Abstracts

Rationale: Mesial temporal lobe epilepsy (MTLE) is associated with a significant proportion of patients who do not respond to treatment with antiepileptic drugs (AEDs). One hypothesis to explain individual differences in drug response is the presence of allelic variations in candidate genes which could be responsible for degreased efficacy of antiepileptic drugs. The purpose of this study was to investigate whether single nucleotide polymorphisms (SNPs) on drug-transporter and drug-metabolism genes could be associated with pharmacoresistance in a large group of patients with MTLE. Methods: : We genotyped 44 dbSNPs within 4 different drug-transporter genes (RALBP1, ABCB1, ABCC2, ABCC4) and 95 dbSNPs within 9 drug-metabolism genes (CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5). We ascertained 164 drug-resistant and 78 drug-responsive patients, who were seizure free on AEDs. The significance of allelic and genotypic association was assessed using logistic regression (logistf function in R environment). P-values were corrected by Bonferroni. As a genomic control we genotyped an additional 119 SNPs. Fst and AMOVA (Arlequin v.3.11) were performed in order to analyze the genetic structure of both groups. In addition, we quantified the expression of ABCC2 transcripts (using Real-Time PCR, ABI7500, TaqMan system ) in hippocampal tissue collected during epilepsy surgery in 11 patients with refractory MTLE. Results: We found a significant association for allele rs3740066C (Ile1324Ile) in the ABCC2 gene, which was more frequent in the pharmacoresistant group (p=0.04). In addition, we found that expression of ABCC2 was higher in patients with refractory MTLE when compared to autopsy controls (ANOVA, p=0.0170). In addition, we found significant associations with 4 intronic SNPs in 3 drug metabolism genes: CYP1B1: rs2551188TT (p=0.02); CYP2C9: rs4086116CT (p=0.005) and rs2153628AA (p=0.02), and CYP1A2: rs12904742GG (p=0.005). We calculated that the overall contribution of the 4 associated genes to phenotype of pharmacoresistance was around 10%. Conclusions: We found evidence that multiple genetic factors are involved in determining pharmacoresistance in patients with MTLE, thus confirming the polygenic nature of the trait.