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Decreased DNA Methylation of RGMA is Associated with Intracranial Hypertension After Severe Traumatic Brain Injury: An Exploratory Epigenome-Wide Association Study

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An Invited Commentary to this article was published on 27 January 2022

Abstract

Background

Cerebral edema and intracranial hypertension are major contributors to unfavorable prognosis in traumatic brain injury (TBI). Local epigenetic changes, particularly in DNA methylation, may influence gene expression and thus host response/secondary injury after TBI. It remains unknown whether DNA methylation in the central nervous system is associated with cerebral edema severity or intracranial hypertension post TBI. We sought to identify epigenome-wide DNA methylation patterns associated with these forms of secondary injury after TBI.

Methods

We obtained genome-wide DNA methylation profiles of DNA extracted from ventricular cerebrospinal fluid samples at three different postinjury time points from a prospective cohort of patients with severe TBI (n = 89 patients, 254 samples). Cerebral edema and intracranial pressure (ICP) measures were clustered to generate composite end points of cerebral edema and ICP severity. We performed an unbiased epigenome-wide association study (EWAS) to test associations between DNA methylation at 419,895 cytosine–phosphate–guanine (CpG) sites and cerebral edema/ICP severity categories. Given inflated p values, we conducted permutation tests for top CpG sites to filter out potential false discoveries.

Results

Our data-driven hierarchical clustering across six cerebral edema and ICP measures identified two groups differing significantly in ICP based on the EWAS-identified CpG site cg22111818 in RGMA (Repulsive guidance molecule A, permutation p = 4.20 × 10−8). At 3–4 days post TBI, patients with severe intracranial hypertension had significantly lower levels of methylation at cg22111818.

Conclusions

We report a novel potential relationship between intracranial hypertension after TBI and an acute, nonsustained reduction in DNA methylation at cg22111818 in the RGMA gene. To our knowledge, this is the largest EWAS in severe TBI. Our findings are further strengthened by previous findings that RGMA modulates axonal repair in other central nervous system disorders, but a role in intracranial hypertension or TBI has not been previously identified. Additional work is warranted to validate and extend these findings, including assessment of its possible role in risk stratification, identification of novel druggable targets, and ultimately our ability to personalize therapy in TBI.

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Acknowledgements

We thank the participants of this study for making this work possible.

Funding

The authors are grateful to funding from the following grants: National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) Grant K23NS101036 (RMJ), NIH/NINDS Grant R01NS115815 (RMJ), NIH Grant R21NR015142 (YPC), NIH/National Institute of Nursing Research (NINR) Grant R00 NR013176 (AMP), NIH Grant P50 NS30318 (DOO), NIH/NINDS Grant 1R01NS087978-01 (PMK), NIH/NINR Grant R01NR013342 (YPC), the Chuck Noll Foundation (PMK and RMJ), and the Barrow Neurological Foundation (RMJ).

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Authors and Affiliations

  1. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY, 10029, USA

    Dongjing Liu

  2. School of Medicine, University of Pittsburgh, 3550 Terrace St, Pittsburgh, PA, 15213, USA

    Benjamin E. Zusman

  3. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 130 De Soto St, Pittsburgh, PA, 15261, USA

    John R. Shaffer, Annie I. Arockiaraj, Shuwei Liu, Daniel E. Weeks & Yvette P. Conley

  4. Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, 3501 Terrace St, Pittsburgh, PA, 15213, USA

    John R. Shaffer

  5. Institute for Public Health Genetics, School of Public Health, University of Washington, 1959 NE Pacific St, Seattle, WA, 98195, USA

    Yunqi Li

  6. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, 130 De Soto St, Pittsburgh, PA, 15261, USA

    Daniel E. Weeks

  7. Department of Neurology, Neurobiology and Neurosurgery, Barrow Neurological Institute and St. Joseph’s Hospital and Medical Center, 240 West Thomas Road, Phoenix, AZ, 85013, USA

    Shashvat M. Desai & Ruchira M. Jha

  8. Safar Center for Resuscitation Research, John G Rangos Research Center, University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA

    Patrick M. Kochanek

  9. Department of Neurological Surgery, School of Medicine, University of Pittsburgh, 200 Lothrop Street, Suite B-400, Pittsburgh, PA, 15213, USA

    Ava M. Puccio

  10. School of Nursing, University of Pittsburgh, 200 Lothrop Street, Suite B-400, Pittsburgh, PA, 15261, USA

    David O. Okonkwo & Yvette P. Conley

  11. Department of Neurobiology, Barrow Neurological Institute and St. Joseph’s Hospital and Medical Center, 240 West Thomas Road, Phoenix, AZ, 85013, USA

    Ruchira M. Jha

  12. Department of Neurosurgery, Barrow Neurological Institute and St. Joseph’s Hospital and Medical Center, 240 West Thomas Road, Phoenix, AZ, 85013, USA

    Ruchira M. Jha

  13. St Joseph’s Hospital and Medical Center, 240 W Thomas Rd, Phoenix, AZ, 85013, USA

    Ruchira M. Jha

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  1. Dongjing Liu
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  2. Benjamin E. Zusman
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Contributions

RMJ and YPC are the principal investigators of the cerebral edema and epigenome-wide association studies of TBI, respectively. RMJ, YPC, DEW, JRS, and DL conceived and designed the study. BEZ, SMD, AMP, and DOO collected the phenotype data. DL, YL, AIA, and SL performed the statistical analysis and contributed to the initial writing of the manuscript. All authors reviewed, edited, and approved the final manuscript.

Corresponding authors

Correspondence to Yvette P. Conley or Ruchira M. Jha.

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Conflicts of Interest

RMJ is a paid consultant and is on advisory boards for Biogen and ASTRAL (Antagonizing SUR1-TRPM4 to Reduce the Progression of Intracerebral Hematoma and Edema Surrounding Lesions clinical trial). The other authors declare no conflicts of interest.

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The University of Pittsburgh Institutional Review Board approved this study.

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Liu, D., Zusman, B.E., Shaffer, J.R. et al. Decreased DNA Methylation of RGMA is Associated with Intracranial Hypertension After Severe Traumatic Brain Injury: An Exploratory Epigenome-Wide Association Study. Neurocrit Care 37, 26–37 (2022). https://doi.org/10.1007/s12028-021-01424-9

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  • DOI: https://doi.org/10.1007/s12028-021-01424-9

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