Lack of Association between the C3435T Polymorphism in the Human Multidrug Resistance (MDR1) Gene and Response to Antiepileptic Drug Treatment

Abstract

Summary:Purpose: P-glycoprotein (P-gp) has been implicated in the causation of refractory epilepsy. The expression and efflux efficiency of P-gp is influenced by a polymorphism (C3435T) in the encoding gene (MDR1). Recent evidence suggests that the homozygous C-variant, which is associated with higher expression and increased activity of P-gp, is more common in patients with pharmacoresistant epilepsy. We have investigated the prevalence of this polymorphism in a series of patients attending a specialist epilepsy clinic.Methods: DNA samples were obtained from 400 patients, irrespective of seizure type or drug treatment. Genotype of the C3435T polymorphism was determined by traditional polymerase chain reaction (PCR) followed by restriction digest. Classification of response to treatment was determined in a blinded fashion by an independent physician. Results were expressed as genotype and allele frequencies per response group and compared by logistic regression analysis. Results:In total, 170 patients were classified as responders, with ≥12 months seizure freedom on current treatment. The remaining 230 patients were classified as nonresponders. Comparison of responders and nonresponders revealed no significant difference in allele frequency (C vs. T; odds ratio, 1.03; 95% CI, 0.78-1.37; p = 0.83) or genotype frequency (CC vs TT; odds ratio, 1.07; 95% CI, 0.60-1.91; p = 0.81). Subanalyses of individual seizure types were similarly unremarkable.Conclusions: This study failed to corroborate a previously reported association between the C3435T polymorphism in the human MDR1 gene and pharmacoresistant epilepsy. Whether the C3435T polymorphism can act as a marker for the natural history of treated epilepsy remains to be determined.

Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

“…The 1236C>T and 2677G>T/A/C polymorphisms have also been linked to several diseases such as pharmacoresistant epilepsy and Parkinsons disease [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. Studies on these polymorphisms have yielded contradictory results, possibly due to small sample sizes and the isolated nature of the study populations.…”

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

“…Inferred haplotypes were analysed using a logistic regression model, and the CGC haplotype was found to be significantly overrepresented in group C compared to group A (P ¼ Three further studies have since confused the picture. Sills et al 84 studied a consecutive series of 400 epilepsy patients, who were genotyped for the 3435C4T SNP. Patients were defined as resistant if they had experienced seizures in the previous 12 months despite exposure to at least two appropriate regimens of anti-epileptic drugs at maximally tolerated dosages.…”

Pharmacogenetics and the concept of individualized medicine

“…For example, in the multidrug resistant gene (MDR1), certain polymorphisms may not have any effect on the drug response. 22 However, this could be due to nonsignificant statistical power. Thus, pharmacological studies on drug transporters (another target) are beneficial for predicting patients who are at risk in some cases at least.…”