AUTHOR=Fan Xiaomei , Chen Yuna , Lu Jieluan , Li Wenzhou , Li Xi , Guo Huijuan , Chen Qing , Yang Yanxia , Xia Hanbing 

TITLE=AS3MT Polymorphism: A Risk Factor for Epilepsy Susceptibility and Adverse Drug Reactions to Valproic Acid and Oxcarbazepine Treatment in Children From South China

JOURNAL=Frontiers in Neuroscience

VOLUME=15

YEAR=2021

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.705297

DOI=10.3389/fnins.2021.705297

ISSN=1662-453X

ABSTRACT=<p>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. <italic>AS3MT</italic> variation has been linked to the progression of various diseases including schizophrenia and attention deficit or hyperactivity disorder. Whether genetic polymorphism of <italic>AS3MT</italic> contributes to epilepsy remains unclear. In this study, we investigated the association of <italic>AS3MT</italic> gene polymorphism with susceptibility to epilepsy in children from south China. We also explored the effect of <italic>AS3MT</italic> variation on the safety of antiepileptic drugs. Genotypic analysis for <italic>AS3MT</italic> rs7085104 was performed using samples from a Chinese cohort of 200 epileptic children and 244 healthy individuals. The results revealed a genetic association of <italic>AS3MT</italic> rs7085104 with susceptibility to pediatric epilepsy. Mutant homozygous GG genotype exhibited a lower susceptibility to childhood epilepsy than AA genotype. Carriers of <italic>AS3MT</italic> 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 <italic>AS3MT</italic> target genes related to epilepsy and three <italic>AS3MT</italic>-associated genes in VPA-related dADRs. The effects of AS3MT on epilepsy might involve multiple targets including <italic>CNNM2</italic>, <italic>CACNB2</italic>, <italic>TRIM26</italic>, <italic>MTHFR</italic>, <italic>GSTM1</italic>, <italic>CYP17A1</italic>, <italic>NT5C2</italic>, and <italic>YBX3</italic>. This study reveals that <italic>AS3MT</italic> may be a new gene contributing to epileptogenesis. Hence, analysis of <italic>AS3MT</italic> polymorphisms will help to evaluate susceptibility to pediatric epilepsy and drug safety.</p>