Differential DNA Methylation of the Brain-Derived Neurotrophic Factor Gene is Observed after Pediatric Traumatic Brain Injury Compared to Orthopedic Injury.

IMPORTANCE

Pediatric traumatic brain injury (TBI) triggers biological changes that may differ from those observed in non-brain injuries. DNA methylation (DNAm) may serve as a novel, dynamic biomarker of the brain's response and help identify TBI-specific epigenetic patterns relevant to later recovery.

OBJECTIVE

To determine whether DNAm differed between children with TBI and those with orthopedic injury (OI, comparison group) acutely and over time.

DESIGN

The Epigenetic Effects on TBI Recovery (EETR) study is a prospective, longitudinal, cohort study with phenotype data and peripheral blood collection at approximately 24 hours, 6 months, and 12 months post-injury.

SETTING

Single-site study conducted at UPMC Children's Hospital of Pittsburgh.

PARTICIPANTS

Consecutive sampling of children aged 3-18 years hospitalized for a minimum of overnight for complicated mild to severe non-penetrating TBI (n=189) or OI without evidence of head trauma (n=105). Participants were excluded for pre-existing neurological or psychiatric conditions, sensory or motor impairments precluding study participation, and prior hospitalization for TBI.

EXPOSURE

The primary exposure was injury type (TBI vs. OI), with severity examined as a secondary exposure within the TBI group.

MAIN OUTCOMES AND MEASURES

The primary outcome was DNAm measured via pyrosequencing at seven sites (five retained for analysis) acutely (mean=31.6 hours post-injury) and 6 (mean=216.9 days) and 12 months (mean=405.9 days post-injury). Primary covariates included age, sex, and race; secondary covariates included age-adjusted body mass index, non-head injury severity score, pubertal status, socioeconomic status, and psychosocial adversity. Outcomes, covariates, and hypotheses were prespecified.

RESULTS

Participants were 66.3% male, 82.3% White, and had a mean age of 11.7 (±4.2) years. Acutely, children with TBI showed significantly lower DNAm at three of five sites (1.8%-8.7% lower; p=0.0042 to 5.76E-06). One site remained significantly lower at 12 months (p=0.0038); no significant differences were observed at 6 months. TBI severity (measured via Glasgow Coma Scale) was not associated with DNAm at any time point.

CONCLUSIONS AND RELEVANCE

DNAm appears to differ in children with TBI vs OI, particularly in the acute period. DNAm differences may reflect early biological responses that are specific to TBI.