基于转录组学及表观遗传组学筛选与血管紧张素-Ⅱ相关的胸主动脉瘤/夹层诊断标志物

Angiotensin-ⅡRelated Diagnostic Markers in Thoracic Aortic Aneurysms/Dissection Based on Transcriptomics and Epigenomics

目的探讨基于转录组学及表观遗传组学筛选与血管紧张素-Ⅱ(Ang-Ⅱ)作用相关的胸主动脉瘤/夹层(Thoracic aortic aneurysms/dissection,TAAD)诊断标志物。方法利用数据集GSE35627筛选Ang-Ⅱ作用于大鼠原代主动脉平滑肌细胞的差异表达基因(DEGs)。取与Ang-Ⅱ相关数据集DEGs的交集,使用GeneMANIA数据库对交集基因进行功能分析和DO分析。使用R软件ChAMP包分析正常人和主动脉夹层(AD)患者升主动脉组织的表观基因组数据集GSE84274的差异甲基化水平,分析关键DEGs甲基化水平。使用人胸主动脉瘤(TAA)外周血样本全基因组基因表达谱数据集GSE9106 testing组绘制受试者工作特征曲线(ROC),预测诊断的有效性。结果在细胞水平、动物模型和TAAD临床病例的基础上,从GSE35627、GSE64613和GSE52093数据集得到6个交集基因:SLC7A8、WISP1、IL1R1、BCAT1、NID2及ATOH8。表观遗传组学分析发现,WISP1和NID2分别有5个和3个差异甲基化位点(DMPs)的甲基化水平存在明显差异。ROC曲线验证结果显示,WISP1的AUC为0.7,其特异度和敏感度较强,具有较高的准确性。结论通过转录组学及表观遗传组学分析可知,Ang-Ⅱ相关基因WISP1和NID2有助于TAAD的早期诊断。

Objective Exploring the screening of diagnostic markers in thoracic aortic aneurysm/dissection(TAAD)related to the action of angiotensin-Ⅱbased on transcriptomics and epigenetics.Method Use dataset GSE35627 to screen differentially expressed genes(DEGs)of Ang-Ⅱacting on primary aortic smooth muscle cells of rats.Take the intersection of Ang-Ⅱrelated datasets,and perform function and DO analysis on the intersection genes using GeneMANIA database.Use R software ChAMP package to analyze the differential methy-lation levels of the epigenome dataset GSE84274 in ascending aorta tissues of normal individuals and patients with aortic dissection(AD),and analyze the methylation levels of key DEGs.The GSE9106 testing group of human thoracic aortic aneurysm(TAA)peripheral blood samples was used to predict the diagnostic validity of receiver operating characteristic curve(ROC)and expression levels.Results Based on the combination of cell level,animal model and TAAD clinical cases,six intersection genes were obtained from three datasets GSE35627,GSE64613 and GSE52093:SLC7A8,WISP1,IL1R1,BCAT1,NID2 and ATOH8.Finally,in epigenetics analysis,it was found that there were significant differences in the methylation levels of 5 and 3 differentially methylated sites(DMPs)between WISP1 and NID2,respectively.The ROC curve validation result shows that the AUC of WISP1 is 0.7,with strong specificity and sensitivity,and high accuracy.Conclusion Transcriptomic and epigenetic analysis show that Ang-Ⅱrelated genes WISP1 and NID2 contribute to the early diagnosis of TAAD.