Abu-Halima Masood, Ludwig Nicole, Rädle-Hurst Tanja, Keller Andreas, Motsch Lars, Marsollek Ina, El Rahman Mohammed Abd, Abdul-Khaliq Hashim, Meese Eckart
Department of Human Genetics, Saarland University, Homburg/Saar, Germany.
Department of Pediatric Cardiology, Saarland University Medical Center, Homburg/Saar, Germany.
Thorac Cardiovasc Surg. 2018 Jan;66(1):116-124. doi: 10.1055/s-0037-1604083. Epub 2017 Jul 5.
Marfan's syndrome (MFS) is an autosomal dominant inheritance disorder with a 1/5,000 live-birth prevalence. It is characterized by a wide range of clinical manifestations with more than 3,000 mutations identified in the gene. In this study, we aimed to determine if specific patterns of circulating micro-RNAs (miRNAs) are associated with MFS-associated with cardiovascular diseases.
Microarray-based miRNA profiling was performed on blood samples of 12 MFS patients, and 12 healthy volunteers (HVs) controls and the differences in miRNA abundance between the two groups were validated using independent cohorts of 22 MFS and of 22 HV controls by real-time quantitative polymerase chain reaction (RT-qPCR). Enrichment analyses of altered miRNA abundance were predicted using bioinformatics tools.
Altered miRNA abundance levels were determined between MFS ( = 34) and HVs ( = 34). In a screening phase, we analyzed 12 patients with MFS and 12 HVs by miRNA microarray. We found 198 miRNAs that were significantly altered in MFS patients as compared with HVs, including 16 miRNAs with a more than 1.5-fold change. Out of these 16 miRNAs, 10 showed a decreased abundance and 6 showed an increased abundance. In the validation phase, we analyzed independent cohorts of 22 MFS and of 22 HV controls by RT-qPCR. We confirmed the direction of abundance changes and the significance of different abundances between MFS patients and HVs for four miRNAs, namely, miR-362-5p, miR-339-3p, miR-340-5p, and miR-210-3p. Only the miR-150-5p showed a significant correlation with mitral valve prolapse ( = 0.010). The predicted targets for the validated miRNAs were associated with signal transduction, tissue remodeling, and cellular interaction pathways.
The altered abundance level of different miRNAs in whole blood of MFS patients lays the ground to the development of novel diagnostic approaches with altered miRNAs levels associated with MFS with manifestations associated with cardiovascular diseases.
马凡综合征（MFS）是一种常染色体显性遗传疾病，活产患病率为1/5000。其临床表现多样，该基因已鉴定出3000多种突变。在本研究中，我们旨在确定循环微RNA（miRNA）的特定模式是否与MFS相关的心血管疾病有关。
对12例MFS患者和12例健康志愿者（HV）的血液样本进行基于微阵列的miRNA分析，并通过实时定量聚合酶链反应（RT-qPCR），使用22例MFS患者和22例HV对照的独立队列验证两组之间miRNA丰度的差异。使用生物信息学工具预测miRNA丰度改变的富集分析。
确定了MFS患者（n = 34）和HV（n = 34）之间miRNA丰度水平的改变。在筛选阶段，我们通过miRNA微阵列分析了12例MFS患者和12例HV。我们发现与HV相比，MFS患者中有198种miRNA发生了显著改变，其中16种miRNA的变化超过1.5倍。在这16种miRNA中，10种丰度降低，6种丰度增加。在验证阶段，我们通过RT-qPCR分析了22例MFS患者和22例HV对照的独立队列。我们证实了4种miRNA，即miR-362-5p、miR-339-3p、miR-340-5p和miR-210-3p在MFS患者和HV之间丰度变化的方向以及不同丰度的显著性。只有miR-150-5p与二尖瓣脱垂显著相关（P = 0.010）。验证的miRNA的预测靶标与信号转导、组织重塑和细胞相互作用途径有关。
MFS患者全血中不同miRNA丰度水平的改变为开发新的诊断方法奠定了基础，这些方法利用与MFS相关且与心血管疾病表现相关的miRNA水平的改变。
