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Circulating MicroRNAs as Potential Molecular Biomarkers for Intracranial Aneurysmal Rupture

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Abstract

Introduction

Diagnosis of the rupture of an intracranial aneurysm (IA) relies on sophisticated neuro-imaging studies, and molecular biomarkers to identify an IA or predict its rupture are still unavailable.

Objective

Our objective was to determine the plasma microRNA (miRNA) expression profile in patients with ruptured IA presenting as aneurysmal subarachnoid hemorrhage (aSAH) and identify potential biomarkers of aneurysmal rupture.

Methods

Plasma miRNA profiling was carried out using quantitative real-time polymerase chain reaction (qRT-PCR) in 20 patients with aSAH and 20 age- and sex-matched healthy controls. Eight differentially expressed miRNAs were validated by qPCR in a larger cohort of 88 patients with aSAH and 110 healthy controls. A receiver operating characteristic (ROC) curve was constructed to evaluate the overall performance of the miRNA-based assay. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was used to determine the potential pathway of miRNA-target genes.

Results

The miRNA profiles were clearly distinct in patients compared with controls. Validation studies showed that three upregulated miRNAs (miR-15a-5p, miR-34a-5p, miR-374a-5p) and five downregulated miRNAs (miR-146a-5p, miR-376c-3p, miR-18b-5p, miR-24-3p, miR-27b-3p) could distinguish patients with aSAH from healthy controls with high predicted probability (0.865 and 0.995, respectively). Further, the expression levels of the eight candidate miRNAs were significantly dysregulated only in aSAH cases and not in patients with SAH due to other causes. Plasma miR-146a-5p and miR-27b-3p were associated with clinical outcomes in patients with aSAH. Functional analysis of the eight differentially expressed miRNA showed that the target genes involved in signaling pathways were related to inflammation.

Conclusions

Our study determined the plasma miRNA signature of ruptured IAs and identified eight candidate miRNAs that could be useful biomarkers for this condition. We hypothesize that these differentially expressed miRNAs may play pivotal roles in IA pathology.

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Authors and Affiliations

  1. Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences(NIMHANS), Bengaluru, 560029, India

    Manjunath Supriya & Rita Christopher

  2. Department of Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bengaluru, 560029, India

    Bhagavatula Indira Devi, Dhananjaya Ishwar Bhat & Dhaval Shukla

Authors
  1. Manjunath Supriya
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  2. Rita Christopher
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  3. Bhagavatula Indira Devi
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  4. Dhananjaya Ishwar Bhat
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  5. Dhaval Shukla
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Corresponding author

Correspondence to Rita Christopher.

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Funding

The equipment (Applied Biosystems™ 7500 Real-Time PCR Systems) and consumables used for the study were  provided by the Vision Group on Science and Technology (VGST), Government of Karnataka, India (VGST/CESEM (2014-15)/GRD-311/2015-16). Ms. Supriya is a recipient of a CSIR-SRF fellowship. No other sources of funding were used to conduct this study or prepare this manuscript.

Disclosures

Manjunath Supriya, Rita Christopher, Bhagavatula Indira Devi, Dhananjaya Ishwar Bhat, and Dhaval Shukla have no conflicts of interest that are directly relevant to the content of this article.

Ethical approval and informed consent

This study was approved by the Ethical Committee of National Institute of Mental Health and Neuro Sciences (No. NIMH/DO/ethics sub-committee 11th meeting/2015). Written informed consent was obtained from all subjects or their legal guardians or to participate in the study.

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Supriya, M., Christopher, R., Indira Devi, B. et al. Circulating MicroRNAs as Potential Molecular Biomarkers for Intracranial Aneurysmal Rupture. Mol Diagn Ther 24, 351–364 (2020). https://doi.org/10.1007/s40291-020-00465-8

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