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Acetylglutamine Differentially Associated with First-Time Versus Recurrent Stroke

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Abstract

Approximately one-quarter of strokes occur in individuals with prior stroke. Despite the advancement in secondary stroke prevention, the long-term risk of recurrent stroke has remained unchanged. The objective of this study was to identify metabolite risk markers that are associated with recurrent stroke. We performed targeted metabolomic profiling of 162 metabolites by liquid chromatography-tandem mass spectrometry in baseline plasma in a stroke case-cohort study nested within the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, an observational cohort study of 30,239 individuals aged 45 and older enrolled in 2003–2007. Weighted Cox proportional hazard models were used to identify metabolites that had a differential effect on first-time versus recurrent stroke using an interaction term between metabolite and prior stroke at baseline (yes or no). The study included 1391 incident stroke cases identified during 7.1 ± 4.5 years of follow-up and 1050 participants in the random cohort sample. Among 162 metabolites, 13 candidates had a metabolite-by-prior stroke interaction at a p-value <0.05, with one metabolite, acetylglutamine, surpassing the Bonferroni adjusted p-value threshold (p for interaction = 5.78 × 10−5). In an adjusted model that included traditional stroke risk factors, acetylglutamine was associated with recurrent stroke (HR = 2.27 per SD increment, 95% CI = 1.60–3.20, p = 3.52 × 10−6) but not with first-time stroke (HR = 0.96 per SD increment, 95% CI = 0.87–1.06, p = 0.44). Acetylglutamine was associated with recurrent stroke but not first-time stroke, independent of traditional stroke risk factors. Future studies are warranted to elucidate the pathogenesis of acetylglutamine and recurrent stroke risk.

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Data Availability

The datasets generated during the current study are available from the corresponding author upon reasonable request, and in accordance with REGARDS data sharing policy.

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Funding

This work was supported by the National Institutes of Health (NIH) R01 NS099209 (Dr. Kimberly), American Heart Association (AHA) 17CSA33550004 (Dr. Kimberly), and NIH P20 GM135007 (Dr. Cushman). REGARDS is supported by cooperative agreement U01 NS041588 co-funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), NIH, Department of Health and Human Service. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS or the NIA. Representatives of the NINDS were involved in the review of the manuscript but were not directly involved in the collection, management, analysis, or interpretation of the data. The authors thank the other investigators, the staff, and the participants of the REGARDS study for their valuable contributions. A full list of participating REGARDS investigators and institutions can be found at https://www.uab.edu/soph/regardsstudy/.

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Authors and Affiliations

  1. Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Naruchorn Kijpaisalratana, Zsuzsanna Ament & W. Taylor Kimberly

  2. Division of Neurology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Naruchorn Kijpaisalratana

  3. Division of Academic Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Naruchorn Kijpaisalratana

  4. Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA

    Naruchorn Kijpaisalratana, Zsuzsanna Ament, Ana-Lucia Garcia Guarniz & W. Taylor Kimberly

  5. Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA

    Amit Patki, Alana C. Jones, Catharine A. Couch & M. Ryan Irvin

  6. Harvard Medical School, Boston, MA, USA

    Varun M. Bhave & W. Taylor Kimberly

  7. Department of Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT, USA

    Mary Cushman

  8. Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA

    D. Leann Long

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  1. Naruchorn Kijpaisalratana
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  2. Zsuzsanna Ament
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  3. Amit Patki
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  10. M. Ryan Irvin
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  11. W. Taylor Kimberly
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Contributions

Drs. Kimberly and Kijpaisalratana had full access to all data in this study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Kimberly. Acquisition, analysis, or interpretation of data: Kijpaisalratana, Patki, Ament, Cushman, Irvin, and Kimberly. Drafting of the manuscript: Kijpaisalratana and Kimberly. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Kijpaisalratana, Patki, and Kimberly. Obtained funding: Kimberly. Administrative, technical, or material support: Ament, Patki, and Irvin. Supervision: Irvin and Kimberly

Corresponding author

Correspondence to W. Taylor Kimberly.

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The REGARDS study protocol was approved by the institutional review boards of all collaborating centers.

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All participants provided written informed consent.

Conflict of Interest

DLL received investigator-initiated research support from Amgen, Inc. for work unrelated to this manuscript. All other authors declare that they have no conflicts of interest.

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Kijpaisalratana, N., Ament, Z., Patki, A. et al. Acetylglutamine Differentially Associated with First-Time Versus Recurrent Stroke. Transl. Stroke Res. (2023). https://doi.org/10.1007/s12975-023-01181-1

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