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Impact of UGT1A6 SNPs on valproic acid pharmacokinetics: a study on dose-normalised serum concentrations in Indian patients with epilepsy

Surajj S Archana,S. Paneyala,Anju Srinivas,Sumayakausar S Kalaigar,Neha Ranjith,Shashi Rekha Basavaraju,Akila Prashant

Published 2025 in BMJ Connections Clinical Genetics and Genomics

ABSTRACT

Valproic acid (VPA) exhibits substantial interindividual variability in serum levels due to genetic and non-genetic influences. Among the major metabolic pathways, glucuronidation via UGT1A6 is genetically polymorphic, but its clinical relevance remains unclear, particularly in Indian populations. This study aimed to evaluate the effect of three common UGT1A6 single nucleotide polymorphisms (SNPs)—c.19T>G, c.541A>G and c.552A>C—on dose-normalised serum VPA concentrations and explore haplotype-based associations. A total of 71 South Indian patients with epilepsy on VPA monotherapy were included in a cross-sectional observational study. Three UGT1A6 SNPs were genotyped using PCR-based methods. The primary outcome was dose-normalised VPA serum concentration (concentration to dose ratio, CDR). CDRs were compared across genotype, haplotype and diplotype groups using analysis of variance (ANOVA), and significant findings were further evaluated using multiple linear regression adjusting for age, sex, body mass index and dose per kilogram. No significant genotype–CDR association was found in the total cohort, though a significant association for SNP c.552A>C was observed in the paediatric subgroup (p=0.035), which did not persist after multivariate adjustment. Haplotype and diplotype analyses showed significant associations with CDR by ANOVA (p=0.0101 and p=0.0178, respectively), but no haplotype remained an independent predictor in regression modelling. UGT1A6 polymorphisms and haplotypes were not independent predictors of VPA pharmacokinetics after adjusting for clinical covariates. These findings underscore the need for larger, multidimensional pharmacogenetic studies in Indian populations.

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