Genetic variation in neuronal glutamate transport genes and associations with posttraumatic seizure

Summary Objective Posttraumatic seizures (PTS) commonly occur following severe traumatic brain injury (sTBI). Risk factors for PTS have been identified, but variability in who develops PTS remains. Excitotoxicity may influence epileptogenesis following sTBI. Glutamate transporters manage glutamate l...

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Published in:Epilepsia (Copenhagen) 2016-06, Vol.57 (6), p.984-993
Main Authors: Ritter, Anne C., Kammerer, Candace M., Brooks, Maria M., Conley, Yvette P., Wagner, Amy K.
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Confidence intervals
Epilepsy, Post-Traumatic - genetics
Epileptogenesis
Excitatory Amino Acid Transporter 3 - genetics
Excitatory Amino Acid Transporter 4 - genetics
Female
Follow-Up Studies
Genes
Genetic Association Studies
Genetic Predisposition to Disease - genetics
Genotype
Glasgow Coma Scale
Humans
Male
Middle Aged
Outcome Assessment (Health Care)
Polymorphism
Polymorphism, Single Nucleotide - genetics
Posttraumatic epilepsy
Proportional Hazards Models
SLC1A1
SLC1A6
Statistics, Nonparametric
Traumatic brain injury
Young Adult
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Summary:Summary Objective Posttraumatic seizures (PTS) commonly occur following severe traumatic brain injury (sTBI). Risk factors for PTS have been identified, but variability in who develops PTS remains. Excitotoxicity may influence epileptogenesis following sTBI. Glutamate transporters manage glutamate levels and excitatory neurotransmission, and they have been associated with both epilepsy and TBI. Therefore, we aimed to determine if genetic variation in neuronal glutamate transporter genes is associated with accelerated epileptogenesis and increased PTS risk after sTBI. Methods Individuals (N = 253) 18–75 years of age with sTBI were assessed for genetic relationships with PTS. Single nucleotide polymorphisms (SNPs) within SLC1A1 and SLC1A6 were assayed. Kaplan‐Meier estimates and log‐rank statistics were used to compare seizure rates from injury to 3 years postinjury for SNPs by genotype. Hazard ratios (HRs) were estimated using Cox proportional hazards regression for SNPs significant in Kaplan‐Meier analyses adjusting for known PTS risk factors. Results Thirty‐two tagging SNPs were examined (SLC1A1: n = 28, SLC1A6: n = 4). Forty‐nine subjects (19.37%) had PTS. Of these, 18 (36.7%) seized within 7 days, and 31 (63.3%) seized between 8 days and 3 years post‐TBI. With correction for multiple comparisons, genotypes at SNP rs10974620 (SLC1A1) were significantly associated with time to first seizure across the full 3‐year follow‐up (seizure rates: 77.1% minor allele homozygotes, 24.8% heterozygotes, 16.6% major allele homozygotes; p = 0.001). When seizure follow‐up began day 2 postinjury, genotypes at SNP rs7858819 (SLC1A1) were significantly associated with PTS risk (seizure rates: 52.7% minor allele homozygotes, 11.8% heterozygotes, 21.1% major allele homozygotes; p = 0.002). After adjusting for covariates, we found that rs10974620 remained significant (p = 0.017, minor allele versus major allele homozygotes HR 3.4, 95% confidence interval [CI] 1.3–9.3). rs7858819 also remained significant in adjusted models (p = 0.023, minor allele versus major allele homozygotes HR 3.4, 95%CI 1.1–10.5). Significance Variations within SLC1A1 are associated with risk of epileptogenesis following sTBI. Future studies need to confirm findings, but variation within neuronal glutamate transporter genes may represent a possible pharmaceutical target for PTS prevention and treatment.
ISSN:0013-9580
1528-1167
DOI:10.1111/epi.13397