The genetic variant “C588T” of GABARG2 is linked to childhood idiopathic generalized epilepsy and resistance to antiepileptic drugs

Ella, Soheir S. Abou El; Tawfik, Maha A; Fotoh, Wafaa Moustafa M. Abo El; Soliman, Omar Ahmed M.

doi:10.1016/j.seizure.2018.06.004

“…However, different results about association between GABRG2 rs211037 and ASM response were obtained among previous studies, likely because of differences in ethnicities of study participants, types of epilepsy, ASM for treatment, and sample size. 20 , 22 …”

Section: Discussionmentioning

confidence: 99%

“… 36 The association of decreased drug efficacy with GABRG2 rs211037 polymorphism in our study may be explained due to overstimulated glutamate excitation, resistant genes triggered, and changed configuration and functional properties of GABA A receptors. 20 …”

Section: Discussionmentioning

confidence: 99%

Genetic Polymorphism of GABRG2 rs211037 is Associated with Drug Response and Adverse Drug Reactions to Valproic Acid in Chinese Southern Children with Epilepsy

Lu¹,

Xia

²

,

Li

³

et al. 2021

PGPM

2

0

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Background Valproic acid (VPA) is recommended as a first-line treatment for children with epilepsy. GABRG2 polymorphism is found to be associated with epilepsy susceptibility and therapeutic response of anti-seizure medications (ASM); however, the role of GABRG2 in VPA treatment still remains unknown. Objective The purpose of this study was to explore the association of GABRG2 gene polymorphism with the drug response and adverse drug reactions (ADRs) related to VPA. Methods A retrospective study including 96 Chinese children with epilepsy treated by VPA was carried out. The ADRs were collected during VPA therapy and GABRG2 rs211037 in enrolled patients was genotyped using Sequenom MassArray system. A network pharmacological analysis involved protein–protein interaction and enrichment analysis was constructed to investigate the potential targets and pathways of GABRG2 on VPA-related ADRs. Results Among 96 patients, 41 individuals were defined as seizure together with 49 patients with seizure-free and 6 patients unclassified. Carriers of homozygote GABRG2 rs211037 CC genotype exhibited seizure-free to VPA ( P = 0.042), whereas those with CT genotype showed seizure. Furthermore, CC genotype had predisposition to digestive ADRs ( P = 0.037) but was a protective factor for VPA-associated weight gain ( P = 0.013). Ten key genes related to digestive ADRs and weight gain induced by VPA were identified by network pharmacological analysis and mainly involved in “GABAergic synaptic signaling”, “GABA receptor signaling”, and “taste transduction” pathways/processes through enrichment analysis. Conclusion This study revealed that GABRG2 variation exerted a predictable role in the efficacy and safety of VPA treatment for Chinese children with epilepsy.

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“…This is particularly important for potential future application of c-tDCS, known to historically induce inhibition, on excitotoxic populations such as Epilepsy and those prone to seizures. Drug-resistance is considered common in Epileptic populations (Abou El Ella et al, 2018;Assenza et al, 2017;Hung et al, 2013;Naimo et al, 2019;Tecchio et al, 2018). Links between drug-resistance and particular gene variants (Baghel et al, 2016;Hung et al, 2013) offer insight into the role gene variants play in the activity of inhibitory cortical pathways.…”

Section: Genetic Analysismentioning

confidence: 99%

Genetic Polymorphisms Do Not Predict Interindividual Variability to Cathodal Transcranial Direct Current Stimulation of the Primary Motor Cortex

Pellegrini

¹

,

Zoghi

²

,

Jaberzadeh

³

2021

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High variability between individuals (i.e. inter-individual variability) in response to transcranial direct current stimulation (tDCS) has become a commonly reported issue in the tDCS literature in recent years. Inherent genetic differences between individuals has been proposed as a contributing factor to observed response variability. This study investigated whether tDCS inter-individual variability was genetically mediated. A large sample-size of sixty-one healthy males received cathodal-tDCS (c-tDCS) and sham-tDCS, of the primary motor cortex at 1mA and 10-minutes via 6x4cm active and 7x5cm return electrodes. Corticospinal excitability (CSE) was assessed via twenty-five single-pulse transcranial magnetic stimulation motor evoked potentials (MEP). Intracortical inhibition (ICI) was assessed via twenty-five 3ms inter-stimulus interval (ISI) pairedpulse MEPs, known as short-interval intracortical inhibition (SICI). Intracortical facilitation (ICF) was assessed via twenty-five 10ms ISI paired-pulse MEPs. Gene variants encoding for excitatory and inhibitory neuroreceptors were determined via saliva samples. Pre-determined thresholds and statistical cluster analyses were used to subgroup individuals. Two distinct subgroups were identified, 'responders' reducing CSE following c-tDCS and 'non-responders' showing no reduction or even increase in CSE. Differences in CSE between responders and non-responders following c-tDCS were not explained by changes in SICI or ICF. No significant relationships were reported between gene variants and inter-individual variability to c-tDCS suggesting the chosen gene variants did not influence the activity of the neuroreceptors involved in eliciting changes in CSE in responders following c-tDCS. In this largest c-tDCS study of its kind, novel insights were reported into the contribution genetic factors may play in observed inter-individual variability to c-tDCS.

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“…This is particularly important for potential future application of c-tDCS, known to historically induce inhibition, on excitotoxic populations such as Epilepsy and those prone to seizures. Drug-resistance is considered common in Epileptic populations (Abou El Ella et al, 2018;Assenza et al, 2017;Hung et al, 2013;Naimo et al, 2019;Tecchio et al, 2018). Links between drug-resistance and particular gene variants (Baghel et al, 2016;Hung et al, 2013) offer insight into the role gene variants play in the activity of inhibitory cortical pathways.…”

Section: Genetic Analysismentioning

confidence: 99%

Genetic polymorphisms do not predict inter-individual variability to cathodal transcranial direct current stimulation of the primary motor cortex

Pellegrini

¹

,

Zoghi

²

,

Jaberzadeh

³

2020

Preprint

0

View full text Add to dashboard Cite

High variability between individuals (i.e. inter-individual variability) in response to transcranial direct current stimulation (tDCS) has become a commonly reported issue in the tDCS literature in recent years. Inherent genetic differences between individuals has been proposed as a contributing factor to observed response variability. This study investigated whether tDCS inter-individual variability was genetically mediated. A large sample-size of sixty-one healthy males received cathodal-tDCS (c-tDCS) and sham-tDCS, of the primary motor cortex at 1mA and 10-minutes via 6x4cm active and 7x5cm return electrodes. Corticospinal excitability (CSE) was assessed via twenty-five single-pulse transcranial magnetic stimulation motor evoked potentials (MEP).Intracortical inhibition (ICI) was assessed via twenty-five 3ms inter-stimulus interval (ISI) pairedpulse MEPs, known as short-interval intracortical inhibition (SICI). Intracortical facilitation (ICF) was assessed via twenty-five 10ms ISI paired-pulse MEPs. Gene variants encoding for excitatory and inhibitory neuroreceptors were determined via saliva samples. Pre-determined thresholds and statistical cluster analyses were used to subgroup individuals. Two distinct subgroups were identified, 'responders' reducing CSE following c-tDCS and 'non-responders' showing no reduction or even increase in CSE. Differences in CSE between responders and non-responders following c-tDCS were not explained by changes in SICI or ICF. No significant relationships were reported between gene variants and inter-individual variability to c-tDCS suggesting the chosen gene variants did not influence the activity of the neuroreceptors involved in eliciting changes in CSE in responders following c-tDCS. In this largest c-tDCS study of its kind, novel insights were reported into the contribution genetic factors may play in observed inter-individual variability to c-tDCS. Key WordsCorticospinal excitability, Gamma-aminobutyric acid, Inter-individual variability, N-methyl-daspartic acid, Single nucleotide polymorphism This study therefore aimed to be the first of its kind to investigate the relationship between NMDA and GABA receptor gene variants and inter-individual variability to c-tDCS. In a large sample-size, this study also aimed to investigate the predictive value of the selected gene variants for response to c-tDCS. The significance of this study will be its novelty in investigating c-tDCS, and its largescale nature which will facilitate meaningful subgroup statistical analysis, thus increasing the power and impact of the research findings. This may provide insight into future studies investigating the application of c-tDCS whereby reductions in cortical excitability and CSE is desired such as in excitotoxic neurological populations such as Epilepsy and those prone to seizures.We hypothesised there would be an association and predictive capacity between the selected gene variants and c-tDCS response. We hypothesised normal expression of genes encoding for GABA receptors would be associated...

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The genetic variant “C588T” of GABARG2 is linked to childhood idiopathic generalized epilepsy and resistance to antiepileptic drugs

Abstract: The C588 T polymorphism of GABARG2 is associated with an increased risk of developing childhood IGE and may modulate patients' response to antiepileptic drugs.

Cited by 25 publications

References 31 publications

Genetic Polymorphism of GABRG2 rs211037 is Associated with Drug Response and Adverse Drug Reactions to Valproic Acid in Chinese Southern Children with Epilepsy

Genetic Polymorphism of GABRG2 rs211037 is Associated with Drug Response and Adverse Drug Reactions to Valproic Acid in Chinese Southern Children with Epilepsy

Genetic Polymorphisms Do Not Predict Interindividual Variability to Cathodal Transcranial Direct Current Stimulation of the Primary Motor Cortex

Genetic polymorphisms do not predict inter-individual variability to cathodal transcranial direct current stimulation of the primary motor cortex

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The genetic variant “C588T” of GABARG2 is linked to childhood idiopathic generalized epilepsy and resistance to antiepileptic drugs

Abstract: The C588 T polymorphism of GABARG2 is associated with an increased risk of developing childhood IGE and may modulate patients' response to antiepileptic drugs.

Cited by 25 publications

References 31 publications

Genetic Polymorphism of GABRG2 rs211037 is Associated with Drug Response and Adverse Drug Reactions to Valproic Acid in Chinese Southern Children with Epilepsy

Genetic Polymorphism of GABRG2 rs211037 is Associated with Drug Response and Adverse Drug Reactions to Valproic Acid in Chinese Southern Children with Epilepsy

Genetic Polymorphisms Do Not Predict Interindividual Variability to Cathodal Transcranial Direct Current Stimulation of the Primary Motor Cortex

Genetic polymorphisms do not predict inter-individual variability to cathodal transcranial direct current stimulation of the primary motor cortex

Contact Info

Product

Resources

About

Abstract: The C588 T polymorphism of GABARG2 is associated with an increased risk of developing childhood IGE and may modulate patients' response to antiepileptic drugs.