Gene Expression Signature in Patients With Symptomatic Peripheral Artery Disease.
Gene Expression Signature in Patients With Symptomatic Peripheral Artery Disease.
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DOI：
10.1161/atvbaha.120.315857
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Berger JS
中科院分区：
文献类型：
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作者：
Newman JD;Cornwell MG;Zhou H;Rockman C;Heguy A;Suarez Y;Cheng HS;Feinberg MW;Hochman JS;Ruggles KV;Berger JS
外周动脉疾病（PAD）是一种下肢动脉粥样硬化血栓形成性疾病，具有相当高的发病率和死亡率。我们使用新一代测序技术来鉴定与PAD及其预后相关的全基因组表达特征。我们对接受下肢血管重建术的严重症状性PAD患者和对照组进行了全血RNA测序。通过比较PAD患者（n=42）与年龄和性别匹配的对照组（N=29），确定了失调的通路和血液转录模块。在LER之前，在有或没有发生主要不良心脏或肢体事件（MACLE）的PAD患者中比较了识别的特征。然后在小鼠后肢缺血模型中评估与普遍的PAD和事件MACLE相关的新的microRNA（miRNA）。127个转录物差异表达（77个上调和50个下调;调整的p < 0.05，|对数2倍变化|> 0.5），并使用加权基因共表达网络分析（WGCNA）进行分析。WGCNA显示，PAD患者的血液模块富含免疫激活、分泌颗粒和凝血功能。在这127个差异表达的转录物中，40个与MACLE显著相关（对数秩FDR < 0.1）。microRNA（miR）miR-4477 b在PAD患者中和随后的MACLE中以及在小鼠后肢缺血模型中显著增加。全血转录特征识别出具有症状性PAD的患者和MACLE风险增加的PAD患者。先前未表征的转录物miRNA（miR-4477 b）在普遍的PAD、事件MACLE和小鼠后肢缺血模型中过表达。我们新的转录组学特征为严重症状性PAD患者的潜在机制提供了深入了解。
Peripheral artery disease (PAD) is an atherothrombotic disease of the lower limbs with substantial morbidity and mortality. We used next-generation sequencing to identify genome-wide expression signatures associated with prevalent PAD and its outcomes. We performed whole blood RNA sequencing among severe symptomatic PAD patients undergoing lower extremity revascularization and controls. Dysregulated pathways and blood transcriptional modules were identified by comparing PAD patients (n=42) to age- and sex-matched controls (N=29). The identified signature was compared in PAD patients prior to LER with or without incident major adverse cardiac or limb events (MACLE). A novel microRNA (miRNA) associated with prevalent PAD and incident MACLE was then evaluated in a mouse hindlimb ischemia model. 127 transcripts were differentially expressed (77 upregulated and 50 downregulated; adjusted p < 0.05, |log2foldchange| > 0.5) and analyzed using Weighted Gene Co-expression Network Analysis (WGCNA). WGCNA revealed blood modules enriched for immune activation, secretory granules, and coagulation in patients with PAD. Of these 127 differentially expressed transcripts, 40 were significantly associated with MACLE (log-rank FDR < 0.1). MicroRNA (miR) miR-4477b was significantly increased in PAD patients with subsequent MACLE and in a mouse hindlimb ischemia model. A whole-blood transcript signature identified patients with symptomatic PAD and PAD patients at increased risk of MACLE. A previously uncharacterized transcript miRNA (miR-4477b) was overexpressed in prevalent PAD, incident MACLE, and in a mouse hindlimb ischemia model. Our novel transcriptomic signature provides insight into potential mechanisms of patients with severe symptomatic PAD.