微小RNA与ADMA双生物标志物预测肝脏移植后糖尿病合并心血管事件发生以及判断预后的实验诊断研究

Long-term survival rates of recipients have declined due to cardiovascular events, which is considered as a main cause after liver transplantation. Post-diabetes and post-hypertension are the major risk factors. Numerous studies have demonstrated that large numbers of miRNAs have been found to participate in the regulation of expression of genes related with hypertension vascular injury, cardiac hypertrophy and acute or chronic heart failure. It is widely known that ADMA is an inhibitor of endogenous NO. Metabolism of in-vivo ADMA and NO levels are regulated by DDAH. Applicants have already confirmed that marcovascular events occurred with DDAH1 genetic variability and plasma ADMA levels significantly. Preliminary experiments conducted by applicant have showed that both of miR-101 and miR-143 are able to regulate DDAH1 gene expression. We proposed to assume miR-101/143 as the functional biomarkers involved in the regulation pathway of DDAH1-ADMA-NO affect incidences and outcomes in post-liver transplantation recipients with diabetes undergoing cardiovascular complications or events. This study has the main subjects in terms of diagnostic efficacy between candidate miRNAs and clinical characteristics, association of end-points events and candidate miRNAs, estimation of recipients with risk by use of COX model, ROC curve of FOS-DM and SADPM scores.

肝移植后导致受者长期生存率下降甚至死亡主要是由于糖尿病（包括胰岛素抵抗、肥胖和代谢综合征）合并心血管事件的发生。迄今为止，已发现众多的miRNAs参与高血压、血管损伤、心肌肥厚和心力衰竭等相关基因的调节。ADMA抑制机体NO的生成，然而机体ADMA代谢受到DDAH家族调节。申请者前期证实大血管事件发生与DDAH1基因遗传变异、血浆ADMA水平存在显著性关联。体外实验证实miR-101/143为调节DDAH1表达的miRNAs。我们认为miR-101/143调节 DDAH1-ADMA通路的活化，那么进一步可将其作为肝移植后糖尿病合并心血管事件发生及其判断预后的功能性生物标志物。因此，本课题主要研究miR-101/143和ADMA双生物标志物在肝移植后糖尿病合并心血管事件发生及判断预后的诊断效能、与事件终点相关性、并运用已有的生物统计方法建立相关风险模型。

肝移植后糖尿病（包括胰岛素抵抗、肥胖和代谢综合征）合并心血管事件的发生是导致受者长期生存率下降甚至死亡的主要原因之一。目前已发现众多的 miRNAs 参与高血压、血管损伤、心肌肥厚和心力衰竭等相关基因的调节，ADMA抑制机体NO的生成，然而机体ADMA 代谢受到DDAH家族调节。申请者前期证实大血管事件发生与 DDAH1 基因遗传变异、血浆 ADMA 水平存在显著性关联。体外实验证实miR-101/143为调节DDAH1表达的miRNAs。在本课题研究中，我们收集肝移植受者并按照是否发生移植后糖尿病或心血管事件分组，分析比较不同受者DDAH1-ADMA 表达情况及miR-101/143表达水平，发生糖尿病或心血管事件的肝移植受者，其血清中的ADMA显著高于未发生者，DDAH1显著低于未发生者，提示DDAH1和ADMA有可能作为肝移植受者发生糖尿病或心血管事件的生物标志物。miR-101和miR-143在术后表达增高的肝移植受者具有更高的心血管并发症风险。提示这两种miRNAs 与肝移植受者发生心血管事件的风险有关。miR-101/143 和 ADMA 双生物标志物在肝移植后糖尿病合并心血管事件发生及判断预后中具有重要价值。进一步可将其作为肝移植后糖尿病合并心血管事件发生及其判断预后的功能性生物标志物。