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. 2021 Sep 15:14:1141-1150.
doi: 10.2147/PGPM.S329594. eCollection 2021.

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

Jieluan Lu  1 , Hanbing Xia  2 , Wenzhou Li  2 , Xianhuan Shen  1 , Huijuan Guo  2 , Jianping Zhang  1 , Xiaomei Fan  2
Affiliations

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

Jieluan Lu et al. Pharmgenomics Pers Med. .

Abstract

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.

Keywords: GABRG2; adverse drug reactions; children with epilepsy; gene polymorphism; therapeutic response; valproic acid.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Protein–protein interaction (PPI) network analysis. (A) PPI network analysis of GABRG2 consisted of 20 nodes and 146 edges. (B) The PPI network for ten common target genes of GABRG2 in VPA-induced ADRs. Each target gene is represented by nodes and the association between two nodes is represented by lines.
Figure 2
Figure 2
GO enrichment analysis and KEGG pathway analysis of 10 common genes. (A) GO analysis for ten target genes of GABRG2 and VPA-induced ADRs. Polka dots, triangles, and squares refer to biological process (BP), cellular components (CC), and molecular function (MF), respectively. (B) The KEGG pathway analysis of VPA-induced ADRs. Gene ratio represents the ratio of enriched genes to all target genes, and counts refer to the number of the enriched genes.
See this image and copyright information in PMC

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