Kuscu Canan, Mallisetty Yamini, Naik Surabhi, Han Zhongji, Berta Caleb J, Kuscu Cem, Kovesdy Csaba P, Sumida Keiichi
Transplant Research Institute, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
J Clin Med. 2023 Jul 30;12(15):5010. doi: 10.3390/jcm12155010.
Patients with kidney failure with replacement therapy (KFRT) suffer from a disproportionately high cardiovascular disease burden. Circulating small non-coding RNAs (c-sncRNAs) have emerged as novel epigenetic regulators and are suggested as novel biomarkers and therapeutic targets for cardiovascular disease; however, little is known about the associations of c-sncRNAs with premature cardiovascular death in KFRT.
In a pilot case-control study of 50 hemodialysis patients who died of cardiovascular events as cases, and 50 matched hemodialysis controls who remained alive during a median follow-up of 2.0 years, we performed c-sncRNAs profiles using next-generation sequencing to identify differentially expressed circulating microRNAs (c-miRNAs) between the plasma of cases and that of controls. mRNA target prediction and pathway enrichment analysis were performed to examine the functional relevance of differentially expressed c-miRNAs to cardiovascular pathophysiology. The association of differentially expressed c-miRNAs with cardiovascular mortality was examined using multivariable conditional logistic regression.
The patient characteristics were similar between cases and controls, with a mean age of 63 years, 48% male, and 54% African American in both groups. We detected a total of 613 miRNAs in the plasma, among which five miRNAs (i.e., miR-129-1-5p, miR-500b-3p, miR-125b-1-3p, miR-3648-2-5p, and miR-3150b-3p) were identified to be differentially expressed between cases and controls with cut-offs of < 0.05 and log2 fold-change (log2FC) > 1. When using more stringent cut-offs of -adjusted < 0.05 and log2FC > 1, only miR-129-1-5p remained significantly differentially expressed, with higher levels of miR-129-1-5p in the cases than in the controls. The pathway enrichment analysis using predicted miR-129-1-5p mRNA targets demonstrated enrichment in adrenergic signaling in cardiomyocytes, arrhythmogenic right ventricular cardiomyopathy, and oxytocin signaling pathways. In parallel, the circulating miR-129-1-5p levels were significantly associated with the risk of cardiovascular death (adjusted OR [95% CI], 1.68 [1.01-2.81] for one increase in log-transformed miR-129-1-5p counts), independent of potential confounders.
Circulating miR-129-1-5p may serve as a novel biomarker for premature cardiovascular death in KFRT.
接受替代治疗的肾衰竭患者（KFRT）承受着过高的心血管疾病负担。循环小非编码RNA（c-sncRNAs）已成为新型表观遗传调节因子，并被认为是心血管疾病的新型生物标志物和治疗靶点；然而，关于c-sncRNAs与KFRT患者心血管过早死亡之间的关联，我们知之甚少。
在一项病例对照试点研究中，我们以50例死于心血管事件的血液透析患者为病例组，50例匹配的在中位随访2.0年期间存活的血液透析患者为对照组，使用下一代测序技术进行c-sncRNAs分析，以鉴定病例组和对照组血浆之间差异表达的循环微小RNA（c-miRNAs）。进行mRNA靶标预测和通路富集分析，以检查差异表达的c-miRNAs与心血管病理生理学的功能相关性。使用多变量条件逻辑回归分析差异表达的c-miRNAs与心血管死亡率之间的关联。
病例组和对照组的患者特征相似，两组的平均年龄均为63岁，男性占48%，非裔美国人占54%。我们在血浆中总共检测到613种miRNA，其中5种miRNA（即miR-129-1-5p、miR-500b-3p、miR-125b-1-3p、miR-3648-2-5p和miR-3150b-3p）在病例组和对照组之间差异表达，截断值为<0.05且log2倍数变化（log2FC）>1。当使用更严格的截断值调整后<0.05且log2FC>1时，只有miR-129-1-5p仍有显著差异表达，病例组中miR-129-1-5p的水平高于对照组。使用预测的miR-129-1-5p mRNA靶标的通路富集分析表明，其在心肌细胞的肾上腺素能信号传导、致心律失常性右室心肌病和催产素信号通路中富集。同时，循环miR-129-1-5p水平与心血管死亡风险显著相关（经log转换的miR-129-1-5p计数每增加1个单位，调整后的OR[95%CI]为1.68[1.01-2.81]），独立于潜在的混杂因素。
循环miR-129-1-5p可能是KFRT患者心血管过早死亡的新型生物标志物。
