Epilepsy, a common disorder of the brain, exhibits a high morbidity rate in children. Childhood epilepsy (CE) is frequently comorbid with neurologic and developmental disorders, sharing underlying genetic factors. This study aimed to investigate the impact of ADORA2A , BDNF , and NTRK2 gene polymorphisms on the risk of childhood epilepsy and their associations with predisposition to epileptic comorbidities. A total of 444 children were enrolled in this study, and three single nucleotide polymorphisms, including ADORA2A rs2298383, BDNF rs6265, and NTRK2 rs1778929, were genotyped. The frequency distribution of genotypes was compared not only between CE patients and healthy children but also between CE patients with and without comorbidities. The results indicated that the carriers of ADORA2A rs2298383 TT genotype tended to have a lower risk of epilepsy (OR = 0.48, 95% CI = 0.30–0.76), while the CT genotype was related to a higher risk (OR = 1.56, 95% CI = 1.06–2.27). The ADORA2A rs2298383 CC genotype predisposed CE patients to comorbid neurologic disorders (OR = 2.76, 95% CI = 1.31–5.80). Genetic variations in BDNF rs6265 and NTRK2 rs1778929 had no significant association with CE and its comorbidities. Fourteen ADORA2A target genes related to epilepsy were identified by the protein–protein interaction analysis, which were mainly involved in the biological processes of “negative regulation of neuron death” and “purine nucleoside biosynthetic process” through the gene functional enrichment analysis. Our study revealed that the genetic polymorphism of ADORA2A rs2298383 was associated with CE risk and predisposition to neurologic comorbidity in children with epilepsy, and the involved mechanism might be related to the regulation of neuron death and purine nucleoside biosynthesis.
Epilepsy is a common neurologic disorder characterized by intractable seizures, involving genetic factors. There is a need to develop reliable genetic markers to predict the risk of epilepsy and design effective therapies. Arsenite methyltransferase (AS3MT) catalyzes the biomethylation of arsenic and hence regulates arsenic metabolism. AS3MT variation has been linked to the progression of various diseases including schizophrenia and attention deficit or hyperactivity disorder. Whether genetic polymorphism of AS3MT contributes to epilepsy remains unclear. In this study, we investigated the association of AS3MT gene polymorphism with susceptibility to epilepsy in children from south China. We also explored the effect of AS3MT variation on the safety of antiepileptic drugs. Genotypic analysis for AS3MT rs7085104 was performed using samples from a Chinese cohort of 200 epileptic children and 244 healthy individuals. The results revealed a genetic association of AS3MT rs7085104 with susceptibility to pediatric epilepsy. Mutant homozygous GG genotype exhibited a lower susceptibility to childhood epilepsy than AA genotype. Carriers of AS3MT rs7085104 AA genotype exhibited a higher risk of digestive adverse drug reactions (dADRs) in children when treated with valproic acid (VPA) or oxcarbazepine (OXC). Additionally, bioinformatics analysis identified eight AS3MT target genes related to epilepsy and three AS3MT-associated genes in VPA-related dADRs. The effects of AS3MT on epilepsy might involve multiple targets including CNNM2, CACNB2, TRIM26, MTHFR, GSTM1, CYP17A1, NT5C2, and YBX3. This study reveals that AS3MT may be a new gene contributing to epileptogenesis. Hence, analysis of AS3MT polymorphisms will help to evaluate susceptibility to pediatric epilepsy and drug safety.
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