Variability with Astroglial Glutamate Transport Genetics Is Associated with Increased Risk for Post-Traumatic...

Excitotoxicity contributes to epileptogenesis after severe traumatic brain injury (sTBI). Demographic and clinical risk factors for post-traumatic seizures (PTS) have been identified, but genetic risk remains largely unknown. Thus, we investigated whether genetic variation in astroglial glutamate transporter genes is associated with accelerated epileptogenesis and PTS risk after sTBI. Adults (n = 267) 18-75 years old were assessed over a three-year period post-TBI. Single nucleotide polymorphisms (SNPs) throughout the SLC1A2 and SLC1A3 genes were assayed. Kaplan-Meier estimates and log-rank statistics were used to compare seizure frequencies by genotype. Multivariate Cox proportional hazards regression was used to estimate hazard ratios (HRs) for genotypes significant in Kaplan-Meier analyses. Thirty-nine tagging SNPs were examined (SLC1A2: n = 21, SLC1A3: n = 18). PTS developed in 57 (21.4%) individuals. Of those with PTS, n = 20 (35.7%) had an immediate/early seizure within the first seven days, and n = 36 (64.3%) had a late seizure occurring between eight days and three years post-TBI. When adjusting for multiple comparisons, rs4869682 genotypes (SLC1A3, GG vs. T-carriers) were associated with time to first seizure (p = 0.003). Median time until first seizure was 20.4 days for individuals with a GG genotype and 44.8 days for T-carriers. After adjusting for covariates, rs4869682 GG-homozygotes had a 2.05 times increased PTS risk versus T-carriers (aHR = 2.08, 95% confidence interval: 1.20, 3.62, p = 0.009). Variation within SLC1A3 is associated with accelerated epileptogenesis and clinical PTS development after sTBI. Future studies should validate these findings and examine how genetic variation at rs4869682 may be a target for PTS prevention and treatment.