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Profiling of Circulating Gene Expression Reveals Molecular Signatures Associated with Intracranial Aneurysm Rupture Risk

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Abstract

Background

Following detection, rupture risk assessment for intracranial aneurysms (IAs) is critical. Towards molecular prognostics, we hypothesized that circulating blood RNA expression profiles are associated with IA risk.

Methods

We performed RNA sequencing on 68 blood samples from IA patients. Here, patients were categorized as either high or low risk by assessment of aneurysm size (≥ 5 mm = high risk) and Population, Hypertension, Age, Size, Earlier subarachnoid hemorrhage, Site (PHASES) score (≥ 1 = high risk). Modified F-statistics and Benjamini-Hochberg false discovery rate correction was performed on transcripts per million-normalized gene counts. Protein-coding genes expressed in ≥ 50% of samples with a q value < 0.05 and an absolute fold-change ≥ 2 were considered significantly differentially expressed. Bioinformatics in Ingenuity Pathway Analysis was performed to understand the biology of risk-associated expression profiles. Association was assessed between gene expression and risk via Pearson correlation analysis. Linear discriminant analysis models using significant genes were created and validated for classification of high-risk cases.

Results

We analyzed transcriptomes of 68 IA patients. In these cases, 31 IAs were large (≥ 5 mm), while 26 IAs had a high PHASES score. Based on size, 36 genes associated with high-risk IAs, and two were correlated with the size measurement. Alternatively, based on PHASES score, 76 genes associated with high-risk cases, and nine of them showed significant correlation to the score. Similar ontological terms were associated with both gene profiles, which reflected inflammatory signaling and vascular remodeling. Prediction models based on size and PHASES stratification were able to correctly predict IA risk status, with > 80% testing accuracy for both.

Conclusions

Here, we identified genes associated with IA risk, as quantified by common clinical metrics. Preliminary classification models demonstrated feasibility of assessing IA risk using whole blood expression.

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Acknowledgements

The authors thank the patients who participated in this study. Special thanks also to Brandon Marzullo, MS, and Jonathan Bard, MS, for RNAseq data analysis assistance, and Jennifer Gay, CCRP, and Elizabeth Bommaraju for study protocol management. This work was performed in part at the New York State Center of Excellence in Bioinformatics and Life Sciences’ Genomics and Bioinformatics Core.

Author information

Authors and Affiliations

  1. Canon Stroke and Vascular Research Center, University at Buffalo, 875 Ellicott Street, Buffalo, NY, 14203, USA

    Kerry E. Poppenberg, Briana A. Santo, Lee Chaves, Sricharan S. Veeturi, Muhammad Waqas, Andre Monteiro, Kenneth V. Snyder, Adnan H. Siddiqui & Vincent M. Tutino

  2. Department of Neurosurgery, University at Buffalo, Buffalo, NY, USA

    Kerry E. Poppenberg, Lee Chaves, Muhammad Waqas, Andre Monteiro, Kenneth V. Snyder, Adnan H. Siddiqui & Vincent M. Tutino

  3. Department of Pathology and Anatomical Sciences, University at Buffalo, Buffalo, NY, USA

    Briana A. Santo & Vincent M. Tutino

  4. Department of Mechanical and Aerospace Engineering, University at Buffalo, Buffalo, NY, USA

    Sricharan S. Veeturi & Vincent M. Tutino

  5. Department of Radiology, University of California Los Angeles, Los Angeles, CA, USA

    Aichi Chien

  6. Neuroendovascular Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Adam A. Dmytriw

  7. Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA

    Jan-Karl Burkhardt

  8. Department of Neurosurgery, University of South Florida, Tampa, FL, USA

    Maxim Mokin

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  1. Kerry E. Poppenberg
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  2. Aichi Chien
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  10. Maxim Mokin
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  12. Adnan H. Siddiqui
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  13. Vincent M. Tutino
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Corresponding author

Correspondence to Vincent M. Tutino.

Ethics declarations

Ethics approval and consent to participate

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Human Research Institutional Review Board of the University at Buffalo (study number 030474433). Informed consent was obtained from all participants involved in the study, and the study was carried out in accordance with the approved protocols.

Consent for publication

No specific patient information or images are given in the article.

Availability of data and materials

The datasets used in the current study are available from the corresponding author upon reasonable request.

Competing Interests

KEP—None. AC—Awardee of NIH grant, 1R01HL152270-01 and a UCLA Exploratory Research Grant. BAS—None. LC—None. SSV—None. MW—None. AM–None. AAD—None. J-KB—None. MM—None. KVS—Consulting/teaching: Canon Medical Systems Corporation, Penumbra Inc., Medtronic, Jacobs Institute; co-founder: Neurovascular Diagnostics, Inc. AHS—Financial interest/investor/stock options/ownership: Adona Medical, Inc., Amnis Therapeutics, BlinkTBI, Inc., Boston Scientific Corp. (for purchase of Claret Medical), Buffalo Technology Partners, Inc., Cardinal Consultants, LLC, Cerebrotech Medical Systems, Inc., Cognition Medical, Endostream Medical, Ltd, Imperative Care, Inc., International Medical Distribution Partners, Neurovascular Diagnostics, Inc., Q’Apel Medical, Inc., Radical Catheter Technologies, Inc., Rebound Therapeutics Corp. (purchased 2019 by Integra Lifesciences, Corp.), Rist Neurovascular, Inc., Sense Diagnostics, Inc., Serenity Medical, Inc., Silk Road Medical, Spinnaker Medical, Inc., StimMed, Synchron, Three Rivers Medical, Inc., Vastrax, LLC, VICIS, Inc., Viseon, Inc.; consultant/advisory board: Amnis Therapeutics, Boston Scientific, Canon Medical Systems USA, Inc., Cerebrotech Medical Systems, Inc., Cerenovus, Corindus, Inc., Endostream Medical, Ltd, Imperative Care, Inc., Integra LifeSciences Corp., Medtronic, MicroVention, Minnetronix Neuro, Inc., Northwest University – DSMB Chair for HEAT Trial, Penumbra, Q’Apel Medical, Inc., Rapid Medical, Rebound Therapeutics Corp., Serenity Medical, Inc., Silk Road Medical, StimMed, Stryker, Three Rivers Medical, Inc., VasSol, W.L. Gore & Associates; national PI/steering committees: Cerenovus LARGE trial and ARISE II trial, Medtronic SWIFT PRIME and SWIFT DIRECT trials, MicroVention FRED Trial and CONFIDENCE study, MUSC POSITIVE trial, Penumbra 3D Separator trial, COMPASS trial, INVEST trial; research grants: co-investigator, NIH/NINDS 1R01NS091075 Virtual Intervention of Intracranial Aneurysms; role: co-principal investigator, NIH-NINDS R21 NS109575-01 Optimizing Approaches to Endovascular Therapy of Acute Ischemic Stroke. VMT—Principal investigator: National Science Foundation Award No. 1746694 and NIH NINDS award R43 NS115314-0; awardee of a Brain Aneurysm Foundation grant, a Center for Advanced Technology grant, and a Cummings Foundation grant; co-founder: Neurovascular Diagnostics, Inc., QAS.AI, Inc.

Funding

Research reported in this publication was supported, in part, by the Brain Aneurysm Foundation (VMT) and by the National Institute of Neurological Disorders and Stroke of the NIH under award number 1 R43 NS115314-01 to Neurovascular Diagnostics, Inc. (VMT). Additional support was received from the National Heart, Lung, and Blood Institute of the NIH under award number 1R01HL152270-01 (AC) and a UCLA Exploratory Research Grant (AC).

Authors’ contributions

Conceptualization: KEP and VMT; methodology: KEP, BAS, LC, and VMT; software: KEP and VMT; validation: KEP, LC, and VMT; formal analysis: KEP, BAS, LC, SSV, and VMT; investigation: KEP, AHS, and VMT; resources: AHS and VMT; data curation: KEP, MW, AM, J-KB, MM, KVS, AHS, and VMT; writing—original draft preparation: KEP, AC, and VMT; writing—review and editing: all authors; visualization: KEP, SSV, and VMT; supervision: AHS and VMT; project administration: VMT; funding acquisition: VMT. All authors have read and agreed to the published version of the manuscript.

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Poppenberg, K.E., Chien, A., Santo, B.A. et al. Profiling of Circulating Gene Expression Reveals Molecular Signatures Associated with Intracranial Aneurysm Rupture Risk. Mol Diagn Ther 27, 115–127 (2023). https://doi.org/10.1007/s40291-022-00626-x

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