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

Ritter, Anne C.; Kammerer, Candace M.; Brooks, Maria M.; Conley, Yvette P.; Wagner, Amy K.

doi:10.1111/epi.13397

Cited by 36 publications

(40 citation statements)

References 47 publications

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“…However, previous work developing prognostic models for PTS using a more recent cohort from the TBIMS‐NDB did not find race to be associated with PTS and did not investigate race as a PTS predictor in multivariable modeling . Differences in late PTS risk by race may also potentially reflect genetic differences thought to influence PTS risk . Future work might investigate racial/ethnic differences in epilepsy‐related outcomes and comorbidity burden …”

Section: Discussionmentioning

confidence: 96%

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Incidence and risk factors of posttraumatic seizures following traumatic brain injury: A Traumatic Brain Injury Model Systems Study

et al. 2016

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SUMMARYObjective: Determine incidence of posttraumatic seizure (PTS) following traumatic brain injury (TBI) among individuals with moderate-to-severe TBI requiring rehabilitation and surviving at least 5 years. Methods: Using the prospective TBI Model Systems National Database, we calculated PTS incidence during acute hospitalization, and at years 1, 2, and 5 postinjury in a continuously followed cohort enrolled from 1989 to 2000 (n = 795). Incidence rates were stratified by risk factors, and adjusted relative risk (RR) was calculated. Late PTS associations with immediate (<24 h), early (24 h-7 day), or late seizures (>7 day) versus no seizure prior to discharge from acute hospitalization was also examined. Results: PTS incidence during acute hospitalization was highest immediately (<24 h) post-TBI (8.9%). New onset PTS incidence was greatest between discharge from inpatient rehabilitation and year 1 (9.2%). Late PTS cumulative incidence from injury to year 1 was 11.9%, and reached 20.5% by year 5. Immediate/early PTS RR (2.04) was increased for those undergoing surgical evacuation procedures. Late PTS RR was significantly greater for individuals who self-identified as a race other than black/white (year 1 RR = 2.22), and for black individuals (year 5 RR = 3.02) versus white individuals. Late PTS was greater for individuals with subarachnoid hemorrhage (year 1 RR = 2.06) and individuals age 23-32 (year 5 RR = 2.43) and 33-44 (year 5 RR = 3.02). Late PTS RR years 1 and 5 was significantly higher for those undergoing surgical evacuation procedures (RR: 3.05 and 2.72, respectively).

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Section: Discussionmentioning

confidence: 96%

“…31 Differences in late PTS risk by race may also potentially reflect genetic differences thought to influence PTS risk. [34][35][36][37] Future work might investigate racial/ethnic differences in epilepsyrelated outcomes and comorbidity burden. 38 Individuals age 23-44 years had increased incident PTS risk 5 years postinjury.…”

Section: Discussionmentioning

confidence: 99%

Incidence and risk factors of posttraumatic seizures following traumatic brain injury: A Traumatic Brain Injury Model Systems Study

et al. 2016

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“…Given our limited sample size, we used a candidate gene approach and did not evaluate the impact of genetic variability on other related proteins in the pathway, such as the Sur1 regulated channel Trpm4. Moreover, although we are limited in terms of sample size due to the incidence of severe TBI, this is one of the largest polymorphism studies reported in this disease[1,14,21,25,40]. We eagerly anticipate validation in future cohorts facilitated by emerging multi-center studies such as Transforming Research and Clinical Knowledge in TBI (TRACK-TBI).…”

Section: Discussionmentioning

confidence: 99%

ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI

et al. 2016

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Objective Cerebral Edema (CE) in TBI is the consequence of multiple underlying mechanisms, and is associated with unfavorable outcomes. Genetic variability in these pathways likely explains some of the clinical heterogeneity observed in edema development. A role for Sulfonylurea-receptor-1 (Sur1) in CE is supported. However, there are no prior studies examining the effect of genetic variability in the Sur1 gene (ABCC8) on the development of CE. We hypothesize that ABCC8 single nucleotide polymorphisms (SNP) are predictive of CE. Methods DNA was extracted from 385 patients. SNPs in ABCC8 were genotyped using the Human Core Exome v1.2 (Illumina). CE measurements included acute CT edema, mean and peak intracranial pressure (ICP), and need for decompressive craniotomy. Results 14 SNPs with minor-allele frequency>0.2 were identified. 4 SNPS rs2283261, rs3819521, rs2283258 and rs1799857 were associated with CE measures. In multiple regression models, homozygote-variant genotypes in rs2283261, rs3819521, and rs2283258 had increased odds of CT edema (OR=2.45, p=0.007; OR=2.95, p=0.025; OR=3.00, p=0.013), had higher mean (β=3.13,p=0.000; β=2.95,p=0.005; β=3.20,p=0.008) and peak (β=8.00,p=0.001; β=7.64,p=0.007; β=6.89,p=0.034) ICP. The homozygote wild-type genotype of rs1799857 had decreased odds of decompressive craniotomy (OR=0.47, p=0.004). Conclusions This is the first report assessing the impact of ABCC8 genetic variability on CE development in TBI. Minor allele ABCC8 SNP genotypes had increased risk of CE, while major SNP alleles were protective—potentially suggesting an evolutionary advantage. These findings could guide risk stratification, treatment responders, and the development of novel targeted or gene-based therapies against CE in TBI and other neurological disorders.

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“…Some of these genes are of particular interest given the roles of inflammatory factors and growth factors in epileptogenesis . Other reports have implicated glutamic acid decarboxylase, glutamate transport genes, and the adenosine A1 receptor . Only 2 studies have reported genetic associations with poststroke epilepsy (PSE); 1 identified a polymorphism in a TNF receptor, CD4, and the other in mitochondrial aldehyde dehydrogenase 2 .…”

Section: Genetic Aspects In Patientsmentioning

confidence: 99%

Commonalities in epileptogenic processes from different acute brain insults: Do they translate?

et al. 2017

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Summary The most common forms of acquired epilepsies arise following acute brain insults such as traumatic brain injury, stroke, or central nervous system infections. Treatment is effective for only 60%‐70% of patients and remains symptomatic despite decades of effort to develop epilepsy prevention therapies. Recent preclinical efforts are focused on likely primary drivers of epileptogenesis, namely inflammation, neuron loss, plasticity, and circuit reorganization. This review suggests a path to identify neuronal and molecular targets for clinical testing of specific hypotheses about epileptogenesis and its prevention or modification. Acquired human epilepsies with different etiologies share some features with animal models. We identify these commonalities and discuss their relevance to the development of successful epilepsy prevention or disease modification strategies. Risk factors for developing epilepsy that appear common to multiple acute injury etiologies include intracranial bleeding, disruption of the blood‐brain barrier, more severe injury, and early seizures within 1 week of injury. In diverse human epilepsies and animal models, seizures appear to propagate within a limbic or thalamocortical/corticocortical network. Common histopathologic features of epilepsy of diverse and mostly focal origin are microglial activation and astrogliosis, heterotopic neurons in the white matter, loss of neurons, and the presence of inflammatory cellular infiltrates. Astrocytes exhibit smaller K+ conductances and lose gap junction coupling in many animal models as well as in sclerotic hippocampi from temporal lobe epilepsy patients. There is increasing evidence that epilepsy can be prevented or aborted in preclinical animal models of acquired epilepsy by interfering with processes that appear common to multiple acute injury etiologies, for example, in post–status epilepticus models of focal epilepsy by transient treatment with a trkB/PLCγ1 inhibitor, isoflurane, or HMGB1 antibodies and by topical administration of adenosine, in the cortical fluid percussion injury model by focal cooling, and in the albumin posttraumatic epilepsy model by losartan. Preclinical studies further highlight the roles of mTOR1 pathways, JAK‐STAT3, IL‐1R/TLR4 signaling, and other inflammatory pathways in the genesis or modulation of epilepsy after brain injury. The wealth of commonalities, diversity of molecular targets identified preclinically, and likely multidimensional nature of epileptogenesis argue for a combinatorial strategy in prevention therapy. Going forward, the identification of impending epilepsy biomarkers to allow better patient selection, together with better alignment with multisite preclinical trials in animal models, should guide the clinical testing of new hypotheses for epileptogenesis and its prevention.

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

Cited by 36 publications

References 47 publications

Incidence and risk factors of posttraumatic seizures following traumatic brain injury: A Traumatic Brain Injury Model Systems Study

Incidence and risk factors of posttraumatic seizures following traumatic brain injury: A Traumatic Brain Injury Model Systems Study

ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI

Commonalities in epileptogenic processes from different acute brain insults: Do they translate?

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