Genetic Influences in Traumatic Brain Injury

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, affecting all ages and demographics. In the United States alone, approximately 1.7 million new cases are reported yearly,– resulting in death in roughly 5% of individuals, long-term disability in greater than 40%, and 25% of affected adults unable to return to work 1 year following the injury. Symptoms associated with TBI can appear immediately following injury or days to weeks later, and result in wide-ranging physical and psychological deficits including motor impairment, epilepsy, personality change, and memory impairment. TBI is classified into three categories designated mild, moderate, and severe, based on the severity of injury using the Glasgow Coma Score (GCS) and other clinical measures., These tools assess whether the individual was unconscious and duration, length of amnesia, resulting cognitive, behavioral or physical disability, and subsequent recovery. Mild TBI (mTBI) is the most common subtype of TBI, with estimates ranging from 1.6 million to 3.8 million annually among U.S. athletes alone. Despite its designation, a mild TBI should not be viewed as an inconsequential injury, as some mTBIs can result in prolonged cognitive, emotional, and functional disabilities, significantly impacting quality of life.

Predicting outcome following TBI is challenging, and cannot be made based solely on clinical presentation and radiological findings since patients with comparable injuries may have variable outcomes. The injury itself can be viewed as occurring in two distinct phases, a primary phase and secondary phase. The primary phase occurs at impact from the mechanical forces of the injury which can disrupt the brain parenchyma and integrity of the blood–brain barrier (BBB). This is followed by a systemic and neuroinflammatory response or secondary phase, mediated by peripheral immune cells and activation of resident neural cells, triggering the release of molecular mediators such as cytokines, growth factors, and adhesion molecules, and activation of a complex network of pathways. Secondary injury can develop over a period of hours to days and months following the primary injury. Some of these pathways are involved in reparative processes,, whereas others contribute to metabolic dysregulation that may result in secondary brain injury. Apoptosis of neurons and glia contribute to the overall pathology of TBI, and neurons undergoing apoptosis have been identified within contusions in the acute post-traumatic phase, as well as in regions remote from the site of injury in the days and weeks following trauma.

The genes involved in TBI can be roughly categorized into those that influence the extent of the injury (e.g., pro-and anti-inflammatory cytokines) and those that effect repair and plasticity (e.g., neurotrophic genes). An additional category of genes that should be considered are those that effect pre-and postinjury cognitive and neurobehavioral capacity (e.g., catecholamine genes). A growing body of literature has attributed a role for genetic factors in the interindividual variability observed in TBI, and in predicting functional and cognitive outcome following brain injury.– These variations are a result of alterations in the DNA sequence within a given gene and are referred to as genetic polymorphisms. Polymorphisms can arise from insertions or deletions of short lengths of DNA within a particular gene, interfering with the normal function of the gene, or at a single nucleotide (G, A, T, or C). When a single nucleotide is responsible for the modification in the DNA, it is referred to as a single nucleotide polymorphism or SNP. SNPs are the most common type of genetic variation, occurring once every 100–300 nucleotides, amounting to approximately 10 million in the human genome. A SNP can reside within the coding sequence of a gene where it may alter the amino acid composition of a protein, or within a noncoding region of a gene, such as a promoter or intron, where it may influence expression of the gene and protein production. The nomenclature for SNPs can be confusing since an individual SNP may be represented in several different ways in the literature. A common depiction can be illustrated with the SNP –174 G/C in the interleukin-6 (IL-6) gene; here, the “174” denotes the nucleotide number at which the variation occurs, the “–” designates that it occurs upstream of the transcription start site (designated +1) in the noncoding region of the gene, and the G/C refers to the nucleotide change at that position, in this case within the promoter region. For the SNP +3953 C/T in the interleukin-1 beta (IL1B) gene, the “+” denotes that the variation occurs downstream from the transcription start site at nucleotide position 3953. The most prevalent variation is commonly referred to as “allele 1” or “major allele”. When a SNP is officially registered in a public database maintained by the U.S. National Center for Biotechnology Information, it is assigned a unique identifier referred to as an rs number (e.g., rs1800795 identifies IL6 SNP –174 G/C).

To date, numerous genes have been implicated in the pathophysiology and outcome following moderate to severe TBI. More recently, considerable attention has focused on genes associated with mild and repetitive mTBIs, notably among combat veterans and professional athletes.– Although inheriting a single “good” or “bad” allele of a specific gene may predispose an individual to better or worse outcome following injury, it is becoming increasingly apparent that recovery from TBI is polygenic in nature, involving the interaction of numerous genes from multiple pathways. Moreover, one must also consider the role of epigenetic mechanisms in disease and injury,– processes that can effect gene expression without altering the DNA sequence (e.g., DNA methylation, chromatin modifications).

The purpose of this chapter is to provide a current overview of genetic polymorphisms associated with recovery and outcome following acute TBI in an adult population. It is not intended to serve as an in-depth study of the individual genes and possible mechanisms of action; several reviews exist in the literature that address this in greater detail.