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

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posted on 24.06.2021, 04:45 by Frederick Adam Zeiler, Charles McFadyen, Virginia Newcombe, Anneliese SynnotAnneliese Synnot, Emma L Donoghue, Samuli Ripatti, Ewout W Steyerberg, Russell L Gruen, Thomas McAllister, Jonathan Rosand, Aarno Palotie, Andrew Maas, David Menon
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.


The authors received funding from the European Union FP 7th Framework program under grant agreement no. 602150 (CENTER-TBI).F.A.Z. has received salary support for dedicated research time, during which this project was completed. Such salary support came from: the Cambridge Commonwealth Trust Scholarship, the University of Manitoba Clinician Investigator Program, the Royal College of Surgeons of Canada-Harry S. Morton Travelling Fellowship in Surgery, R. Samuel McLaughlin Research and Education Award, the Manitoba Medical Service Foundation, the University of Manitoba-Faculty of Medicine Dean's Fellowship Fund, and the Royal College of Surgeons of Canada-Harry S. Morton Travelling Fellowship.D.K.M. is supported by funding from the National Institute for Health Research (NIHR; UK) through a Senior Investigator Award and funding to the Cambridge NIHR Biomedical Research Centre.V.F.J.N. is supported by a Heath Foundation/Academy of Medical Sciences Clinician Scientist Fellowship.S. R. is supported by the Academy of Finland Center of Excellence for Complex Disease Genetics.


Publication Date



Journal of Neurotrauma






17p. (p. 1107-1123)


Mary Ann Liebert



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