Glutamate Receptor, Ionotropic N-methyl-D-aspartate 2B Polymorphisms and Concussive Recovery in Athletes

Abstract

Athletes vary in their ability to recover from concussions. Following a concussion, a pathophysiological cascade of events transpires, rendering symptoms. One such event, the indiscriminate release of the excitatory neurotransmitter glutamate, may result in hyperactivation of glutamate receptors (e.g., N-methyl-D-aspartate receptors [NMDARs]) and self-propagate a state of neurotoxicity that may be enhanced via the concomitant release of Ca2+, particularly through NMDARs containing the NR2B subunit. Genetic variation in regulatory regions of the glutamate receptor, ionotropic N-methyl-D-aspartate 2B (GRIN2B) gene, which codes for the NR2B subunit, may play a role in varied recovery among concussed athletes. Indeed, the rs1019385 promoter single nucleotide polymorphism (SNP) has been shown to alter transcription in dominant versus recessive allele carriers such that expression of the T allele results in increased upregulation of the GRIN2B gene. Therefore, the primary purpose of this study was to determine the association of this GRIN2B SNP and concussive recovery; a second GRIN2B SNP (rs890), in the 3'untranslated region, was also explored. A secondary purpose was to examine SNP associations with initial evaluation concussion severity scores. A triple-blind, between-subjects, genetic association design was utilized. The independent variable was genotype for both GRIN2B SNPs (rs1019385, rs890). The primary dependent variable, concussive recovery, was defined as the number of days from the time of injury until full return-to-play (RTP) clearance was granted by a university concussion center's physician; recovery was categorized as either normal (≤ 20 days) or prolonged (> 20 days). The secondary dependent variables were initial evaluation concussion severity scores and consisted of: (a) vestibulo-ocular reflex (VOR) result, (b) Balance Error Scoring System (BESS) sum, and (c) Immediate Postconcussion Assessment and Cognitive Testing (ImPACT) composite scores. Fifty-three, mostly White (69.7%), male (75.0%) concussed athletes (18.96 ± 6.31 years of age) participated in the study; two participants were excluded due to inconclusive genetic results. Participants were evaluated at a university concussion center per standardized concussion assessment battery, using the aforementioned severity indicators, and provided saliva samples for genotyping experiments. Follow-up visits were performed, as needed, until participants were asymptomatic and cleared for full RTP. No significant associations were demonstrated for the codominant (p = .35, p = .70), dominant (p = .39, p = 1.00) or recessive (p = .72, p = .51) genetic models for the rs1019385 and rs890 SNPs (respectively). Similarly, there were no significant differences in any initial evaluation severity scores between genotype for any genetic model. This exploratory study investigated the association between two GRIN2B SNPs and varied concussive recovery among athletes. Although no statistical and minimal clinical significance was demonstrated, future investigations should incorporate a larger sample and next-generation sequencing to investigate the 21,000 to 25,000 genes and their variations across the human genome as complex disorders (e.g., concussions) likely involve a multitude of genetic variations (and their interactions), many with small effects. Further elucidation of genetic factors involved in concussive recovery could equip clinicians with superior counseling methods and treatment options for athletes at-risk for prolonged recovery.