Association of genetic variants in UGT1A6 genes and non-genetic variant with valproic acid doses and plasma concentration in Thai epileptic patients

Abstract

The aim of this study was to investigate the association of genetic variants in UGT1A6 19T>G, 541A>G and 552A>C together with non-genetic variant with VPA dose and plasma concentrations in Thai epileptic patients. Eighty four Thai epileptic patients who were treated with VPA maintenance dose at Phramongkutklao Hospital were enrolled to this study. Three candidates single nucleotide polymorphisms (SNPs), including UGT1A6 19T>G, 541A>G and 552A>C were genotyped by using Taqman SNP genotyping assay. Non-genetic factor, co-medication, was divided into three categories including drug inducer, drug inhibitor and drug with no effect. Nonparametric methods (Mann-Whitney U and Kruskal-Wallis test) were used to identify the association of genetic and nongenetic variants, drug interaction, with VPA maintenance dose and steady state trough plasma concentration. The three candidate SNPs of 84 patients were genotyped. All of the genotypic distributions were consistent with Hardy-Weinberg equilibrium. For co-medication, only drug inducer and drug with no effect which were 37 and 47 respectively were found. Results of this study demonstrated that UGT1A6 541A>G and 552A>C variants were associated with lower VPA dose (p-value = 0.037, 0.031, respectively). Whereas, non-genetic factor, drug inducer tended to be associated with higher VPA dose. In line with this, drug inducer was found to be associated with lower VPA plasma concentration (p-value = 0.002) while UGT1A6 polymorphisms were shown a tendency of association with higher VPA plasma level. The present study demonstrated that genetic variants in UGT1A6 influenced variability in VPA dose while drug interaction had an impact on VPA plasma concentration in Thai epileptic patients. These finding suggested that genetic variants in ge ne encoding drug metabolizing enzyme and non-genetic factor, drug inducer, could explain in part the inter-individual variability in VPA maintenance dose and blood levels.