Deregulated microRNA and mRNA expression profiles in the peripheral blood of patients with Marfan syndrome

Masood Abu-Halima,Dominic Henn,Hashim Abdul-Khaliq,Andreas Keller,Tanja Rädle-Hurst,Mustafa Kahraman,Eckart Meese

doi:10.1186/s12967-018-1429-3

Abstract

BackgroundMicroRNAs (miRNAs) are small RNAs regulating gene expression post-transcriptionally. While acquired changes of miRNA and mRNA profiles in cancer have been extensively studied, little is known about expression changes of circulating miRNAs and messenger RNAs (mRNA) in monogenic constitutional anomalies affecting several organ systems, like Marfan syndrome (MFS). We performed integrated miRNA and mRNA expression profiling in blood samples of Marfan patients in order to investigate deregulated miRNA and mRNA networks in these patients which could serve as potential diagnostic and prognostic tools for MFS therapy.MethodsMiRNA and mRNA expression profiles were determined in blood samples from MFS patients (n = 7) and from healthy volunteer controls (n = 7) by microarray analysis. Enrichment analyses of altered mRNA expression were identified using bioinformatic tools.ResultsA total of 28 miRNAs and 32 mRNAs were found to be significantly altered in MFS patients compared to controls (> 2.0-fold change, adjusted P < 0.05). The expression of 11 miRNA and 6 mRNA candidates was validated by RT-qPCR in an independent cohort of 26 MFS patients and 26 matched HV controls. Significant inverse correlations were evident between 8 miRNAs and 5 mRNAs involved in vascular pathology, inflammation and telomerase regulation. Significant positive correlations were present for 7 miRNAs with age, for 2 miRNAs with the MFS aortic root status (Z-score) and for 7 miRNAs with left ventricular end-diastolic diameter in MFS patients. In addition, miR-331-3p was significantly up-regulated in MFS patients without mitral valve prolapse (MVP) as compared with patients with MVP.ConclusionsOur data show deregulated gene and miRNA expression profiles in the peripheral blood of MFS patients, demonstrating several candidates for prognostic biomarkers for cardiovascular manifestations in MFS as well as targets for novel therapeutic approaches. A deregulation of miRNA expression seems to play an important role in MFS, highlighting the plethora of effects on post-transcriptional regulation of miRNAs and mRNAs initiated by constitutional mutations in single genes.Trial registration Nr: EA2/131/10. Registered 28 December, 2010

Highlights

MicroRNAs are small RNAs regulating gene expression post-transcriptionally
The correlation heatmaps illustrated that the correlation was strong (Pearson correlation coefficient r of mostly > 0.80 and > 0.92 for miRNA and messenger RNAs (mRNA), respectively) in both Marfan syndrome (MFS) patients and healthy volunteer (HV) controls, except for two samples which we identified as outliers in the mRNA data by applying Hampel’s rule for outlier detection [17]
A strong deregulation of both miRNA and mRNA expression profiles was present in MFS patients including multiple genes with high relevance to cardiovascular pathogenesis and diseases

Summary

Introduction

While acquired changes of miRNA and mRNA profiles in cancer have been extensively studied, little is known about expression changes of circulating miRNAs and messenger RNAs (mRNA) in monogenic constitutional anomalies affecting several organ systems, like Marfan syndrome (MFS). We performed integrated miRNA and mRNA expression profiling in blood samples of Marfan patients in order to investigate deregulated miRNA and mRNA networks in these patients which could serve as potential diagnostic and prognostic tools for MFS therapy. It is conceivable that in addition to an entire miRNome expression profiling, the search for miRNAs whose expression inversely correlates with the expression of mRNA targets may demonstrate another layer of the molecular diversity of this pleiotropic syndrome and may potentially be a useful diagnostic and prognostic tool for MFS therapy and treatment. This is the first large-scale investigation of the association between miRNA-related mRNAs in patients with MFS

Methods

Results

Discussion

Conclusion