The Genetics and Epigenetics of Inflammation in Traumatic Brain Injury
Abstract
Inflammation has been implicated as an important player in both traumatic brain injury (TBI) and Alzheimer’s disease (AD). TBI has been described as a risk factor for AD. Our group and others have described an inflammation-related gene, TREM2, as an important player in AD pathology. Genetic variants in inflammation-related genes, such as TREM2 and APOE, are strongly associated with AD, suggesting the inflammation may be influenced at the DNA level. Our group has preliminary data that suggest that alteration of DNA by methylation of both APOE and TREM2 is associated with AD. Since methylation of DNA can change with exposure to brain injury and since methylation of DNA from blood may be an easily accessible biomarker of poor outcome after TBI, remaining critical questions include: Is TBI associated with altered methylation of inflammation related genes, such as TREM2 and APOE? Do active fighters have change in TREM2 methylation? For example, is there a methylation change present in fighter DNA when comparing the first visit to the second visit (after 1 year), or compared to age-matched controls? Is a methylation change in the active fighters also present in retired fighters and AD? Alternatively, since the retired fighters have a longer history of TBI, are their TREM2 methylation levels higher than active fighters? Or are high methylation levels in a different genetic location for active fighters compared to AD or retired fighters, such as in the TREM2 3´UTR compared to the promoter? Furthermore, is this epigenetic profile associated with specific genetic variants or traits, such as gene expression, biomarkers, hippocampal volume, or cognitive tests, that are similar to AD? We have developed the following hypothesis to address these questions. The hypothesis of the proposed investigation is that epigenetic and genetic variability in inflammation pathway genes, especially those implicated in AD, but also those implicated in TBI, may promote AD-like neurodegeneration following TBI. The overall goal is to identify individuals post-TBI that have shared similarities in their inflammation-related genetic and epigenetic signature as seen in AD patients. This information will help identify individuals exposed to TBI that are susceptible to AD and may offer critical information about how to treat inflammation in these individuals. The Professional Fighters Brain Health Study (PFBHS). PFBHS is a study of professional fighters (i.e., boxers and mixed martial artists) currently underway at the Lou Ruvo Center for Brain Health (LRCBH). Funded largely by two Department of Defense grants, participants in the PFBHS undergo an annual comprehensive evaluation that evaluates “quantitative traits” such as, volumetric magnetic resonance imaging (MRI; hippocampal volume), neuropsychological assessment and neurological examination as well as genetic and biomarker analyses obtained from blood draws. In the present proposed investigation, will leverage blood from PFBHS fighter and LRCBH AD cohort first and second visits; active professional fighters (n = 50), young age-matched controls (n=25), retired professional fighters (n = 50) and AD patients (n=50), and older age-matched control groups (n = 25). The specific aim is to examine the relationship between inflammatory pathway gene methylation in the PFBHS TBI and LRCBH AD and age-matched control cohorts by demonstrating that quantitative traits, such as hippocampal volume, cognitive tests, AD-relevant biomarkers, and gene expression, are associated with changes in inflammatory pathway genes. Examination of the association between TBI and AD genetic and epigenetic variability in inflammation pathway genes will yield important clues about how environmental exposure to brain injury influences disease. Importantly, next-generation sequencing results will provide a unique large resource of data for TBI-related studies that can be expanded beyond inflammation-related genes.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710321
Entities
People
- Lynn Bekris
Organizations
- Cleveland Clinic
- United States Army