Genetic Influences in Traumatic Brain Injury

Ellen R Bennett; Karin Reuter-Rice; Daniel T Laskowitz

Chapter 9Genetic Influences in Traumatic Brain Injury

Bennett ER, Reuter-Rice K, Laskowitz DT.

INTRODUCTION

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,¹^–³ 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.⁴ 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.⁵^,⁶ 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,⁷^,⁸ 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.⁹

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).¹⁰ 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.¹⁰^–¹⁴ 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.¹⁵^–¹⁷ 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,¹⁸^–²⁰ 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.

CYTOKINE POLYMORPHISMS AND TRAUMATIC BRAIN INJURY (TBI) OUTCOME

Background

The mechanisms mediating the host’s response to brain injury are complex and not fully understood. Following TBI, the integrity of the BBB is compromised, accompanied by a state of oxidative stress and an increase in expression of cell adhesion molecules on the brain endothelium, which in turn promotes the influx of peripheral inflammatory cells into the injured brain parenchyma.²¹ Coupled with this, the brain undergoes gliosis, a state in which resident cells within the central nervous system (CNS), such as astrocytes and microglia, become activated and secrete inflammatory mediators and other cellular mediators.²²^,²³ As a result, the initial neuroinflammatory response following injury can promote secondary neuronal death and the development of cerebral edema. Cytokines are among the major mediators during the initial phase of brain injury, where they can both exacerbate the injury early, yet paradoxically may contribute to recovery and repair at later stages.²¹^,²⁴^,²⁵ Experimental models of closed head injury show that tumor necrosis factor a (TNFα), a proinflammatory cytokine, is upregulated immediately following TBI, peaking within hours, and returning to normal baseline levels within 24 hours of injury.²⁶ Preclinical studies using knockout animals have demonstrated that TNFα deficiency is beneficial early after experimental brain injury but deleterious over the long term, suggesting that TNFα plays both a neuroprotective and neurotoxic role.²⁷ The interleukin-1 (IL-1) family consists of two proinflammatory cytokines, IL-1α and IL-1β, and a receptor antagonist, IL-1RA. IL-1 acts together with TNFα to increase inflammation and pyrexia following injury. In experimental models of concussion, IL-1α and IL-1β increase within hours of injury, with IL-1α spiking initially and IL-1β exhibiting a more gradual increase, remaining elevated for days following the injury.²⁸^,²⁹ In addition, IL-1β levels correspond to the level of injury severity, with greater levels of IL-1β mRNA observed in more severe injuries.²⁸ The production of IL-6 is stimulated by TNFα and IL-1 and secreted by microglial during the acute phase of TBI.³⁰ Winter et al. reported that increased levels of IL-6 correlated with improved outcome following TBI, suggesting that IL-6 has neuroprotective properties following acute brain injury.⁷ An additional biological mediator in TBI is transforming growth factor-β (TGF-β).³¹ TGF-β is induced by the presence of cytokines yet forms a negative feedback system where it exerts a predominantly anti-inflammatory role during the acute phase of brain injury, inhibiting the production of IL-1, IL-6, and TNFα. TGF-β peaks within 24 hours in clinical studies of severe TBI (sTBI)³² and can promote tissue repair, decrease brain edema, and reduce brain lesions following ischemia,²⁴^,²⁵^,³³ although excessive TGF-β expression can hinder repair mechanisms in the brain and predispose to infections.³³^,³⁴

The inflammatory modulators described above represent only a fraction of the molecules involved in this complex neuroinflammatory response following TBI. The following section will focus on genetic polymorphisms within these neuroinflammatory mediators that have been associated with TBI.

TNF-α Polymorphisms

TNFα plays a role in mediating neuronal death in the acute phase of brain injury as well as promoting neuronal repair and plasticity in the long term.³⁵^,³⁶ The gene encoding human TNFα is ~3 kb and is located within the major histocompatibility complex (MHC) on chromosome 6.³⁷ Herrmann et al. screened the entire coding region of TNFα as well as over 1 kb of upstream regulatory sequences and identified five polymorphisms, four of which reside within regulatory sequences.³⁸ Two of these are SNPs located at nucleotide position –238 (rs361525) and –308 (rs1800629) and are G/A substitutions; the G-allele, sometimes referred to as allele 1, is the more common allele, occurring at a frequency of ~90% in the population as a whole (1000 genomes³⁹).

These SNPs (–238 A/G and –308 A/G) have been extensively studied and associated with outcome from a number of inflammatory conditions including rheumatoid arthritis (RA), psoriasis, Crohn’s disease, cerebral malaria, septic shock, and meningococcal disease.⁴⁰ By contrast, very few studies have been reported on TNFα SNPs and TBI. In 2013, Waters et al. looked for an association between the TNFα –238 and –308 SNPs and clinical outcome at 6 months (GOS) in 1096 sTBI patients, 937 of which were included in the genetic analysis.¹² They observed no association between the –238 A/G polymorphism and outcome; however, when the data was dichotomized into unfavorable (death, vegetative survival, or severe disability) and favorable (moderate disability or good recovery) outcome, individuals with the –308 A-allele (allele 2) were more likely to have unfavorable outcome at 6 months compared to noncarriers (39% vs. 31%). Although mortality was similar for those with a –308 A-allele relative to those without (13% vs. 12%), among survivors, those harboring the –308 A-allele were more likely to have a severe disability (25% vs. 18%) and less likely to have a favorable outcome (37% vs. 43%). The authors argue that association of the –308 A-allele with poor outcome following TBI is biologically plausible since this SNP resides within the promoter region of the gene, and the A-allele (allele 2) has been associated with a higher expression of TNFα.⁴¹^,⁴² They reason that patients with the –308 A polymorphism have increased expression of TNFα following TBI and as a result have worse outcome. It is tempting to suggest that the low frequency rate of the –308 A-allele in the general population (~10%) is selectively advantageous, however, given the multifaceted nature of the neuroinflammatory response and the temporal regulation of its many roles within the brain, cerebrospinal fluid (CSF), and plasma, the relationship is likely more complex. Waters et al. propose that further studies measuring TNFα levels in serum, CSF, and the brain, will help elucidate the hypothesis. Other studies have examined TNFα SNPs in other neuroinflammatory conditions such as Alzheimer’s disease (AD)⁴³ and stroke⁴⁴; however, to our knowledge, this represents the only reported study on TNFα polymorphism and TBI.

IL-1 Polymorphisms

The IL-1 family consists of two proinflammatory cytokines, IL-1α and IL-1β, and a receptor antagonist, IL-1RA, which are located on chromosome 2, and encoded by the genes IL-1A, IL-1B, and IL-1RN, respectively.⁴⁵ The IL-1RA modulates the immune response by binding to the IL-1 receptors, which in turn inhibit the actions of IL-1α and IL-1β. In the CNS, microglial are the primary producers of IL-1, and following TBI there is a rapid increase in IL-1 production,⁴⁶ which has been associated with injury to hippocampal neurons.⁴⁷ A number of genetic polymorphisms have been identified within IL-1 that influence gene expression and are associated with AD and stroke.⁴⁸^,⁴⁹ These include: IL-1A –899 C/T (rs1800587), IL-1B –31 C/T (rs1143627), IL-1B –511 G/T (rs16944), and IL-1B +3953 C/T (rs1143634). An additional polymorphism is associated with IL-1RN and can result in five different alleles with a variable copy number (2-6) of an 86-bp repeat within intron 2.⁵⁰^,⁵¹ The most prevalent repeats, a 4-repeat and 2-repeat, are designated as IL1RN*1 and IL1RN*2, respectively.⁵¹ Numerous groups have looked for an association between the IL-1 polymorphisms and outcome after TBI (Table 9.1). In 2005, Uzan et al. looked in a small cohort of 69 mild to severe TBI patients and reported that the minor alleles (allele 2) of IL-1B –511 (G-allele) and +3953 (T-allele) were significantly associated with 6-month unfavorable outcome.⁵² In contrast, Hadjigeorgiou et al. detected no association between the IL-1B –511 G-allele and outcome in a population of 151 TBI patients, but did observe an association with the IL1RN*2 allele and increased likelihood of cerebral hemorrhages at 6 months after TBI.⁵³ Two additional groups observed no association with IL-1α –889 and 6-month outcome in cohorts of 71 and 215 patients⁵⁴^,⁵⁵ with mild to severe TBI. In a report published by Waters and colleagues in 2013, 11 cytokine polymorphisms, including IL-1α –899 C/T, IL-1B –31 C/T, IL-1B –511 G/T, and IL-1B +3953 C/T, were analyzed for an association with 6-month outcome in a population of 1096 sTBI patients.¹² In their initial multi-SNP screen, none of the SNPs reached statistical significance at the 0.05 level with 6-month outcome, although they did observe several associations between these SNPs and secondary complications. For example, possession of a copy of the minor T-allele of IL-1α –899 was weakly associated with seizures (p = 0.049) as well as raised intracranial pressure (ICP; p = 0.01). The IL-1B +3953 T-allele was similarly associated with raised ICP (p = 0.027), whereas the less common C-allele of IL-1B –31 was associated with a reduced likelihood of experiencing a serious infection following TBI.

TABLE 9.1

Gene Association Studies in Traumatic Brain Injury

IL-6 Polymorphisms

The human IL-6 gene is a relatively small gene located on chromosome 7. Three common DNA variants identified in the regulatory region of the gene include IL-6 –174 G/C (rs1800795), –572 G/C (rs1800796), and –597 G/A (rs1800797). Together, these three SNPs have been shown to influence IL-6 transcription through a complex interaction, and the G alleles at these loci have been associated with increased IL-6 expression.⁵⁶ Numerous studies examining IL-6 expression in the context of disease and brain injury have been reported in the literature.⁵⁷^–⁵⁹ The G alleles of the –597 and –174 polymorphisms have been associated with higher levels of circulating IL-6 in healthy female subjects.⁶⁰ In other clinical studies, the IL-6 –174 GG genotype is associated with higher IL-6 protein and mRNA levels in the brains of patients with brain arteriovenous malformations relative to the GC and CC genotypes.⁶¹ Several additional groups have suggested that CSF and parenchymal IL-6 levels may correlate with improved outcome following TBI.⁷^,³⁰ In a small study conducted in 2003, Minambres et al.⁶² examined jugular vein and systemic arterial IL-6 levels in 62 patients with sTBI or hemorrhagic acute brain injury, genotyping the IL-6 –174 promoter polymorphism. Their results revealed that the –174 C allele was significantly associated with lower concentrations of IL-6 but not with high or low responders and 6-month outcome. Furthermore, they detected a significant relationship between severity of injury and transcranial IL-6 gradient at admission. More recently, Dalla Libera⁶³ tested whether the –174 C/G SNP is associated with primary short-term outcome (death or ICU discharge) in 77 male patients in Brazil with sTBI. The frequencies of the IL-6 –174 C and G-alleles among the 77 patients were 26% and 74%, respectively. When the group was divided into survivor and nonsurvivors, the GG genotype was significantly more frequent among the survivor group compared to nonsurvivors (67% vs. 41%; p = 0.038), and the G-allele was more prevalent in survivors compared to nonsurviving patients (81% vs. 65%; p = 0.031), suggesting that the G-allele has significant impact on short-term outcome following sTBI. In contrast, others have reported no significant association between the IL-6 promoter polymorphisms –174 C/G, –572 G/C, and –597 G/A and outcome following sTBI¹²; however, in a recent prospective study of 3255 college athletes, Terrell and associates observed a significant association between IL-6 –572 C/C genotype and concussion risk (personal communication, in press).

TGF-β Polymorphisms

TGF-β is a potent suppressive cytokine that plays a pivotal role in maintaining a balanced host response during inflammation and inflammatory conditions.⁶⁴^,⁶⁵ TNFB1, the gene encoding human TGF-β, is located on human chromosome 19. Two SNPs identified within TNFB1 reside within its promoter region at nucleotide positions –800 (G/A substitution; rs1800468) and –509 (C/T substitution; rs1800469).⁶⁶ Clinical studies have demonstrated that the –509 T-allele is associated with enhanced TGF-β plasma levels,⁶⁷ and it has been postulated to be a risk factor for sporadic AD, cystic fibrosis, and other diseases.⁶⁸ In vitro studies suggest that presence of a C at nucleotide position –500 reduces gene expression by interfering with transcription factor binding.⁶⁹ Few clinical studies have examined TGF-β polymorphisms in the context of TBI. To date, the only reported study is that of Waters et al., who genotyped 11 cytokine SNPs (including TNFB SNPs –800 G/A and –509 C/T) in a large cohort (n = 1096) of sTBI patients, and observed no association between these two SNPs and secondary complications following injury, nor with outcome at 6 months post-TBI.¹² Consistent with a lack of association between TGF-β and outcome, Csuka et al. observed no longitudinal differences in serum and CSF TGF-β levels in a small population (n = 28) of sTBI patients.³²

APOLIPOPROTEIN E

Background

Apolipoprotein E (apoE, protein; APOE, gene) is the most studied gene with respect to outcome after neurotrauma.⁷⁰ Although originally studied for its role in cholesterol metabolism,⁷¹ apoE is the major apolipoprotein produced in the central nervous system (CNS) where it is synthesized by astrocytes and microglia, and in neurons under conditions of stress.⁷² Numerous functions have been attributed to apoE including promoting repair and growth of neurons, maintenance of synaptodendritic connections,⁷³ and mediating brain inflammatory responses.⁷⁴^–⁷⁸ Interest in the neurobiology of apoE intensified following its identification as a susceptibility gene associated with familial and sporadic Alzheimer’s disease (AD)⁷⁹^,⁸⁰ and later shown to be associated with neuroinflammatory disorders including multiple sclerosis,⁸¹ recovery following cardiopulmonary bypass,⁸² intracerebral hemorrhage⁸³^–⁸⁵ and TBI.⁷⁰ The human APOE gene resides on chromosome 19 and is a relatively small gene, comprised of approximately 3.7 kb consisting of 4 exons separated by 3 introns, with additional upstream and downstream regulatory regions (Figure 9.1). Human apoE is a 34 kDa, 299 amino acid protein, and has three common isoforms, designated apoE2, E3, and E4, which differ by single amino acid interchanges (cysteine and arginine) at residues 112 and 158 (Figure 9.1) (E2,Cys112-Cys158; E3,Cys112-Arg158; E4Arg112-Arg158⁷¹). The E2/E3/E4 haplotype is defined by two nonsynonymous SNPs within exon 4 resulting in three distinct alleles (E2, E3, and E4) with six possible genotypes (APOE2/E2, E2/E3, E2/E4, E3/E3, E3/E4, and E4/E4).⁸⁶ The allele frequencies in Caucasians is 7% (E2), 78% (E3), and 15% (E4); however, these gene allele frequencies vary significantly among different geographical or ethnic groups.⁸⁷ Two SNPs consisting of C to T nucleotide changes at amino acid residue 112 (rs429358) and 158 (rs7412), result in an arginine (C) or cysteine (T) substitution (Figure 9.1). Additional SNPs within and surrounding APOE have been identified and studied in brain injury and disease.⁸⁸^–⁹² Three of these, –219 G/T (rs405509), –427 rs769446 T/C, and –491 A/T (rs449647), reside within regulatory sequences of the gene where they can potentially influence APOE gene expression.

FIGURE 9.1

Schematic of APOE locus on chromosome 19 showing regional genes (TOMM40, APOC1, APOC4, and APOC2), putative multienhancer regulatory elements (ME1 and ME2), brain control region (BCR), and hepatic enhancers (HCR1 and HCR2). The APOE gene is approximately (more...)

APOE Coding Polymorphisms and TBI

Before focusing on specific APOE genetic polymorphisms studied in the context of TBI, it will be helpful to briefly review several independent lines of evidence that first alluded to a possible connection between APOE, AD, and TBI. First, before an association was made between APOE and AD, case control and epidemiologic studies performed by numerous groups showed that prior head injury was a risk factor for developing AD later in life.⁹³^–⁹⁶ Second, boxers who developed chronic traumatic encephalopathy (CTE) due to repetitive blows to the head throughout their boxing careers were shown to be at risk for developing AD and, moreover, shared similar brain pathology at autopsy to that of AD brains.⁹⁷^,⁹⁸ Third, when the brains of sTBI patients were examined postmortem, 30% were shown to have deposition of amyloid beta (Aβ), a key constituent of plaques associated with AD.⁹⁹^–¹⁰¹ Interestingly, accumulation of Aβ plaques following both acute and mild TBI was subsequently confirmed by others and shown to occur within hours of injury.¹⁰²^–¹⁰⁵ Last, the APOE genotype has been shown to influence Aβ accumulation in senile plaques of AD brains, with more abundant levels observed among E4 carriers relative to noncarriers (reviewed by Kanekiyo et al.¹⁰⁶). Taken together, it seemed reasonable to hypothesize an association between APOE genotype and severity and outcome following TBI.

In a key study conducted by Mayeux and associates, they observed that individuals with an APOE4 allele and history of TBI had a 10-fold increase risk of developing AD relative to a twofold increase of risk for those with APOE4 in the absence of injury, whereas TBI in the absence of APOE4 did not increase risk.¹⁰⁷ Although the study was limited in size and relied on patient interview to establish a history of head injury with loss of consciousness, the results nonetheless suggested that APOE4 may act synergistically with TBI to increase the risk of AD. Shortly thereafter, Teasdale and coworkers conducted a prospective study of head injured patients admitted to the neurosurgical unit, grouping them according to the Glasgow Coma Score (GCS 3–8, n = 22; GCS 9–12, n = 19; and GCS 13–15, n = 48), and followed them for 6 months.⁷³ They observed that patients with an APOE4 allele were more than twice as likely to have an unfavorable outcome at 6 months following injury relative to those without. Moreover, homozygotes for APOE4 were more disabled relative to heterozygotes, suggesting an APOE4 dose effect. These initial investigations were followed by a myriad of other studies examining APOE in TBI, some of which reported that TBI patients with an APOE4 allele experienced longer hospital stays and loss of consciousness,¹⁰⁸ higher fatality rates and length of coma,¹⁰⁹^–¹¹¹ increase hematoma volume,¹¹² poorer memory outcome,¹¹³ a higher risk of post-traumatic seizures,¹¹⁴ and slower recovery rate.¹¹⁵ By contrast, other studies described little or no evidence supporting an association between the two.¹¹⁶^–¹²³ The conflicting results may in part be attributed to inconsistencies in severity of injury, outcome methodology, and limitations in sample size and statistical power, thereby limiting the accuracy of results. To better delineate these discrepancies, in 2008 Zhou and colleagues conducted a meta-analysis designed to determine whether the presence of APOE4 contributes to initial injury severity and/or poor outcome following TBI.⁷⁰ One hundred studies conducted from 1993 to 2007 were identified and of those, 14 cohort studies were selected, totaling 2527 participants comprising mild, moderate, and severe TBI, 736 with and 1791 without the APOE4 allele (Table 9.1). From this meta-analysis, the authors concluded that the presence of the APOE4 allele is not associated with the initial severity of brain injury but is associated with a slight (1.36) increased risk of poor long-term outcome at 6 months following injury. It is noteworthy that within this analysis is a later prospective study reported by Teasdale’s group,¹²⁴ designed to confirm their earlier results. Approximately 1000 TBI patients (GCS 3–8, n = 267; GCS 9–12, n = 178; and GCS 13–15, n = 513) were assessed for outcome at 6 months following injury using the Glasgow Outcome Scale (GOS), a measure of gross functional outcome often used in the TBI population.¹²⁵^,¹²⁶ In agreement with others, they observed no association between APOE4 and severity of injury, however, in contrast to their previous results, they observed no overall association between APOE genotype and unfavorable outcome at 6 months. Interestingly, they did observe an effect between age and APOE4 on outcome, which was most pronounced in children (age <15) and young adults (16–30), concluding that the influence of APOE4 on unfavorable outcome is greater among younger TBI patients. In a more recent study of 648 patients with mild to severe TBI, Ponsford and colleagues¹²⁷ detected an association between APOE4 and poorer long-term outcome between 1 and 5 years after injury, proposing that the detrimental effects of APOE4 become more apparent over time. In addition, poorer outcome was more pronounced in APOE4 positive females over 55 years of age compared to men, inferring a protective role for estrogen in APOE4 females. In a smaller study of sTBI patients (n = 48), it was suggested that patients with APOE4 may be more predisposed to brain cellular damage.¹²⁸

APOE Promoter Polymorphisms and TBI

In addition to the SNPs that reside within the protein coding region of the gene and determine APOE genotype (rs429358 and rs7412), numerous other SNPs have been detected in and around the APOE gene.¹²⁹ Three SNPs identified within the promoter region of the gene, –219 G/T (rs405509), –427 T/C (rs769446), and –491 A/T (rs449647),⁸⁹^,⁹⁰^,¹³⁰^,¹³¹ have been studied in the context of head injury (Figure 9.1). This region of DNA, located immediately upstream of the gene, serves as a binding site for the transcriptional machinery to initiate transcription and gene expression. As a result, single nucleotide changes within this region can alter transcriptional activity in a cell-specific manner. For example, the –219 G/T and –491 A/T polymorphisms have been shown to influence APOE expression in hepatocytes, by either increasing (–219 G) or decreasing (–491 T) mRNA expression, presumably by altering the binding of specific cellular factors to the promoter, whereas the –427 C/T appears to have no effect.⁸⁹ In 1988, Lambert et al. compared the effect of the same promoter polymorphisms in 573 AD cases relative to 509 controls.¹³¹ Interestingly, the risk of AD was increased in individuals with –219 T (also referred to as the Th1/E47cs mutation) and decreased in those carrying the –491 T-allele, whereas the –427 C/T had no effect. Moreover, the relative mRNA expression level of the E4 allele in brain tissue from AD subjects (n = 49) correlated according to which promoter polymorphism was present, with –219 T augmenting expression and –491 T reducing mRNA levels. A subsequent study by Laws et al. demonstrated that the –491 A allele imparted a dose-dependent effect on apoE levels in the frontal cortex.¹³² A later meta-analysis investigation led by Lambert et al. examining 1732 AD subjects and 1926 controls, showed that in addition to APOE4 acting as a risk factor for AD, the –491 and –219 polymorphisms serve as additional risk factors, with age accentuating the effect of the –219 TT genotype.¹³³ Additional studies have similarly implicated an association with the –219 and –491 polymorphisms and AD.⁸⁸^,⁹¹^,¹³⁴^–¹³⁶ Other groups examining the effect of these promoter polymorphisms in plasma report that the –219 T allele is associated with decreased plasma apoE expression in a dose-dependent fashion, whereas the –427 and –491 have no effect.¹³⁷ Berkis et al. studied the effect of the –491 A/T SNP in CSF and observed that carriers of an AA genotype have higher levels of CSF apoE levels relative to individuals with an AT or TT genotype.⁹⁰ This is consistent with the observations of Laws et al. who reported that a –491 AA genotype was associated with increased apoE expression in the brain and plasma.¹³²

Fewer studies have been conducted investigating an association between the APOE promoter polymorphisms and TBI. In one study, Lendon and coworkers looked for an association between –219 G/T, –427 T/C, and –491 A/T SNPs and 6-month outcome in 92 patients with moderate to severe TBI.¹³⁸ Although no association was detected between the –427 and –491 promoter polymorphisms and poorer outcome, an association was observed between –219 TT individuals and poor recovery. In addition, the –219 G/T frequency was comparable between the TBI group and controls, suggesting that this polymorphism may influence poorer outcome following TBI. In a subsequent study, Jiang et al.¹³⁹ looked at the relationship between APOE4 and the three promoter polymorphisms in clinical deterioration within the acute phase (<7 days) of TBI in a Chinese population (n = 100). Patients were monitored in the intensive care unit, and clinical deterioration was judged by one of the following criteria: decrease GCS relative to admission, increase in hematoma volume, or delayed hematoma detected by serial CT scanning. Their results indicated that –491 AA acted synergistically with APOE4 to confer an increased risk of clinical deterioration following TBI. By contrast, they observed no association with –219 G/T or –427 T/C and clinical deterioration. It should be noted that the allele frequencies of genes can vary considerably between different populations, and as a result one must be cautious when making comparisons between diverse ethnic and geographical populations. For example, the frequency rate of the –491 T-allele promoter polymorphism of APOE is 17% and 3% in European and Asian populations, respectively. Similarly, the C-allele of APOE rs429358, which accounts for the arginine (C) to cysteine (T) substitution at amino acid 112, occurs at a frequency of 16% (European) and 9% (Asian).⁸⁷

APOE, Concussion, and CTE

An increased awareness of the dangers and long-term effects associated with concussions, particularly among professional and college athletes, has recently received considerable attention. In the United States alone, it is estimated that approximately 300,000 sports-related concussions occur annually and that the true incidence is even higher due to many going unreported.¹⁴⁰^–¹⁴³ Recent reports in the media of high-profile professional football players struggling with the deleterious consequences associated with concussion and those being diagnosed with chronic traumatic encephalopathy (CTE), as well as the growing numbers of young athletes involved in contact sports, underscore the importance of increasing the awareness of concussion risks and developing strategies to reduce its devastating long-term effects. CTE, previously referred to as punch drunk syndrome or dementia pugilistica, is a neurodegenerative disorder believed to result from repetitive brain trauma, with or without symptomatic concussion, similar to that experienced among athletes involved in contact sports such as boxing, football, and hockey.¹⁴⁴^,¹⁴⁵ It is postulated that these repeated blows to the head set off a cascade of neurodegenerative changes that can present clinically years or decades after the sports career ends, causing progressive neurological and cognitive impairment as well as behavioral and mood disturbances. As early as 1997, Jordan et al. reported that boxers with the APOE4 allele suffered from CTE,¹⁴⁶ and in 2000, Kutner and colleagues reported that older professional football players with an APOE4 allele scored lower on cognitive tests than those without.¹⁴⁷ More recently, in a literature review of 47 cases of neuropathologically verified CTE, 46 of which were of athletes, APOE genotyping was reported in 10 cases and of these, half carried at least one APOE4 allele.¹⁴⁸ Given that the percentage of APOE4 carriers in the population is significantly lower, the authors suggest that APOE4 is a risk factor for development of CTE. Several other groups have considered APOE4 as a possible risk factor for concussion among college athletes and have reported conflicting results.¹⁴⁹^–¹⁵¹ For example, Terrell et al. and Kristman and associates observed no association between the APOE4 allele and prior concussion.¹⁴⁹^,¹⁵⁰ By comparison, Tierney et al.¹⁵¹ report an association with APOE4 and history of concussion among athletes that carry a combination of an APOE2 and E4 allele together with the APOE promoter –219 T allele, but not in athletes with the APOE4 variant alone. Terrell et al. similarly observed a correlation between the APOE –219 TT genotype and increased risk for history of concussion. However, in a more recent prospective study of 3255 college athletes, this group found no association.¹⁵² In addition, in this latter study the APOE4 allele was significantly associated with reduced concussion risk. As intriguing as these observations are, they should be approached with caution given differences in study design and the population size. It is of interest that the 2013 “Summary of Evidence-Based Guideline Update: Evaluation and Management of Concussion in Sports” listed APOE4 genotype and concussion exposure as a risk factor for chronic neurobehavioral impairment.¹⁵³

MICROTUBULE-ASSOCIATED PROTEIN TAU AND TBI

Tau, a member of a large family of microtubule (MT)-associated binding proteins, stabilizes the assembly of MT in neurites and is abundantly expressed in axons of neurons in both the CNS and peripheral nervous system (PNS), and to lower levels in oligodendrocytes and astrocytes.¹⁵⁴^–¹⁵⁸ Tau is phosphorylated at multiple sites and hyperphosphorylation of tau has been linked to the formation of neurofibrillary tangles (NFTs) associated with AD.¹⁵⁹^–¹⁶² In addition to its association with AD and CTE,¹⁶³ pathological tau protein inclusions have been associated with numerous neurodegenerative disorders, collectively referred to as tauopathies. These include frontotemporal lobar degeneration and progressive supranuclear palsy (PSP) (reviewed in Pittman et al.¹⁶⁴). Human tau is encoded by the MAPT gene located on chromosome 17 and is a large gene comprised of ~150 kb and 15 exons. Alternative splicing of exons 2, 3, and 10 of the tau gene yields six major isoforms in the healthy adult human brain,¹⁶⁵ however, several tauopathies have been associated with aberrant splicing of exon 10, presumably causing an imbalance of specific tau isoform ratios.¹⁶⁴ In addition to neurodegenerative diseases, tau has also been associated with acute brain injury. Elevated levels of tau protein have been detected in human CSF following acute ischemic stroke¹⁶⁶^,¹⁶⁷ as well as in severe TBI, with higher levels correlating with severity of brain damage and 1-year outcome.¹⁶⁸^,¹⁶⁹ Several studies conducted among amateur boxers have shown elevated CSF tau levels following matches, which correlate with the number and severity of head blows, returning to normal levels after rest.¹⁷⁰^,¹⁷¹ In a recent study conducted among Swedish professional hockey players (n = 47), concussed players had increased levels of plasma tau compared to preseason values, with the highest levels detected immediately following concussion and decreasing during rehabilitation.¹⁷² Furthermore, tau levels detected at 1 hour following concussion predicted the length of time for symptoms to resolve and the players return to unrestricted competition. Despite the studies examining CSF and plasma tau protein levels following acute brain injury, very few studies have evaluated the association between tau genetic polymorphisms and TBI. In fact to date, only one group has reported on tau polymorphisms and acute head injury.¹⁴⁹ In 2008, Terrell et al. performed tau genetic testing (^Ser53^Pro and ^His47^Tyr in exon 6) in 195 college football and soccer athletes and observed the TT genotype of tau ^Ser53^Pro (rs10445337) to be weakly associated with increased concussion risk. More recently, the same analysis was repeated in a larger cohort of college athletes (n = 3218), and no significant association was observed between either of the tau SNPs and concussion incidence; however, a trend between self-reported prior concussion and the tau ^Ser53^Pro TT genotype was observed (T. Terrell, 2014, personal communication). Given the paucity of studies investigating tau genetic polymorphisms and TBI, further exploration is warranted.

OTHER GENETIC ASSOCIATIONS AND TBI

NOS3

Endothelial nitric oxide synthase (NOS3) has been postulated to play a role in maintaining cerebral blood flow following TBI.¹⁷³ The gene for human NOS3 is located on chromosome 7 and several polymorphisms identified (–786 T/C, 894 G/T, and a 27 bp insertion/deletion variant, VNTR) have been examined for a possible link with cerebrovascular disease. One of these, –786 T/C (rs2070744), is located within the promoter and has been shown to influence nitric oxide (NO) mRNA levels¹⁷⁴^–¹⁷⁶ and to be associated with cerebral vasospasm.¹⁷⁷^,¹⁷⁸ In 2011, Robertson et al. reported an association with the NOS3 –786 C-allele and reduced cerebral blood flow (CBF) among a population of 51 sTBI patients.¹⁷⁹

COMT

The catechol-O-methyltransferase (COMT) gene, located on chromosome 22, encodes for a protein that is believed to functionally modulate dopamine (DA) neurons, and thereby likely influence executive function. A decrease in cortical DA is thought to result in poorer executive function and vice versa.¹⁸⁰ A common SNP (rs4680) within COMT results in a valine (Val) to methionine substitution at amino acid 158.¹⁸¹ The Val variant of the COMT Val158Met genotype is associated with high COMT enzymatic activity and lower levels of endogenous DA, whereas COMT Met is associated with low activity and higher levels of DA.¹⁸² Given the evidence that deficits in executive function are observed in patients suffering from TBI,¹⁸³ Lipsky and associates hypothesized that individuals with the Met polymorphism, accompanied by less active enzyme activity and increased DA levels, would perform better on tests of executive function than those with the COMT Val variant.¹⁸⁰ When they compared measures of executive function among a population (n = 113) of active duty and retired army veterans who had sustained TBI and controls, they observed an association between COMT Val158Met genotype and frontal-executive function at 1 year following TBI; specifically, the Val variant was associated with perseveration, suggestive of problems with cognitive flexibility. This result was in agreement with a previous study¹⁸⁴ that demonstrated an association between the Val allele and response latency following mild TBI (n = 39). Contrary to these reports, a more recent report by Willmott and associates of 223 participants with moderate-to-severe TBI, observed no significant interactions between COMT Val158Met genotype and cognitive outcome measures following TBI.¹⁸⁵ They suggest that the differences in outcome measures employed in the two studies could account for the observed disparity, speculating that methods used in the earlier study may have been more selective at detecting catecholamine-mediated cognitive function compared to the more-standard clinical neuropsychological testing used in their current study (Table 9.1).

ACE

The gene for angiotensin-converting enzyme (ACE) resides on human chromosome 17 and codes for an enzyme that regulates blood pressure (reviewed in Sayed-Tabatabaei et al.¹⁸⁶). More than 160 ACE polymorphisms have been identified, the majority of which are SNPs. One ACE genetic variant commonly studied, the ACE I/D polymorphism, involves the presence of an insertion (I-allele) or deletion (D-allele) of a 287 bp DNA sequence within intron 16. The ACE D/D genotype has been associated with increase ACE activity and higher circulating levels¹⁸⁷ and has been extensively investigated in studies of hypertension.¹⁸⁶^,¹⁸⁸ The ACE I/D polymorphism was recently explored in a population of moderate to severe TBI patients (n = 73).¹⁸⁹ Individuals with the D-allele performed worse on tests of cognitive performance compared to those with the I-allele. Although the mechanism by which ACE influences TBI outcome is unknown, the authors postulate that it may involve disturbances in cerebral blood flow or cerebrovascular autoregulation, which may influence post-traumatic cerebral hypoperfusion.

BDNF

Additional genes with functional polymorphic alleles have been examined in the context of TBI. One of these, human brain-derived growth factor (BDNF), resides on chromosome 11 and is a major regulator in synaptic connections, plasticity, and in neuronal survival and growth.¹⁹⁰^–¹⁹² In addition, it has been implicated in facilitating episodic and working memory, as well as executive function.¹⁹³^–¹⁹⁶ Many SNPs have been identified in the BDNF gene, one of which is a G to A transition at nucleotide +196 (rs6265), resulting in a valine to methionine (Val66Met) substitution that alters the regulated secretion and neuroplastic function of BDNF.¹⁹³^,¹⁹⁷^–¹⁹⁹ In clinical studies, the Met-allele has been associated with impaired cognitive function in healthy individuals,¹⁹³^,²⁰⁰^,²⁰¹ stroke patients,²⁰² and psychiatric patients.²⁰³^–²⁰⁵ Interestingly, several recent reports of Vietnam War combat veterans who had sustained focal penetrating TBI found the Met-allele to be protective for general intelligence.¹⁹⁶^,²⁰⁶^,²⁰⁷ An additional study detected no association with the BDNF Met-allele and recovery of consciousness and cognitive functions in patients in a vegetative state following TBI.²⁰⁸ Given the abundance of BDNF in the hippocampus and its role in memory, the vulnerability of the hippocampus to TBI²⁰⁹ and attention and processing problems observed following injury, McAllister and colleagues hypothesized that BDNF polymorphisms would influence cognition 1 month after mild to moderate TBI.²¹⁰ In a study of 75 patients with mild to moderate TBI and 38 healthy controls, an association of the Met-allele with slower processing speed (cognition) among the entire group of subjects was detected.²¹⁰ Furthermore, several additional BDNF SNPs (rs11030102, rs11030107, and rs12273363) not previously studied were associated with memory measures within the mTBI group after adjusting for the Met-allele. These results support the hypothesis that polymorphisms in BDNF influence cognitive performance following mTBI.

TP53

The tumor protein 53 gene (TP53) resides on chromosome 17 and encodes p53, a crucial regulator of the cell cycle and apoptosis.²¹¹ In animal models of closed head injury and ischemia, changes in p53 expression have been reported²¹²^,²¹³ and apoptotic neurons have been positively identified in autopsied human brain tissue following TBI.²¹⁴ The most prevalent polymorphism in p53 is a G/T polymorphism within codon 72 (rs1042522) resulting in an arginine (Arg) to proline (Pro) substitution.²¹⁵^–²¹⁷ It has been suggested that homozygous arginine variants are more effective inducers of apoptosis than proline variants.²¹⁶ To determine the relationship between the Argp53Pro polymorphism and outcome following TBI, Martinez-Lucas et al. genotyped 90 sTBI patients and measured outcome at discharge from the surgical ICU (GOS-0) and at 6 months (GOS-6) postinjury.²¹⁸ They reported that the homozygous Arg/Arg genotype was associated with an almost threefold greater risk of having a bad outcome at surgical ICU discharge (GOS-0), and served as an independent risk factor for bad outcome in TBI. A similar association was not observed with GOS-6 nor was it associated with mortality.²¹⁸

PARP-1

The PARP-1 (poly[ADP-ribose]polymerase-1) gene, located on human chromosome 1, encodes a ubiquitously expressed enzyme that functions in the cellular response to stress and DNA damage.²¹⁹^,²²⁰ Excessive activity of PARP-1 is thought to worsen brain injury via NAD+ depletion and energy failure. In a retrospective study, Sarnaik et al.²²¹ reported that an A/T SNP (rs3219119) associated with the automodification and catalytic domains of the PARP-1, was an independent predictor of neurological outcome. Specifically, in a population of 191 patients with sTBI, individuals with the AA-genotype had a favorable GOS at 6 months. A second SNP, rs2271347, involving an A to G substitution in the promoter region of the gene, did not correlate with outcome but did correlate with poly-ADP-ribose levels in the CSF.

MME

Neprilysin is a zinc-dependent metalloprotease encoded by the MME (membrane metallo-endopeptidase) gene located on chromosome 3. The protease is expressed in a variety of tissues, degrades Aβ protein, and is thought to be the rate-limiting step in Aβ degradation.²²² Experiments performed in neprilysin-knockout mice have provided evidence for the association of the neprilysin with the AD process.²²³ TBI has been shown to induce the rapid formation of AD-like Aβ plaques in about 30% of patients although the mechanism behind this selective plaque formation is unclear.²²⁴ A dinucleotide GT repeat polymorphism has been identified in the upstream regulatory region of MME and may be involved in regulating neprilysin expression in neurons.²²⁵ Johnson et al. investigated the potential association between amyloid deposition acutely after TBI and the MME polymorphism in 81 patients.²²⁴ They observed that the length of the MME GT repeats was longer (>41 repeats) in patients that accumulated Aβ following TBI compared to Aβ nonaccumulators. In addition, the presence of 22 repeats in at least one allele was independently associated with Aβ deposition. The authors suggest that these findings provide a potential genetic screening test for individuals at high risk for TBI.

NEFH

The neurofilament heavy (NEFH) gene resides on chromosome 22 and codes for the heavy protein subunit of neurofilament, which combines with the medium and light subunits to make up neuronal cytoskeleton. There have been several reports in the literature suggesting that mutations in NEFH may play a role in neurodegenerative diseases.²²⁶ One study has been reported in the literature studying the effect of NEFH genetic polymorphisms and TBI. McDevitt and colleagues genotyped 48 college athletes for an A to C polymorphism of NEFH (rs165602) looking for an association between genotype and the frequency and severity of previous self-reported concussion.²²⁷ This polymorphism results in an A to C missense SNP that changes a glutamic acid to an alanine at amino acid residue 805. The authors observed no significant association between rs165602 and the occurrence or severity of concussion (mTBI) among the athletes.

5-HTT

The serotonin transporter (5-HTT) gene (solute carrier family 6 member; SLC6A4) is thought to be involved in the pathophysiology of major depression.²²⁸ The 5-HTT gene resides on chromosome 17 and is modulated by the serotonin transporter gene linked polymorphic region (5-HTTLPR). The variant involves the insertion or deletion of a 44 bp DNA sequence resulting in a short (S) allele or long (L) allele.²²⁹^,²³⁰ In addition to the S/L variations, an A/G SNP (rs2553) has been identified in this region resulting in additional allelic combinations: L(A) or L(G); and S(A) or S(G).²³¹ It is generally accepted that one or two copies of the S-allele confer a greater susceptibility at developing major depression in response to stressful life events.²³² Because major depression is a common neurobehavioral complication following TBI, Chan et al. investigated the role of the S/L polymorphisms in the risk of depression secondary to TBI.²³² The population included 75 patients who had sustained a TBI within the past 12 months and met the criteria for mood disorder, and 99 controls with TBI but no mood disorder. The majority of the TBI population fell within an initial GCS of 13–15 (86%), whereas 10.1% were GCS 9–12 and 3.8% GCS <9. They observed no difference in S/L genotype frequencies between the depressed and control groups. Furthermore, for depressed individuals, there was no association between depression scores (Hamilton Depression Rating Score) and these polymorphisms.

PPP3CC

The protein phosphatase 3 catalytic subunit gamma isozyme (PPP3CC) gene is located on chromosome 8 in humans and encodes a regulatory subunit for calcineurin, a calcium-dependent protein phosphatase. Calcineurin is thought to play a role in the regulation of dopaminergic signal transduction and synaptic plasticity,²³³ and has been implicated in neurological disease.²³⁴ In a preliminary study of 277 TBI patients reported by Bales et al. in 2011,²³⁵ an A/G polymorphism (rs2443504) in PPP3CC was found to be a predictor of susceptibility and recovery in TBI, using initial clinical severity (GCS) and recovery (GOS) at 3, 6, and 12 months post-TBI as measures. When individuals with an AA genotype were compared to those homozygous for the G-allele, the results were as follows: chance of an initial GCS <6, 54.2% (AA) vs. 26.6% (GG); 3-month severe GOS, 59.3% (AA) vs. 31.3% (GG); 6-month severe GOC, 53.1% (AA) vs. 32.4% (GG); and 12-month severe GOS, 56.2% (AA) vs. 33.3% (AA). Although these results are compelling, the report was presented in abstract form and lacks a detailed description of the patient population studied.

ANKK1

The ankyrin repeat and kinase domain containing 1 (ANKK1) gene, located on human chromosome 11, is a member of the serine/threonine protein kinase family. ANKK1 contains an A/T SNP referred to as the Taq1A polymorphism (rs1800497) and was originally thought to be the dopamine receptor D2 (DRD2) gene.²³⁶^,²³⁷ The T-allele is associated with a 40% reduction in expression of D2 receptors.²³⁸ McAllister et al.¹⁸⁴ reported an association with the Taq1A T-allele and poorer episodic memory and response latency in a combined group of subjects that included 39 mTBI subjects and controls.¹⁸⁴ The T-allele mTBI carriers had slower response latencies compared to T-allele positive controls. These observations were confirmed when the same group extended their study into a larger population (n = 93) of mild and moderate TBI subjects.²³⁷

KIBRA

KIBRA, kidney and brain expressed protein, represents one of the first genes to be associated with episodic memory. In humans, KIBRA resides on chromosome 5 and encodes a protein involved in synaptic plasticity and transmission, longterm-potentiation, and signal transduction, which, in the brain, is predominantly expressed in the temporal lobe and hippocampus.²³⁹^–²⁴¹ The T-allele of a common T to C polymorphism (rs17070145) identified in KIBRA, has been associated with better performance on episodic memory measures in healthy adults compared to noncarriers.²⁴² However, in elderly adults with memory complaints, the reverse is true.²⁴² Given this observation, Wagner et al. predicted that TBI patients harboring a T-allele would perform less well cognitively following injury.²⁴³ To this end, they conducted a study of 129 patients with sTBI and reported an association between the rs17070145 T-allele and poorer performance on episodic memory at 6 and 12 months, supporting their hypothesis.²⁴³

MITOCHONDRIAL GENES

Background

Mitochondria are the cytoplasmic organelles whose primary function is to generate the cell’s energy in the form of ATP. In addition to being the site for oxidative-phosphorylation and electron transport, they are involved in a number of cellular processes including maintenance of the cell cycle, differentiation, cell signaling, calcium storage, and apoptosis (reviewed in McBride et al.²⁴⁴). Mitochondria are distributed along the microtubules in cells and can vary significantly in number and location, often residing in subcellular regions with high metabolic demands. They exhibit a high degree of plasticity and interconnectivity, forming complex networks inside the cell with the cytoskeleton. The location and mobility of mitochondria in neurons has been well studied, and they are most prominent at sites of intense activity such as synapses and active growth cones in developing neurons.²⁴⁵ Recent evidence suggests that disturbance of this finely balanced mitochondrial network plays a pivotal role in the pathophysiology of a number of diseases including neurodegenerative disorders (reviewed in Burte et al.²⁴⁶). Although some of these diseases are associated with mutations within nuclear DNA that encode mitochondrial proteins, over 150 point mutations and DNA rearrangements have been identified in human mitochondrial (mt) DNA and associated with a variety of conditions (reviewed in Dimauro and Davidzon²⁴⁷). Two examples of neurological diseases associated with mutations in mtDNA include mitochondrial encephalopathy, lactic acidosis, strokelike episodes (MELAS) and myoclonus epilepsy and ragged-red fibers (MERRF).²⁴⁷

Human mtDNA is a double-stranded, circular molecule comprised of 16,569 nucleotides that code for 37 genes, including 2 ribosomal (r) RNA genes, 22 transfer (t) RNA genes, and 13 structural genes critical to the function of the respiratory chain/oxidative phosphorylation system.²⁴⁸ Although nuclear genes encode many mitochondrial proteins including some necessary for cellular respiration, proteins encoded specifically by mtDNA, such as NADH dehydrogenase, are required for a functional electron transport chain and oxidative phosphorylation. Mitochondrial DNA is maternally inherited and each cell contains hundreds to thousands of mtDNA molecules that replicate independently and distribute randomly in daughter cells during cell division. The production of oxygen-free radicals within the mitochondria can cause somatic mutations that occur in some but not all mtDNA molecules, which can then accumulate in postmitotic tissue; the clinical manifestation of a pathogenic mtDNA mutation is largely determined by the relative proportion of mutant to normal genomes. Unlike nuclear DNA, mtDNA lacks protective histones and DNA repair enzymes, and as a result cells accumulate a progressively larger burden of mtDNA damage as they age.²⁴⁹ During cell division, the ratio of mutant to normal molecules in daughter cells can change; this phenomena may partially explain why the disease phenotype of certain patients with mtDNA disorders may vary with age.

Over millennia, a substantial number of mtDNA mutations or SNPs have accumulated, the combination of which define mitochondrial haplotypes, commonly referred to as “haplogroups.”²⁵⁰ Mitochondrial haplogroups have been used to map genetic differences among populations and tend to be continent specific. Nine major haplogroups identified among individuals of European descent include H, T, U, V, W, X, J, Y, and K, with haplogroup H representing the majority (40%) of any European population.²⁵¹ Specific SNPs are associated with particular haplogroups. For example, SNP A10398G is a mitochondrial SNP located within the NADH-ubiquinone oxireductase subunit-3 locus (ND3)²⁵²; the A10398 allele is found in haplogroup H whereas the 10398G allele is associated with haplogroups K and J. Mitochondrial haplogroups have been reported as factors for degenerative pathologies and neurodegenerative conditions including Parkinson’s disease (PD), AD, Huntington’s disease (HD), and motor neuron disease.²⁵³

Mitochondrial Haplogroups and TBI

Mitochondrial dysfunction following TBI has been well documented in the literature in both animal²⁵⁴^–²⁵⁶ and human studies²⁵²^,²⁵⁷^,²⁵⁸ and is characterized by a decrease in ATP production, an increase in lactate accumulation, and uncontrolled regulation of intracellular calcium prior to neuronal loss.²⁵⁹^,²⁶⁰ Despite these observations, the mitochondrial genome has received little attention with respect to TBI. In a recent article, Bulstrode and colleagues²⁵⁸ examined the relationship between mitochondrial genomic variants and 6-month outcome following TBI in a large cohort of 880 patients (mild to severe TBI) admitted to hospitals in Scotland. As expected within a European population, approximately 40% of the patients had the mitochondrial haplogroup H. Interestingly, the authors observed a significant predictive effect of mtDNA genotype with outcome at 6-month (GOS) when the haplogroups were examined individually, with patients possessing the K variant exhibiting a better outcome than those without (odds ratio = 1.64%, confidence interval = 1.08–2.51, p = 0.02). By contrast, no significant association was observed within haplogroups H, J, T, and U on their own. In a recent preclinical model of TBI, Gilmer et al. showed that mitochondrial dysfunction increases in an age-related manner.²⁵⁶ Interestingly, when mitochondrial dysfunction was examined in the current human TBI population, Bulstrode et al. reported that possession of either the haplogroup K or T significantly lessened the negative effect of aging on outcome (p = 0.017 and p = 0.015, respectively).²⁵⁸ Furthermore, these findings corroborate epidemiological studies showing an overrepresentation of haplogroup K in longevity and underrepresentation of haplogroups K and T in neurodegenerative conditions.²⁶¹^–²⁶³ Several lines of evidence have suggested that abnormalities in oxidative metabolism play a role in AD,²⁶⁴^,²⁶⁵ and APOE has been shown to protect neuronal cell lines from oxidative stress in an allele-specific fashion (E2>E3>E4).²⁶⁶ To this end, Bulstrode et al. looked for an interaction between mtDNA haplogroups and APOE polymorphisms in their TBI cohort but failed to detect an association between APOE genotype and outcome. They did, however, observe that patients with an APOE4 allele had a better outcome following TBI if they also possessed the mtDNA K haplogroup,²⁵⁸ supporting the observations of others from an earlier study of 213 TBI patients.²⁶⁷ It is noteworthy that enzymatic components of the electron transport chain encoded by haplotype K are less tightly coupled relative to other mitochondrial variants, resulting in a reduction of reactive oxygen species, key mediators of secondary cell damage following TBI.²⁶²^,²⁶⁸^,²⁶⁹

Conley et al. recently investigated the impact of several mtDNA SNPs on outcomes in 336 sTBI patients up to one year following injury.²⁵² In this study, all TBI patients had external ventricular drains, and measures included the GOS, Neurobehavioral Rating Scale (NRS), Disability Rating Scale (DRS), in-hospital mortality or length of stay, and lactate:pyruvate ratio from CSF. They observed that the A10398G SNP within ND3 was associated with DRS at 6 and 12 months. Specifically, the A10398 allele (associated with haplogroup H) and 10398G (haplogroups K and J) were associated with slower and faster recovery, respectively. A second SNP, T195C, located within a noncoding region of mtDNA, was associated with outcome depending on sex, with the T195 allele associating with poorer outcome in females (p = 0.03). The same allele was similarly associated with mitochondrial dysfunction in females (p = 0.01). These results suggest that mitochondrial variation may be particularly relevant to recovery among female patients. It is noteworthy that a sex-based association favoring protection in females has also been observed with mitochondrial SNP 10398G in PD.²⁷⁰ Altogether, these studies are intriguing and suggest a relationship between mtDNA haplogroups, aging, and the pathophysiology of TBI, as well as a possible interaction of APOE pathways with genetically regulated mitochondrial functions in acute injury.

GENETICS OF PEDIATRIC TBI

TBI in pediatric patients differs significantly from that of adults in multiple aspects and as a result, the pediatric brain should not be viewed simply as a “small adult brain.”²⁷¹ Several of these distinctions include anatomical and functional developmental differences, enhanced apoptotic-induced cell death, increased risk of post-traumatic seizures, and age-specific differences in cerebral blood flow and metabolism.²⁷¹^–²⁷³ Surprisingly, despite the observation that the vast majority of TBIs occur in children and young adults, there is a paucity of genetic association studies specific to pediatric TBI. In fact, a 2012 comprehensive review of genetic association studies and pediatric TBI identified only a handful of vetted studies specific to pediatric TBI, each of which investigated an association between APOE4 and outcome.²⁷⁴ One of these evaluated an association between APOE4 and post-traumatic cerebral swelling in 165 postmortem cases of children aged 2–19 years (median 13 years) who survived 1 hour to 5 months (median 3 days) after injury.²⁷⁵ No significant relationship was detected with possession of an APOE4 allele and brain swelling, however, the authors acknowledge that a bias toward worst possible outcome had been introduced because the patient cohort was selected by death. As cited earlier in this chapter, Teasdale and coworkers observed that possession of an APOE4 allele in children (n = 215) less than 16 years was associated with a 3.06 (95% confidence interval; 1.22–7.65) greater odds of an unfavorable outcome at 6 months following TBI.¹²⁴ An additional study of 70 children ranging in age from 1 month to 17 years, conducted in the Czech Republic, reported that presence of an APOE4 allele was associated with poorer global outcome at 12 months following TBI.²⁷⁶ In 2009, Moran and colleagues evaluated whether APOE genotype could predict outcome in children following mild TBI.²⁷⁷ The study included 99 children (8–15 years) who presented to the emergency room and were subsequently diagnosed with concussion according to the following criteria: loss of consciousness (LOC) less than 30 minutes, GCS score of 13 or 14, or two or more acute symptoms of concussion. Outcomes were assessed at presentation and again at 2 weeks, 3 months, and 12 months postinjury employing a battery of measures to assess memory, development, neuropsychological functioning, general intelligence, and academic achievement. These authors concluded that the APOE4 allele was associated with poor global outcome relative to individuals with an E2/E3 or E3/E3 genotype. A fourth study assessed the association of APOE with cerebral perfusion pressure (CPP) in 65 critically ill children with TBI using modified GCS, global outcome, and CPP as outcome measures, concluding that individuals with an APOE4 allele were less tolerant to increases in CPP.²⁷⁸ Conversely, an earlier study of 71 TBI children requiring inpatient rehabilitation reported that the APOE4 allele (n = 4) was associated with improved outcome at discharge, however, the E4 frequency (4%) was well below that observed in the population at large (15%).²⁷⁹ Despite these differences, a statistical analysis of the combined data of the aforementioned studies revealed a 2.44 (95% confidence interval: 1.25–4.80) greater odds of having poor outcome in children who are carriers of APOE4 compared to noncarriers.²⁸⁰ A more comprehensive review of the literature conducted in May 2014, examining genes associated with pediatric TBI, similarly identified APOE4 as being the lone gene studied in the arena of pediatric TBI.²⁸¹

CONCLUSION

The study of genes that influence outcome following TBI is still in its early stages. Evidence has been rapidly accumulating in the literature, particularly in the last decade, identifying genetic polymorphisms associated with the pathophysiology and outcome following TBI. The genes associated with these polymorphisms play multifactorial roles in regulating the brain’s response to injury and include both anti-and pro-inflammatory cytokines, DNA repair enzymes, signaling molecules, and neurotrophins. The importance of mitochondria in the pathophysiology of brain injury has been well documented, although the mitochondrial genome has received relatively little attention in the setting of TBI. How these diverse genes interact with one another following TBI remains to be elucidated and requires extensive research. Furthermore, an additional significant area of research not addressed in this chapter that must be considered in the context of TBI is that of epigenetic mechanisms (DNA methylation, histone modifications and nucleosome remodeling, RNA editing) that modulate gene expression and cellular activity. The majority of TBI-genetic association studies reported in the literature have been conducted in adult populations, despite the observation that the vast majority of TBIs occur in children and young adults. Clearly, additional genetic association studies are essential to facilitate both the prediction of outcome and clinical management in the pediatric TBI population.

ACKNOWLEDGMENT

We would like to thank Austin M. Cook for his help in constructing Figure 9.1 and Table 9.1.

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Publication Details

Author Information and Affiliations

Authors

Ellen R Bennett, Karin Reuter-Rice, and Daniel T Laskowitz.

Copyright

Publisher

CRC Press/Taylor and Francis Group, Boca Raton (FL)

NLM Citation

Bennett ER, Reuter-Rice K, Laskowitz DT. Genetic Influences in Traumatic Brain Injury. In: Laskowitz D, Grant G, editors. Translational Research in Traumatic Brain Injury. Boca Raton (FL): CRC Press/Taylor and Francis Group; 2016. Chapter 9.

Author	Gene/Allele	TBI (m, mild; M, moderate; s, severe)	n	Evaluation	Post-TBI Testing	Findings
Waters et al.¹²	TNFα –238 G/A, –308 G/A; IL-6–174 G/C, –572 G/C, –597 G/A; IL-1B –31 C/T, –511 G/T, +3953 C/T and for TGFB –509 C/T, –800 G/A	s	1096	GOS	6 months	Only TNFα –308 A (allele 2) carriers show unfavorable outcome compared to noncarriers
Hadjigeorgiou et al.⁵³	IL-1RN*2; IL-1B –511 G/T	m, M, s	151	GOS	6 months	IL-1RN*2 associated with increase likelihood of cerebral hemorrhage after TBI; no association observed with IL-1B
Tanriverdi et al.⁵⁴	IL-1A-889 C/T	m, M, s	71	GOS	6 months	No association observed following TBI
Uzan et al.⁵²	IL-1B-511 G/T,+3933 C/T	m, M, s	69	GOS	6 months	Unfavorable outcome associated with IL-1B +3953 T and –511 G allele
Dardiotis et al.⁵⁵	IL-1A-889 C/T	m, M, s	215	GOS	6 months	No association observed with favorable vs. unfavorable outcome
Minambres et al.⁶²	IL-6 –174 G/C	s	62	GOS	6 months	No correlation between –174 C and outcome
Dalla Libera et al.⁶³	IL-6 –174 G/C	s	77	Survival time/ICU discharge; GOS at SICU discharge	ICU discharge 1–53 days	GG genotype more frequent in survivors; –174 G allele more frequent among survivors
Zhou et al.⁷⁰	APOE4	m, M, s	2527	Meta-analysis	6 months	No association with initial TBI severity but associated with increased risk of poor long-term outcome at 6 months after injury
Ponsford et al.¹²⁷	APOE4	m, M, s	648	GOSE	Mean 1.9 years	Greater susceptibility in older females for worse GOSE scores, and E4 may be associated with poorer long-term outcome, but not injury severity
Lendon et al.¹³⁸	APOE4; APOE –219 G/T, –419 A/T, –427 C/T	m, M, s	92	GOS	6 months	–291 T associated with poor recovery in TT carriers; no association found with –419 ATT or –427 C/T and outcome
Jiang et al.¹³⁹	APOE4; APOE –219 G/T, –419 A/T, –427 C/T	m, M, s	110	Clinical deterioration or stabilization	<7 days	After adjustment for patients’ age, injury severity and injury mechanism, both –49IAA promoter polymorphism and E4 allele were risk factors for poor outcome
Terrell et al.¹⁴⁹	Tau ^tyr53^Pro, ^his47^tyr, APOE4; APOE –219 G/T	m	195	History of multiple concussions	Reported history	Tau ^tyr53^pro TT was weakly associated with increase concussion risk; no association with E4 and history of concussion
Robertson et al.¹⁷⁹	NOS3 –786 T/C	s	51	CBF, mortality internal carotid artery flow volume	12, 48 hours	C-allele associated with reduced CBF following TBI
Lipsky et al.¹⁸⁰	COMT Vall58Met	m, M, s	131	WCST, TMT, COWA, Stroop Color and Word Test	1 year maximum	Val allele was associated with perseveration suggesting problem with cognitive flexibility
McAllister et al.¹⁸⁴	COMT Vall58Met	m	39	WRAT-3, WAIS-III, CVLT, CPT	Mean 38days	Val allele associated with response latency
Willmott et al.¹⁸⁵	COMT Vall58Met	M, s	223	GOSE; measures of cognitive function	GOSE	No association with Vall58Met and cognitive function
Ariza et al.¹⁸⁹	ACE I/D	M, s	73	AVLT, CFT, GOSE, TMT, Grooved peg, COWAT, NRS-R	6 months	Individuals with D-allele performed worse cognitively
McAllister et al.²¹⁰	BDNF Val66Met, rsl 1030102, rsl 1030107, rsl2273363	m, M	75	CVLT, SRTRT, WRAT-3, WAIS-III	1 month	Met-allele associated with slower processing speed among TBI and controls rsll030102, rsll030107, and rsl2273363 associated with memory measures within the mTBI
Martinez-Lucas et al.²¹⁸	TP53 Argp53Pro	s	90	GOS	Discharge from ICU 6 months	Arg/Arg associated with bad outcome at GOS-0 but not at GOS-6
Sarnaik et al.²²¹	PARP-1 SNPA/T (rs3219119); SNP A/G (rs2271347)	s	191	GOS	6 months	SNP rs3219119 A/A genotype associated with favorable outcome at 6 months; no association with SNP (rs2271347)
Johnson et al.²²⁴	MME dinucleotide GT repeat polymorphism	s	81	Presence of Aβ		Subjects with >41 GT repeats associated with Ap accumulation following TBI compared to Ap nonaccumulators
McDevitt et al.²²⁷	NEFH (rsl65602) A/C	m	48	History of multiple concussions, duration of symptoms, return to play	Reported history	No association between rsl65602 and occurrence or severity of concussion
Chan et al.²³²	5-HTT S/L genotype	m, M, s	75	Hamilton Depression Rating Score	Within 12 months of TBI	No association with S/L alleles and depression scores
Bales et al.²³⁵	PPP3CC SNP A/G (rs2443504)	N/A	277	GOS	3, 6, and 12 months	A/G SNP predictor of susceptibility and recovery; AA genotype associated with initial GCS<6 and worse GOS
McAllister et al.¹⁸⁴^,²³⁷	ANKK1 TaqlA A/T SNP (rs 1800497)	m, M	39; 93	WRAT-3, WAIS-III, CVLT, CPT	1 month	T-allele of Taql A associated with poorer episodic memory and response latency
Wagner et al.²⁴³	KIBRA T/C SNP (rsl7070145)	s	129	GOS, DRS, CVLT, SRT, FIM, NRS	6, 12 months	T-allele associated with poorer performance on episodic memory at 6 and 12 months
Bulstrode et al.²⁵⁸	Mitochondrial haplogroup H, J, T, UAPOE4	m, M, s	880	GOS	6 months	K variant associated with better outcome; possession of K or T lessened the negative effect of aging on outcome following TBI; no association with APOE4 alone but individuals with APOE4 and K had better outcome
Conley²⁵²	ND3 A10398G, T195C	s	336	GOS, NRS, DRS, mortality, lactate/pyruvate ratio in CSF	1 year	A 10398 allele (H haplogroup) associated with slower recovery; 10398 G allele (K/J haplogroup) associated with faster recovery; T195 allele associated with worse outcome in females and mitochondria dysfunction in females
Brichtová and Kozák²⁷⁶	APOE4	m, M, s (pediatric)	70	GOS	1 year	E4 carriers more likely to have severe unfavorable outcome
Moran et al.²⁷⁷	APOE2, E3, E4	m (pediatric)	99	CVLT, VMI, CANTAB, WASI, WRAT-3, PCS, HBI	2 weeks, 3 and 12 months	APOE4 allele was associated with poor global outcome relative to individuals with E2/E3 or E3/E3 genotype
Lo et al.²⁷⁸	APOE4, E3/E3	s (pediatric)	65	CPP, consciousness at discharge, GOS	6 months	E4 carriers with poor outcome had lower CPP insult levels than noncarriers; E3/E3 patients had better recovery compared to E3 heterozygotes