Genetic variation in the adenosine regulatory cycle is associated with posttraumatic epilepsy development

Abstract

1 week post-TBI. SNPs remaining significant after correction for multiple comparisons were examined using Cox proportional hazards analyses, adjusting for subdural hematoma, injury severity score, and isolated TBI status. SNPs significant in multivariate models were then entered simultaneously into an adjusted Cox model. Results Comparing Kaplan-Meier curves, rs11001109 (ADK) rare allele homozygosity and rs9444348 (NT5E) heterozygosity were significantly associated with shorter time to first seizure and an increased seizure rate 3 years post-TBI. Multivariate Cox proportional hazard models showed that these genotypes remained significantly associated with increased PTE hazard up to 3 years post-TBI after controlling for variables of interest (rs11001109: hazard ratio (HR) 4.47, 95% confidence interval (CI) 1.27-15.77, p = 0.020; rs9444348: HR 2.95, 95% CI 1.19-7.31, p = 0.019) . Significance Genetic variation in ADK and NT5E may help explain variability in time to first seizure and PTE risk, independent of previously identified risk factors, after TBI. Once validated, identifying genetic variation in adenosine regulatory pathways relating to epileptogenesis and PTE may facilitate exploration of therapeutic targets and pharmacotherapy development.