The genomic regulatory networks underlying the pathogenesis of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) are incompletely understood. As intermediate traits, protein biomarkers report on underlying disease severity and prognosis in NSTE-ACS. We hypothesized that integration of dense microRNA (miRNA) profiling with biomarker measurements would highlight potential regulatory pathways that underlie the relationships between prognostic biomarkers, miRNAs, and cardiovascular phenotypes. We performed miRNA sequencing using whole blood from 186 patients from the TRILOGY-ACS trial. Seven circulating prognostic biomarkers were measured: NH2-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein, osteopontin (OPN), myeloperoxidase, growth differentiation factor 15, monocyte chemoattractant protein, and neopterin. We tested miRNAs for association with each biomarker with generalized linear models and controlled the false discovery rate at 0.05. Ten miRNAs, including known cardiac-related miRNAs 25-3p and 423-3p, were associated with NT-proBNP levels (min. P = 7.5 × 10-4) and 48 miRNAs, including cardiac-related miRNAs 378a-3p, 20b-5p and 320a, -b, and -d, were associated with OPN levels (min. P = 1.6 × 10-6). NT-proBNP and OPN were also associated with time to cardiovascular death, myocardial infarction (MI), or stroke in the sample. By integrating large-scale miRNA profiling with circulating biomarkers as intermediate traits, we identified associations of known cardiac-related and novel miRNAs with two prognostic biomarkers and identified potential genomic networks regulating these biomarkers. These results, highlighting plausible biological pathways connecting miRNAs with biomarkers and outcomes, may inform future studies seeking to delineate genomic pathways underlying NSTE-ACS outcomes.

中文翻译：

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骨桥蛋白和NT-proBNP与急性冠状动脉综合征中循环miRNA水平的关系。

非ST段抬高急性冠状动脉综合征（NSTE-ACS）的发病机理的基因组调控网络尚未完全了解。作为中间性状，蛋白质生物标志物报告了NSTE-ACS中潜在的疾病严重程度和预后。我们假设，密集的microRNA（miRNA）分析与生物标志物测量的整合将突出潜在的调节途径，这些通路是预后生物标志物，miRNA和心血管表型之间关系的基础。我们使用来自TRILOGY-ACS试验的186名患者的全血进行了miRNA测序。测量了七个循环的预后生物标志物：NH2端前B型利尿钠肽（NT-proBNP），高敏C反应蛋白，骨桥蛋白（OPN），髓过氧化物酶，生长分化因子15，单核细胞趋化蛋白，和新蝶呤。我们使用广义线性模型测试了与每种生物标记物相关的miRNA，并将错误发现率控制在0.05。十种miRNA，包括已知的心脏相关miRNA 25-3p和423-3p，与NT-proBNP水平相关（最低P = 7.5×10-4），而48种miRNA，包括与心脏相关的miRNA 378a-3p，20b- 5p和320a，-b和-d与OPN水平相关（最低P = 1.6×10-6）。NT-proBNP和OPN也与样本中出现心血管死亡，心肌梗塞（MI）或中风的时间有关。通过将大型miRNA分析与循环生物标志物整合为中间特征，我们鉴定了已知的心脏相关和新型miRNA与两个预后生物标志物的关联，并鉴定了调节这些生物标志物的潜在基因组网络。这些结果，