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

Abstract

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.

Keywords: Epileptogenesis; Posttraumatic epilepsy; SLC1A1; SLC1A6; Traumatic brain injury.

Figure 1

Haploview generated gene map displaying linkage disequilibrium (D’) for SNPs located on SLC1A1 (panel A) and SLC1A6 (panel C). Deeper red colors are indicative of greater D’ values. Panel B shows a magnified view of SNPs on SLC1A1 shown to be associated with time to first seizure in the current analyses (19=rs10974620, 20=rs10815020, 21=rs7858819, 24=rs301430).

Figure 2

Kaplan Meier estimates for time to first seizure by SLC1A1 SNP rs10974620 genotypes for full follow-up (Time of Injury to Three Years).

Figure 3

Kaplan Meier estimates for time to first Seizure by SLC1A1 SNP rs7858819 genotypes for follow-up beginning day 2 post-injury to three years (individuals seizing or expiring before day 2 excluded).