Influence of UGT2B7 and UGT1A6 polymorphisms on plasma concentration to dose ratio of valproic acid in Chinese epileptic children

Abstract

1. We explored the potential effects of genetic variations on the concentration to dose ratio (CDR) of valproic acid (VPA) in paediatric epilepsy patients.

2. Two hundred and twenty-nine epileptic children on VPA monotherapy were included, and the VPA trough concentrations at steady-state of all subjects were determined.

3. Nineteen single nucleotide polymorphisms (SNPs) of seven selected genes related to the metabolising enzymes and transporters of VPA were identified, and their influences on CDR_VPA (a logarithmic transformation was performed if abnormally distributed) were evaluated.

4. UGT2B7 rs7668258 (C>T) TT genotype was associated with a decrease in lnCDR_VPA among epileptic children receiving VPA monotherapy (β=–0.191, p = 0.036). Significantly lower lnCDR_VPA was also observed in paediatric patients with UGT1A6 rs2070959 (A>G) GG genotype compared to those AA genotype (β=–0.270, p = 0.021).

5. This research indicated that UGT2B7 rs7668258 (C>T) and UGT1A6 rs2070959 (A>G) polymorphisms may be correlated to the normalised plasma concentrations of VPA in Chinese epileptic children. The associations could be abolished after Bonferroni's correction and our findings need to be validated in further and larger investigations.

Keywords:

• Valproic acid
• epilepsy
• children
• concentration to dose ratio
• pharmacogenetics

Ethics approval

This study was conducted in accordance with the Declaration of Helsinki and its later amendments or comparable ethical standards and was approved by the Ethics Committee of Wuhan Children’s Hospital of Huazhong University of Science & Technology in China (serial number: 2015015).

Consent to participate

Written informed consents were obtained from the direct relatives of the paediatric patients.

Consent for publication

The parents signed informed consent regarding publishing the children’s data.

Disclosure statement

The authors declare that they have no conflict of interest.

Additional information

Funding

This work was supported by Wuhan Municipal Health Commission Scientific Research Project [WX16B18] and Construction Project of Clinical Medical Research Center for Neurodevelopmental Disabilities in Children in Hubei Province [HST2020-19].