现患病例），也是由于先前的疾病（新发病例）。
我们通过在双胞胎中进行多组学分析提出了 CVD 的新生物标志物，从而降低了由于共同遗传和早期生活环境造成的混杂——这种研究设计在 CVD 领域非常罕见，非常需要进一步的研究。
