Genetic Influences on Patient-Oriented Outcomes in Traumatic Brain Injury: A Living Systematic Review of Non-Apolipoprotein E Single-Nucleotide Polymorphisms

Abstract

There is a growing literature on the impact of genetic variation on outcome in traumatic brain injury (TBI). Whereas a substantial proportion of these publications have focused on the apolipoprotein E (APOE) gene, several have explored the influence of other polymorphisms. We undertook a systematic review of the impact of single-nucleotide polymorphisms (SNPs) in non-apolipoprotein E (non-APOE) genes associated with patient outcomes in adult TBI). We searched EMBASE, MEDLINE, CINAHL, and gray literature from inception to the beginning of August 2017 for studies of genetic variance in relation to patient outcomes in adult TBI. Sixty-eight articles were deemed eligible for inclusion into the systematic review. The SNPs described were in the following categories: neurotransmitter (NT) in 23, cytokine in nine, brain-derived neurotrophic factor (BDNF) in 12, mitochondrial genes in three, and miscellaneous SNPs in 21. All studies were based on small patient cohorts and suffered from potential bias. A range of SNPs associated with genes coding for monoamine NTs, BDNF, cytokines, and mitochondrial proteins have been reported to be associated with variation in global, neuropsychiatric, and behavioral outcomes. An analysis of the tissue, cellular, and subcellular location of the genes that harbored the SNPs studied showed that they could be clustered into blood-brain barrier associated, neuroprotective/regulatory, and neuropsychiatric/degenerative groups. Several small studies report that various NT, cytokine, and BDNF-related SNPs are associated with variations in global outcome at 6-12 months post-TBI. The association of these SNPs with neuropsychiatric and behavioral outcomes is less clear. A definitive assessment of role and effect size of genetic variation in these genes on outcome remains uncertain, but could be clarified by an adequately powered genome-wide association study with appropriate recording of outcomes.

Role of Sulfonylurea Receptor 1 and Glibenclamide in Traumatic Brain Injury: A Review of the Evidence

“…It follows that the host-response is a key factor in regulating secondary injury processes such as cerebral edema and contusion expansion that significantly influence outcome after TBI. Genetic variation is increasingly recognized as an important contributor to variability in post-traumatic host response [28,[115][116][117][118][119][120][121][122][123][124]. adjacent gene KCNJ11 (encoding KIR6.2).…”

Apolipoprotein E4 Polymorphism and Outcomes from Traumatic Brain Injury: A Living Systematic Review and Meta-Analysis

“…A companion systematic review, which addresses non-APOE genes, has recently been published. 3 APOE is undoubtedly the most extensively studied gene in the field of TBI. It codes for a 34kDa protein, which has a central role in central nervous system lipid transport, including movement of cholesterol into cells to aid repair processes in damaged neurones.…”

The cerebrovascular response to norepinephrine: A scoping systematic review of the animal and human literature

“…Future work into NE models with BBB disruption is required to provide insight into the impact of BBB integrity on NE effects. In parallel to this, the control mechanisms involved in cerebral autoregulation are multifaceted, and are likely the impact of individual genetic polymorphisms in humans 118,119 . Future work, both in humans and genetically controlled animal models may also shed insight into variances in cerebrovascular/CBF catecholamine responses.…”