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

Authors

Dongjing Liu, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY, 10029, USA.
Benjamin E. Zusman, School of Medicine, University of Pittsburgh, 3550 Terrace St, Pittsburgh, PA, 15213, USA.
John R. Shaffer, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 130 De Soto St, Pittsburgh, PA, 15261, USA.
Yunqi Li, Institute for Public Health Genetics, School of Public Health, University of Washington, 1959 NE Pacific St, Seattle, WA, 98195, USA.
Annie I. Arockiaraj, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 130 De Soto St, Pittsburgh, PA, 15261, USA.
Shuwei Liu, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 130 De Soto St, Pittsburgh, PA, 15261, USA.
Daniel E. Weeks, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 130 De Soto St, Pittsburgh, PA, 15261, USA.
Shashvat M. Desai, 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.
Patrick M. Kochanek, Safar Center for Resuscitation Research, John G Rangos Research Center, University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.
Ava M. Puccio, Department of Neurological Surgery, School of Medicine, University of Pittsburgh, 200 Lothrop Street, Suite B-400, Pittsburgh, PA, 15213, USA.
David O. Okonkwo, School of Nursing, University of Pittsburgh, 200 Lothrop Street, Suite B-400, Pittsburgh, PA, 15261, USA.
Yvette P. Conley, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 130 De Soto St, Pittsburgh, PA, 15261, USA. yconley@pitt.edu.
Ruchira M. Jha, 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. Ruchira.jha@barrowneuro.org.Follow

Document Type

Article

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). 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.

Medical Subject Headings

Brain Edema (complications); Brain Injuries, Traumatic (complications, genetics); DNA Methylation; Epigenome; Humans; Intracranial Hypertension (complications, genetics); Intracranial Pressure; Prospective Studies

Publication Date

8-1-2022

Publication Title

Neurocritical care

E-ISSN

1556-0961

Volume

37

Issue

1

First Page

26

Last Page

37

PubMed ID

35028889

Digital Object Identifier (DOI)

10.1007/s12028-021-01424-9

Recommended Citation

Liu, Dongjing; Zusman, Benjamin E.; Shaffer, John R.; Li, Yunqi; Arockiaraj, Annie I.; Liu, Shuwei; Weeks, Daniel E.; Desai, Shashvat M.; Kochanek, Patrick M.; Puccio, Ava M.; Okonkwo, David O.; Conley, Yvette P.; and Jha, Ruchira M., "Decreased DNA Methylation of RGMA is Associated with Intracranial Hypertension After Severe Traumatic Brain Injury: An Exploratory Epigenome-Wide Association Study" (2022). Neurology. 1332.
https://scholar.barrowneuro.org/neurology/1332