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 shows subjects with both risk genotypes have 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 anticonvulsant in Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript preventing and treating PTS, and developing and testing targeted adenosinergic therapies aimed at reducing PTS. KeywordsA1AR; adenosine; ADORA1; brain injury; genetic susceptibility; post-traumatic seizure 1.INTRODUCTION5.3 million American civilians have disabilities after traumatic brain injury (TBI), and the national cost is estimated at $48.3 billion per year (Thurman et al., 1999). Post-traumatic seizures (PTS) are a significant complication after TBI. PTS accounts for 20% of symptomatic seizures and 5% of all seizures in the general population (Englander et al., 2003a). Up to 86% of patients with one late seizure after TBI will have a second within 2 years (Haltiner et al., 1997). Despite recommendations supporting limited treatment for seizure prophylaxis (Temkin, 2002), people with TBI often receive PTS prophylaxis on a long term basis with anticonvulsant medications that require regular monitoring and are associated with unwanted side effects, including sedation. Patients who go on to develop PTS also experience similar issues with long term treatment (Dikmen et al., 1991;Smith Jr. et al., 1994). Importantly, the impact of these dr...

Epileptogenesis after traumatic brain injury in Plau-deficient mice

“…Consistent with this notion, mice with a CD1 background develop epileptogenesis after controlled cortical impact (CCI)-induced TBI more frequently than mice with a B6 background [5,6]. Studies in humans demonstrate that single nucleotide polymorphisms in genes encoding apolipoprotein E4, glutamic acid decarboxylase 1, A1 adenosine receptor, interleukin-1β, and methylenetetrahydrofolate reductase are associated with the development of posttraumatic epilepsy [7][8][9][10][11]. More candidate genes that increase the likelihood for developing posttraumatic epilepsy remain to be discovered.…”

Adenosine A1Receptors Selectively Modulate Oxygen-Induced Retinopathy at the Hyperoxic and Hypoxic Phases by Distinct Cellular Mechanisms

“…From the translational perspective, it would be interesting to study the genetic association between the single nucleotide polymorphism of the human genes encoding the A 1 receptor (AdoraA1) and ROP, as revealed in other pathologic conditions such as apnea of prematurity, 63 ischemic cardiomyopathy, 64 and development of posttraumatic seizures. 65 Lastly, the demonstration of the distinct and coordinated control of OIR by retinal A 1 Rs and A 2A Rs also provides biological basis for the clinical finding that the use of caffeine (the nonselective A 1 R and A 2A R antagonist) in treatment of apnea in premature infants is associated with reduced ROP in a 2-year follow-up study.…”

Epileptogenesis

“…Cite this article as Cold Spring Harb Perspect Med 2015;5:a022822 genetic and environmental influences in a given individual Wagner et al 2010;Darrah et al 2013;Ndode-Ekane and Pitkänen 2013;Diamond et al 2014;Henshall et al 2014;Kobow and Blümcke 2014). All of these aspects pose challenges for the analysis or prediction of epileptogenesis in human populations.…”