Adenosine A1 receptor gene variants associated with post-traumatic seizures after severe TBI

Abstract

Post-traumatic seizures (PTS) are a significant complication from traumatic brain injury (TBI). Adenosine, a major neuroprotective and neuroinhibitory molecule, is important in experimental epilepsy models. Thus, we investigated the adenosine A1 receptor (A1AR) gene and linked it with clinical data extracted for 206 subjects with severe TBI. Tagging SNPs rs3766553, rs903361, rs10920573, rs6701725, and rs17511192 were genotyped, and variant and haplotype associations with PTS were explored. We investigated further genotype, grouped genotype, and allelic associations with PTS for rs3766553 and rs10920573. Multivariate analysis of rs3766553 demonstrated an association between the AA genotype and increased early PTS incidence. In contrast, the GG genotype was associated with increased late and delayed-onset PTS rates. Multivariate analysis of rs10920573 revealed an association between the CT genotype and increased late PTS. Multiple risk genotype analysis showed subjects with both risk genotypes had a 46.7% chance of late PTS. To our knowledge, this is the first report implicating genetic variability in the A1AR with PTS, or any type of seizure disorder. These results provide a rationale for further studies investigating how adenosine neurotransmission impacts PTS, evaluating anticonvulsants in preventing and treating PTS, and developing and testing targeted adenosinergic therapies aimed at reducing PTS.

Figure 1

Gene map depiction of the 5 tSNPs explored in the study along with the 6 exons in the A1 gene (Information generated from the HapMap Database). The two tSNPs found to be significant are rs3766553 and rs10920573.

Figure 2

PTS frequency by genotype for rs3766553 A) associated with early post traumatic seizures within one week of initial injury (p=0.052) (Population sizes by genotype: AA=23, AG= 77, GG=31) B) associated with late post traumatic seizures beyond one week after injury, (p=0.112) (Population sizes by genotype: AA=21, AG= 71, GG=34), C) associated with delayed onset post traumatic seizures beyond six months after injury (p=0.019) (Population sizes by genotype: AA=19, AG= 65, GG=32)

Figure 3

PTS frequency by genotype for rs10920573 A) associated with early post traumatic seizures occurring in the first week post injury (p=0.212) (Population sizes by genotype: CC=64 CT=50 TT=14) B) late post traumatic seizures occurring beyond one week after injury (p=0.039) (Population sizes by genotype: CC=49 CT=59 TT=14) C) delayed onset post traumatic seizures occurring beyond six months after injury (p=0.142) (Population sizes by genotype: CC=47 CT=52 TT=13)

Figure 4

PTS frequency by number of risk genotypes A) Number of risk genotypes associated with late post traumatic seizures beyond one week after injury (p=0.007) (Population sizes by number of risk genotypes: Zero=46 One=60 Two=15) and B) Number of risk genotypes associated with delayed onset post traumatic seizures beyond six months after injury (p=0.003) (Population sizes by number of risk genotypes: Zero=43 One=55 Two=13). For both late and delayed onset PTS, the risk genotype for rs10920573 was CT and the risk genotype for rs3766553 was GG.