Association study of ADORA2A gene polymorphisms with adverse drug reactions to valproic acid and oxcarbazepine in the treatment of children with epilepsy

Adenosine, a purine nucleotide, is implicated in various brain disorders. Our previous study identified a correlation between ADORA2A variants and epilepsy susceptibility. However, it remains unclear whether ADORA2A genetic polymorphisms affect the outcomes of antiseizure medication (ASM) therapy. This study aimed to investigate the association between ADORA2A gene polymorphisms and the efficacy and adverse drug reactions (ADRs) of ASM. In this study, 278 children with epilepsy treated with ASM were retrospectively recruited. Among them, 208 children received valproic acid (VPA), 113 received oxcarbazepine (OXC), and 43 received a combination of VPA and OXC. The ADORA2A rs2298383 polymorphism was genotyped using the Sequenom MassArray system. Additionally, putative targets and pathways associated with ADORA2A in ADRs induced by ASM were identified through protein-protein interaction, Kyoto Encyclopedia of Genes and Genomes, and Gene Ontology functional enrichment analysis. The ADORA2A rs2298383 polymorphism was not significantly associated with drug responsiveness in children with epilepsy. However, the rs2298383 TT genotype was potentially protective against VPA-induced weight gain (p = .006) but may have increased the likelihood of OXC-induced cutaneous ADRs (p = .030). Furthermore, bioinformatic analysis revealed that nine target genes associated with VPA-induced weight gain were primarily involved in the "positive regulation of mitogen-activated protein kinase cascade," "calcium signaling pathway," and "cyclic adenosine monophosphate signaling pathway" pathways/processes. This study demonstrates that ADORA2A gene polymorphisms can assist in predicting the impact of ASM on outcomes in children with epilepsy.