A systematic review of articles examining measurements of DNA cytosine methylation in CVD was conducted in accordance with PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. The search yielded 5,563 articles from PubMed and CENTRAL databases. From 99 studies with a total of 87,827 individuals eligible for analysis, a database was created combining all CpG-, gene- and study-related information. It contains 74,580 unique CpG sites, of which 1452 CpG sites were mentioned in ≥ 2, and 441 CpG sites in ≥ 3 publications. Two sites were referenced in ≥ 6 publications: cg01656216 (near ZNF438) related to vascular disease and epigenetic age, and cg03636183 (near F2RL3) related to coronary heart disease, myocardial infarction, smoking and air pollution. Of 19,127 mapped genes, 5,807 were reported in ≥ 2 studies. Most frequently reported were TEAD1 (TEA Domain Transcription Factor 1) and PTPRN2 (Protein Tyrosine Phosphatase Receptor Type N2) in association with outcomes ranging from vascular to cardiac disease. Gene set enrichment analysis of 4,532 overlapping genes revealed enrichment for Gene Ontology molecular function \"DNA-binding transcription activator activity\" (q = 1.65 × 10-11) and biological processes \"skeletal system development\" (q = 1.89 × 10-23). Gene enrichment demonstrated that general CVD-related terms are shared, while \"heart\" and \"vasculature\" specific genes have more disease-specific terms as PR interval for \"heart\" or platelet distribution width for \"vasculature.\" STRING analysis revealed significant protein-protein interactions between the products of the differentially methylated genes (p = 0.003) suggesting that dysregulation of the protein interaction network could contribute to CVD. Overlaps with curated gene sets from the Molecular Signatures Database showed enrichment of genes in hemostasis (p = 2.9 × 10-6) and atherosclerosis (p = 4.9 × 10-4).
This review highlights the current state of knowledge on significant relationship between DNA methylation and CVD in humans. An open-access database has been compiled of reported CpG methylation sites, genes and pathways that may play an important role in this relationship.
根据PRISMA(系统评价和荟萃分析的首选报告项目)指南,对研究CVD中DNA胞嘧啶甲基化测量的文章进行了系统评价。该搜索从PubMed和CENTRAL数据库中获得了5,563篇文章。从99项研究中,共有87,827人符合分析条件,创建了一个数据库,将所有CpG-,与基因和研究相关的信息。它包含74,580个独特的CpG站点,其中1452个CpG位点在≥2个出版物中提及,441个CpG位点在≥3个出版物中提及。在≥6种出版物中引用了两个位点:cg01656216(接近ZNF438)与血管疾病和表观遗传年龄有关,和cg03636183(接近F2RL3)与冠心病有关,心肌梗塞,吸烟和空气污染。在19,127个映射基因中,在≥2项研究中报告了5,807项。最常见的报道是TEAD1(TEA结构域转录因子1)和PTPRN2(蛋白酪氨酸磷酸酶受体N2型),与从血管到心脏疾病的结局有关。对4,532个重叠基因的基因集富集分析揭示了基因本体分子功能“DNA结合转录激活因子活性”(q=1.65×10-11)和生物学过程“骨骼系统发育”(q=1.89×10-23)。基因富集表明,与CVD相关的一般术语是共有的,而“心脏”和“脉管系统”特定基因具有更多的疾病特异性术语,如“心脏”的PR间隔或“脉管系统”的血小板分布宽度。“STRING分析揭示了差异甲基化基因产物之间的显着蛋白质-蛋白质相互作用(p=0.003),表明蛋白质相互作用网络的失调可能导致CVD。来自分子特征数据库的精选基因集的重叠显示了止血(p=2.9×10-6)和动脉粥样硬化(p=4.9×10-4)中基因的富集。
这篇综述强调了人类DNA甲基化与CVD之间重要关系的知识现状。一个开放访问的数据库已经编制了报告的CpG甲基化位点,可能在这种关系中起重要作用的基因和途径。