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.

Keywords: genetics; living systematic review; outcome; prognosis; traumatic brain injury.

FIG. 1.

PRISMA flowchart. ApoE, apolipoprotein E; SNP, single-nucleotide polymorphism; TBI, traumatic brain injury.

FIG. 2.

Diagrammatic representation of tissue, cellular, and subcellular location of non-APOE target in candidate gene studies. The box at top right depicts a variety of neurochemical synapses and locates the target gene products in pre-synaptic sites, post-synaptic sites, or synaptic cleft. The vessel at bottom left shows interactions with astrocytes, microglia, and egressing neutrophils and lymphocytes. The star-bursts represent sites of inflammatory injury. A = astrocyte, ADP = adenosine diphosphate, ATP = adenosine triphosphate, GABA = gamma aminobutyric acid, M = microglia, MBL = mannose binding lectin, mt = mitochondria, N = neuron, O₂ = oxygen, S = synapse, and SNP = single-nucleotide polymorphism. Diagram depicts a theoretical framework for the interaction of various SNPs identified within the review. Diagram depicts neuronal, microglial, astrocytic, synaptic, endothelial, leukocyte, mitochondrial, nuclear, and cytosolic areas impacted by various SNPs. *Note: SNPs that are italicized could not be slotted into the diagram, but are listed secondary to their identification within the systematic review. APOE, apolipoprotein E.

FIG. 3.

Analysis of sample size versus power in GWAS studies for different rates of risk allele frequency. These analyses have been conducted for a 9600 sample with a 30% unfavorable outcome. The shaded area shows the likely range of target genes in GWAS studies. Simulations were done using simple logistic regression under additive genetic association assumption. The range of effect sizes reflect typical odds ratios observed in first rounds of genetic association studies for complex diseases, such as in the original Wellcome Trust Case-Control Consortium study (WTCCC). With ∼50% more cases (unfavorable outcome) and ∼100% more controls (favorable outcome) than in the original WTCCC study, the figure illustrates that studies of this size should be well powered in this target OR range. GWAS, genome-wide association studies; OR, odds ratio.