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Weight gain is the most frequent adverse effect of valproic acid (VPA) treatment, resulting in poor compliance and many endocrine disturbances. Similarities in the weight change of monozygotic twins receiving VPA strongly suggests that genetic factors are involved in this effect. However, few studies have been conducted to identify the relevant genetic polymorphisms. Additionally, the causal relationship between the VPA concentration and weight gain has been controversial. Thus, we investigated the effects of single nucleotide polymorphisms (SNPs) in several appetite stimulation and energy homeostasis genes and the steady state plasma concentrations (Css) of VPA on the occurrence of weight gain in patients.A total of 212 epilepsy patients receiving VPA were enrolled. Nineteen SNPs in 11 genes were detected using the Sequenom MassArray iPlex platform, and VPA Css was determined by high-performance liquid chromatography (HPLC).After 6 months of treatment, 20.28% of patients were found to gain a significant amount of weight (weight gained ≥7%). Three SNPs in the leptin receptor (LEPR), ankyrin repeat kinase domain containing 1 (ANKK1), and α catalytic subunit of adenosine monophosphate-activated protein kinase (AMPK) showed significant associations with VPA-induced weight gain (p < 0.001, p = 0.017 and p = 0.020, respectively). After Bonferroni correction for multiple tests, the genotypic association of LEPR rs1137101, the allelic association of LEPR rs1137101, and ANKK1 rs1800497 with weight gain remained significant. However, the VPA Css in patents who gained weight were not significantly different from those who did not gain weight (p = 0.121).LEPR and ANKK1 genetic polymorphisms may have value in predicting VPA-induced weight gain.

Association of LEPR and ANKK1 Gene Polymorphisms with Weight Gain in Epilepsy Patients Receiving Valproic Acid