Cardiovascular disease had a global prevalence of 523 million cases and 18.6 million deaths in 2019. The current standard for diagnosing coronary artery disease (CAD) is coronary angiography. Surprisingly, despite well-established clinical indications, up to 40% of the one million invasive cardiac catheterizations return a result of ‘no blockage’. The present studies employed RNA sequencing of whole blood to identify an RNA signature in patients with angiographically confirmed CAD. Whole blood RNA was depleted of ribosomal RNA (rRNA) and analyzed by single-molecule sequencing of RNA (RNAseq) to identify transcripts associated with CAD (TRACs) in a discovery group of 96 patients presenting for elective coronary catheterization. The resulting transcript counts were compared between groups to identify differentially expressed genes (DEGs). Surprisingly, 98% of DEGs/TRACs were down-regulated ~ 1.7-fold in patients with mild to severe CAD (> 20% stenosis). The TRACs were independent of comorbid risk factors for CAD, such as sex, hypertension, and smoking. Bioinformatic analysis identified an enrichment in transcripts such as FoxP1, ICOSLG, IKZF4/Eos, SMYD3, TRIM28, and TCF3/E2A that are likely markers of regulatory T cells (Treg), consistent with known reductions in Tregs in CAD. A validation cohort of 80 patients confirmed the overall pattern (92% down-regulation) and supported many of the Treg-related changes. TRACs were enriched for transcripts associated with stress granules, which sequester RNAs, and ciliary and synaptic transcripts, possibly consistent with changes in the immune synapse of developing T cells. These studies identify a novel mRNA signature of a Treg-like defect in CAD patients and provides a blueprint for a diagnostic test for CAD. The pattern of changes is consistent with stress-related changes in the maturation of T and Treg cells, possibly due to changes in the immune synapse.

中文翻译：

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冠状动脉疾病中血液的 RNA 测序：调节性 T 细胞失衡的参与

2019 年，心血管疾病的全球患病率为 5.23 亿例，死亡人数为 1860 万。目前诊断冠状动脉疾病 (CAD) 的标准是冠状动脉造影。令人惊讶的是，尽管有完善的临床适应症，100 万次侵入性心导管插入术中高达 40% 的结果是“无阻塞”。本研究采用全血 RNA 测序来识别经血管造影证实的 CAD 患者的 RNA 特征。全血 RNA 去除了核糖体 RNA (rRNA)，并通过 RNA 的单分子测序 (RNAseq) 进行分析，以确定与 CAD (TRAC) 相关的转录本，该发现组由 96 名就诊的选择性冠状动脉导管插入术患者组成。在组之间比较所得的转录物计数以鉴定差异表达基因（DEG）。令人惊讶的是，在轻度至重度 CAD（> 20% 狭窄）患者中，98% 的 DEGs/TRACs 下调了约 1.7 倍。TRACs 独立于 CAD 的合并危险因素，如性别、高血压和吸烟。生物信息学分析确定了转录物的富集，例如 FoxP1、ICOSLG、IKZF4/Eos、SMYD3、TRIM28 和 TCF3/E2A，它们可能是调节性 T 细胞 (Treg) 的标志物，这与 CAD 中 Tregs 的已知减少一致。80 名患者的验证队列证实了整体模式（92% 下调）并支持许多与 Treg 相关的变化。TRAC 富含与应激颗粒相关的转录物，其隔离 RNA，以及纤毛和突触转录物，这可能与发育中的 T 细胞免疫突触的变化一致。这些研究确定了 CAD 患者 Treg 样缺陷的新 mRNA 特征，并为 CAD 诊断测试提供了蓝图。这种变化模式与 T 细胞和 Treg 细胞成熟过程中与压力相关的变化一致，可能是由于免疫突触的变化。