Apolipoprotein E Isoform Influence on Outcomes after Pediatric Traumatic Brain Injury
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INTRODUCTION: The ε4 allele of the apolipoprotein E gene (APOε) is associated with poor outcomes in adults with traumatic brain injury (TBI), but its influence on recovery after pediatric TBI is uncertain. The primary aims of this study were to determine if an association exists in the outcome of children after TBI between those with at least one ε4 allele and non ε4 genotypes. Using the Glasgow outcome score (GOS), we examined three outcome variables between the two groups 1) GOS at hospital discharge, 2) GOS at long-term follow-up, and 3) the magnitude of change in GOS from discharge to > 6 month assessment (Δ GOS). METHODS: Data were prospectively collected from 220 children presenting with moderate or severe blunt head trauma between the ages of 0 and 17 years old from 2002-2013. Outcomes were assessed at hospital discharge and 12.7±8.4 months post-injury. Patients in the ε4 and non ε4 groups did not differ in injury mechanism, severity, or demographics; 23.4% had at least one ε4 allele and ε3/ ε3 was the most common genotype (67.4%). Multiple regression model analysis was conducted to determine if associations existed between the genotype combinations and outcome while controlling for age, ER GCS, ICP monitor placement, and whether CPR was performed. For ε4 genotypes analysis, we also stratified patients by admission Glasgow Coma Scale (GCS) into severe (GCS 3-8) versus non-severe (9-15), as well as moderate and severe (3-12) versus mild (13-15) groups. RESULTS: For aim 1, the GOS at discharge did not differ significantly in ε4 versus non- ε4 patients in any injury severity category before or after controlling for cofounding variables. However, after controlling for confounding variables, patients with at least one ε2 allele in the moderate or severe injury category had significantly worse GOS at discharge. For aim 2, after controlling for confounding variables, patients with the ε3/ε3 genotype had significantly better long-term GOS than patients with the genotype ε3/ε2 (p<0.05). However, we did not find a significant difference in long-term outcome between ε4 and non ε4 genotypes in the primary analysis or when stratified by injury severity groups. Finally, between ε4 and non ε4 genotypes, the Δ GOS and neuropsychological scores did not differ significantly between genotypes. DISCUSSION: Overall these results propose that unlike adults, the ε4 allele may not be associated with 12-month outcome or the rate of recovery (ΔGOS) from hospital discharge following pediatric TBI. Our results implicating worse outcomes for the ε2 genotypes suggest that this allele may be a candidate for further study to delineate its role in TBI outcome in children. Unique to this study was our analysis of neuropsychological measures, which were also not affected by the presence of ε4 in a smaller cohort of children. This study adds to current literature suggesting that unlike adults APOε4 may not exert a significant effect on pediatric TBI outcome. However, these results are limited in that any genotypic effect on neurologic repair may not be apparent for much longer time periods in pediatric brain injury as the child continues to develop and grow.